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Choi HJ, Yu XZ. ER stress: an emerging regulator in GVHD development. Front Immunol 2023; 14:1212215. [PMID: 37744326 PMCID: PMC10511645 DOI: 10.3389/fimmu.2023.1212215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient's cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.
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Affiliation(s)
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States
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Abstract
INTRODUCTION Transplantation of the keratinocytes, fibroblasts, bone marrow, and adipose tissue-derived mesenchymal stem cells may improve chronic wound healing by delivery of different cytokines, chemokines, and growth factors, which play an essential role in wound healing. The purposes of this review were to check which cell lines are potentially beneficial in enhancement of wound healing and to describe the safety and efficacy of cell therapies in the clinical treatment of chronic wounds, as well as to summarize the pertinent literature and research progress in this field. METHODS PubMed search engine and ClinicalTrials.gov were used to analyze the available data on cell therapies applied in treatment of chronic wound. The analysis included 51 articles, assessing the use of keratinocytes (10), fibroblasts (7), keratinocytes and fibroblasts (10), bone marrow-derived cells (20), and adipose tissue cells (4). Studies on the cell-based products that are currently available on the market (Dermagraft, EpiDex, Apligraf, and HP802-247) were also included, with majority of reports found on fibroblasts and keratinocytes studies. RESULTS Cell-based therapies have a great potential to improve wound healing without major surgical procedures and donor-site morbidity. There is, however, a lack of guidelines on how the age of the patients, the general health conditions, and the coexistence of different diseases may affect the success of these therapies. Further studies are needed to determine the fate of transplanted cells and the number of cells required to obtain optimal effects and outcomes. CONCLUSIONS Despite many promising clinical trials on application of various stem cell-based therapies for treatment of chronic wounds, there is still a need for multicenter comparative studies assessing the dose response and the cell source response on the efficacy of chronic wound healing.
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Raghuram AC, Yu RP, Lo AY, Sung CJ, Bircan M, Thompson HJ, Wong AK. Role of stem cell therapies in treating chronic wounds: A systematic review. World J Stem Cells 2020; 12:659-675. [PMID: 32843920 PMCID: PMC7415243 DOI: 10.4252/wjsc.v12.i7.659] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/03/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The impairment of cutaneous wound healing results in chronic, non-healing wounds that are caused by altered wound environment oxygenation, tissue injury, and permissive microbial growth. Current modalities for the treatment of these wounds inadequately address the complex changes involved in chronic wound pathogenesis. Consequently, stem cell therapies have emerged as a potential therapeutic modality to promote cutaneous regeneration through trophic and paracrine activity.
AIM To investigate current literature regarding use of stem cell therapies for the clinical treatment of chronic, non-healing wounds.
METHODS PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus were queried with combinations of the search terms “mesenchymal stem cells,” “adult stem cells,” “embryonic stem cells,” “erythroid precursor cells,” “stem cell therapies,” and “chronic wounds” in order to find relevant articles published between the years of 2000 and 2019 to review a 20-year experience. Reference lists from the articles were reviewed to identify additional pertinent articles. Retrieved manuscripts (reviews, case reports/series, retrospective/prospective studies, and clinical trials) were evaluated by the authors for their depiction of clinical stem cell therapy use. Data were extracted from the articles using a standardized collection tool.
RESULTS A total of 43 articles describing the use of stem cell therapies for the treatment of chronic wounds were included in this review. While stem cell therapies have been explored in in vitro and in vivo applications in the past, recent efforts are geared towards assessing their clinical role. A review of the literature revealed that adipose-derived stem cells, bone marrow-derived stem cells, bone marrow-derived mononuclear cells, epidermally-derived mesenchymal stem cells, fibroblast stem cells, keratinocyte stem cells, placental mesenchymal stem cells, and umbilical cord mesenchymal stem cells have all been employed in the treatment of chronic wounds of various etiologies. Most recently, embryonic stem cells have emerged as a novel stem cell therapy with the capacity for multifaceted germ cell layer differentiation. With the capacity for self-renewal and differentiation, stem cells can enrich existing cell populations in chronic wounds in order to overcome barriers impeding the progression of wound healing. Further, stem cell therapies can be utilized to augment cell engraftment, signaling and activity, and resultant patient outcomes.
CONCLUSION Assessing observed clinical outcomes, potential for stem cell use, and relevant therapeutic challenges allows wound care stakeholders to make informed decisions regarding optimal treatment approaches for their patients’ chronic wounds.
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Affiliation(s)
- Anjali C Raghuram
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
| | - Roy P Yu
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
| | - Andrea Y Lo
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
| | - Cynthia J Sung
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
| | - Melissa Bircan
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
| | - Holly J Thompson
- Wilson Dental Library, Herman Ostrow School of Dentistry of USC, Los Angeles, CA 90089, United States
| | - Alex K Wong
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
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Abstract
The functions of lymphocytes, in particular their participation in immune responses, depends on the expression and properties of several molecules that are present on their membranes at different steps in their development and activation. One way to probe this complex and various set of events is to follow the movement of the membrane molecules in different lymphocytes and in different functional conditions and, more specifically, to study their internalization and subsequent fate. In this article, Benvenuto Pernis summarizes the main facts concerning internalization of lymphocyte membrane components, either spontaneous or induced by cross-linking agents, and discusses what they tell us about the physiology of lymphocytes.
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Affiliation(s)
- B Pernis
- Departments of Microbiology and Medicine and Comprehensive Cancer Center, College of Physicians and Surgeons Columbia University, New York, NY 10032, USA
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Hanada H, Ohno J, Seno K, Ota N, Taniguchi K. Dynamic changes in cell-surface expression of mannose in the oral epithelium during the development of graft-versus-host disease of the oral mucosa in rats. BMC Oral Health 2014; 14:5. [PMID: 24433462 PMCID: PMC3903439 DOI: 10.1186/1472-6831-14-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 01/15/2014] [Indexed: 11/10/2022] Open
Abstract
Background The role of cell-surface glycoconjugates in oral mucosal graft-versus-host disease (GVHD) is still unclear, even though molecular changes in the oral epithelium are essential for the pathogenesis of these lesions. In this study, we investigated changes in the binding of mannose (Man)-specific Lens culinaris lectin (LCA) in the oral mucosa of rats with GVHD. Methods Lewis rat spleen cells were injected into (Lewis x Brown Norway) F1 rats to induce systemic GVHD, including oral mucosal lesions. Tongue and spleen samples were evaluated using lectin histochemistry, immunohistochemistry, Western blotting, transwell migration assays and Stamper-Woodruff binding assays. Results Binding of Man-specific LCA expanded to the epithelial layers of the tongue in GVHD-rats. An expansion of LCA binding was related to the increased expression of mannosyltransferase in the oral mucosa. CD8+ cells, effector cells of oral mucosal GVHD, expressed mannose-binding protein (MBP) and migrated to the medium containing Man in the transwell migration assay. Adherence of CD8+ cells to the oral epithelium could be inhibited by pretreating CD8+ cells with MBP antibody and/or by pretreating sections with Man-specific LCA. Conclusions Increased expression of Man on keratinocytes leads to the migration and/or adhesion of CD8+ cells in the surface epithelium, which is mediated in part by the MBP/Man-binding pathway during the development of oral mucosal GVHD.
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Affiliation(s)
| | - Jun Ohno
- Department of Morphological Biology, Division of Pathology, Fukuoka Dental College, Tamura, Fukuoka 2-15-1, Japan.
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MacDonald KP, Shlomchik WD, Reddy P. Biology of graft-versus-host responses: recent insights. Biol Blood Marrow Transplant 2013; 19:S10-4. [PMID: 23290438 DOI: 10.1016/j.bbmt.2012.11.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Tawara I, Shlomchik WD, Jones A, Zou W, Nieves E, Liu C, Toubai T, Duran-Struuck R, Sun Y, Clouthier SG, Evers R, Lowler KP, Levy RB, Reddy P. A crucial role for host APCs in the induction of donor CD4+CD25+ regulatory T cell-mediated suppression of experimental graft-versus-host disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:3866-72. [PMID: 20810991 PMCID: PMC2981818 DOI: 10.4049/jimmunol.1001625] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Allogeneic bone marrow transplantation is an effective treatment for a number of malignant and nonmalignant diseases (Applebaum. 2001. Nature. 411: 385-389 and Copelan. 2006. N Engl J Med. 354: 1813-1826). However, the application of this therapeutic modality has been impeded by a number of confounding side effects, the most frequent and severe of which is the development of graft-versus-host disease (GVHD) (Copelan. 2006. N Engl J Med. 354: 1813-1826 and Blazar and Murphy. 2005. Philos Trans R Soc Lond B Biol Sci. 360: 1747-1767). Alloreactive donor T cells are critical for causing GVHD (Fowler. 2006. Crit Rev Oncol Hematol. 57: 225-244 and Ferrara and Reddy. 2006. Semin Hematol. 43: 3-10), whereas recent data demonstrated a significant role for the naturally occurring thymic-derived donor CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) (Bluestone and Abbas. 2003. Nat Rev Immunol. 3: 253-257 and Shevach. 2006. Immunity. 25: 195-201) in suppressing experimental GVHD after bone marrow transplantation (Blazar and Taylor. 2005. Biol Blood Marrow Transpl. 11: 46-49 and Joffe and van Meerwijk. 2006. Semin Immunol. 18: 128-135) . Host APCs are required for induction of GVHD by the conventional donor T cells. However, it is not known whether they are also obligatory for donor Treg-mediated suppression of GVHD. Using multiple clinically relevant MHC-matched and -mismatched murine models of GVHD, we investigated the role of host APCs in the suppression of GVHD by donor Tregs. We found that alloantigen expression by the host APCs is necessary and sufficient for induction of GVHD protection by donor Tregs. This requirement was independent of their effect on the maintenance of Treg numbers and the production of IL-10 or IDO by the host APCs.
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Affiliation(s)
- Isao Tawara
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | | | | | - Weiping Zou
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | - Evelyn Nieves
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | - Chen Liu
- University of Florida, Gainesville, FL 32611
| | - Tomomi Toubai
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | - Raimon Duran-Struuck
- Department of Surgery, Massachusetts General Hospital, Harvard University, Boston, MA 02114
| | - Yaping Sun
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | - Shawn G. Clouthier
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | - Rebecca Evers
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | - Kathleen P. Lowler
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
| | | | - Pavan Reddy
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Yoshida H, Maeda T, Ishikawa J, Inoue S, Matsunaga H, Kosugi S, Shiraga M, Oritani K, Kanakura Y, Tomiyama Y. Expression of CD27 on Peripheral CD4 + T-Lymphocytes Correlates with the Development of Severe Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation. Int J Hematol 2006; 84:367-76. [PMID: 17118766 DOI: 10.1532/ijh97.05159] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Allogeneic immune responses during hematopoietic reconstitution play central roles in beneficial and adverse effects after allogeneic bone marrow transplantation (allo-BMT). Appropriate regulation of the immune responses might improve the outcome of allo-BMT. However, a useful marker for monitoring allogeneic immune responses remains to be established. We enrolled 22 consecutive patients who underwent myeloablative allo-BMT between March 2002 and March 2006 and examined the relationship between CD27 expression on peripheral blood T-lymphocytes, a possible marker for naive/effector phenotypes, and clinical events, especially acute graft-versus-host disease (aGVHD). In 8 patients with aGVHD of grades II to IV, the CD27+/CD27- ratios of CD4+ (but not CD8+) T-lymphocytes were significantly higher after allo-BMT, even at day 21, than the ratios in patients with aGVHD of grade 0 or I and remained high after day 21. In contrast, the ratios were low after day 21 following allo-BMT in 14 patients with aGVHD of grade 0 or I. Moreover, the clinical analysis suggested a relationship between the ratio and aGVHD grade. Thus, we showed that the CD27+/CD27- ratio in CD4+ T-lymphocytes may have value in predicting the development of severe aGVHD and may correlate with clinical symptoms of aGVHD.
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Affiliation(s)
- Hitoshi Yoshida
- Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan
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Ichiba T, Teshima T, Kuick R, Misek DE, Liu C, Takada Y, Maeda Y, Reddy P, Williams DL, Hanash SM, Ferrara JLM. Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays. Blood 2003; 102:763-71. [PMID: 12663442 DOI: 10.1182/blood-2002-09-2748] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The liver, skin, and gastrointestinal tract are major target organs of acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT). In order to gain a better understanding of acute GVHD in the liver, we compared the gene expression profiles of livers after experimental allogeneic and syngeneic BMT using oligonucleotide microarray. At 35 days after allogeneic BMT when hepatic GVHD was histologically evident, genes related to cellular effectors and acute-phase proteins were up-regulated, whereas genes largely related to metabolism and endocrine function were down-regulated. At day 7 after BMT before the development of histologic changes in the liver, interferon gamma (IFN-gamma)-inducible genes, major histocompatibility (MHC) class II molecules, and genes related to leukocyte trafficking had been up-regulated. Immunohistochemistry demonstrated that expression of IFN-gamma protein itself was increased in the spleen but not in hepatic tissue. These results suggest that the increased expression of genes associated with the attraction and activation of donor T cells induced by IFN-gamma early after BMT is important in the initiation of hepatic GVHD in this model and provide new potential molecular targets for early detection and intervention of acute GVHD.
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Affiliation(s)
- Tamotsu Ichiba
- Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, USA
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11
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Abstract
Graft-versus-host-disease (GVHD) is the major complication of allogeneic Bone Marrow Transplant (BMT) and Older BMT recipients are at greater risk for acute graft-versus-host-disease. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older recipients. GVHD mortality and morbidity, as well as pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice. In a haploidential GVHD model, CD4+ donor T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2FI BM chimeras created with either old or young BM. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. We also evaluated whether alloantigen expression on host target epithelium is essential for tissue damage induced by GVHD in mouse models. In bone marrow chimeras recipients in which either MHC II or MHC I alloantigen was expressed only on APCs, we found that acute GVHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GVHD. These results suggest new strategies for the prevention and treatment of this toxic complication of BMT.
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Teshima T, Ordemann R, Reddy P, Gagin S, Liu C, Cooke KR, Ferrara JLM. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 2002; 8:575-81. [PMID: 12042807 DOI: 10.1038/nm0602-575] [Citation(s) in RCA: 394] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.
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Affiliation(s)
- Takanori Teshima
- Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, Michigan, USA
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Jacobs JJ, Lehé C, Cammans KD, Yoneda K, Das PK, Elliott GR. An automated method for the quantification of immunostained human Langerhans cells. J Immunol Methods 2001; 247:73-82. [PMID: 11150538 DOI: 10.1016/s0022-1759(00)00328-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Allergic contact dermatitis is a frequent and increasing health problem. For ethical reasons, the current animal tests used to screen for contact sensitizers should be replaced by in vitro alternatives. Contact sensitizers have been shown to accelerate Langerhans cell (LC) migration from human organotypic skin explant cultures (hOSECs) more rapidly than non-sensitizers and it has been proposed that the hOSEC model could be used to screen for sensitizers. However, chemically induced decreases in epidermal LC numbers need to be accurately quantified if the alterations in epidermal LC numbers are to form the basis of an alternative system for screening contact sensitizers in vitro. As manual counting of LCs is labour intensive and subject to intra- and inter-personal variation we developed an image analysis routine, using the Leica QWin image analysis software, to quantify LCs in situ using immunohistochemically stained skin sections. LCs can be identified using antibodies against the membrane molecule CD1a or the Lag antibody, which recognises cytoplasmic Birbeck granules. Quantification of epidermal LC number using the image analysis software had a much lower inter-person variation than when the same specimens were counted manually, using both the anti-Lag and CD1a antibodies. The software-aided quantification of epidermal LCs provides an accurate method for measuring chemically-induced changes in LC numbers.
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Affiliation(s)
- J J Jacobs
- Department of Pharmacology, TNO-PML, P.O. Box 45, Rijswijk, The Netherlands
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Oberhuber G, Püspök A, Peck-Radosavlevic M, Kutilek M, Lamprecht A, Chott A, Vogelsang H, Stolte M. Aberrant esophageal HLA-DR expression in a high percentage of patients with Crohn's disease. Am J Surg Pathol 1999; 23:970-6. [PMID: 10435568 DOI: 10.1097/00000478-199908000-00016] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Esophageal histology is not well studied in patients with Crohn's disease (CD). We, therefore, analyzed the histologic and immunohistologic appearance of esophageal mucosa in CD. Biopsy specimens taken from the esophagus of 57 consecutive patients with known CD of the large and/or small bowel, of 200 Crohn's-free controls, of 15 cases with ulcerative colitis, and of 5 cases with viral esophagitis were evaluated. In controls, most patients had either HLA-DR negative esophageal epithelium or showed focal or diffuse basal staining. HLA-DR expression of all epithelial layers (transepithelial staining) was observed in only four (2%) control subjects, in one case with herpes esophagitis, but not in patients with ulcerative colitis. In contrast, transepithelial HLA-DR expression was found in 19 (33%) patients with CD (p < 0.0001). In CD patients, it was associated with a significantly increased epithelial content in T-cells (CD3+, TIA-1+, granzyme B+), B-cells (CD79a+), natural killer cells (CD57+), and macrophages (CD68+). There was no correlation with either histological findings elsewhere in the upper gastrointestinal tract or with laboratory findings, symptoms, CDAI, or medication. Transepithelial esophageal HLA-DR expression is common in CD. Immunohistochemistry may prove useful in supporting the histologic diagnosis of CD in staging procedures, for initial diagnosis as well as in doubtful cases.
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Affiliation(s)
- G Oberhuber
- Department of Clinical Pathology, University of Vienna, Medical School, Austria
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Matsunaga T, Katayama I, Yokozeki H, Nishioka K. Epidermal cytokine mRNA expression induced by hapten differs from that induced by primary irritant in human skin organ culture system. J Dermatol 1998; 25:421-8. [PMID: 9714973 DOI: 10.1111/j.1346-8138.1998.tb02428.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Epidermal cells produce various kinds of cytokines and express cell adhesion molecules. To analyze early events which induced in human epidermis by stimulation with various chemicals, we analyzed mRNA of cytokines expressed in epidermis in a human skin organ culture system. After painting haptens, primary irritants or vehicle control on human skin specimens sliced to 1 mm thickness and cut into approximately 5 x 5 mm blocks, the pieces were cultured in serum-free medium. After separating epidermis from dermis, total RNA was extracted and mRNA of cytokines was assessed by the reverse transcriptase-poly-merase chain reaction. Only haptens induced IL-1 beta mRNA at 1-3 hours. TNF-alpha mRNA was induced 9 hours after application of haptens and 1 hour after application of primary irritants. IL-1 alpha mRNA was not induced by either haptens or primary irritants. Thus, cytokine mRNA expression induced by haptens in epidermis differs from that induced by primary irritants.
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Affiliation(s)
- T Matsunaga
- Department of Dermatology, Tokyo Medical and Dental University, Japan
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Sedgwick JD, Ford AL, Foulcher E, Airriess R. Central Nervous System Microglial Cell Activation and Proliferation Follows Direct Interaction with Tissue-Infiltrating T Cell Blasts. THE JOURNAL OF IMMUNOLOGY 1998. [DOI: 10.4049/jimmunol.160.11.5320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Abstract
Central nervous system (CNS)-resident macrophages (microglia) normally express negligible or low level MHC class II, but this is up-regulated in graft-vs-host disease (GvHD), in which a sparse CNS T cell infiltrate is observed. Relative to microglia from the normal CNS, those from the GvHD-affected CNS exhibited a 5-fold up-regulation of characteristically low CD45, MHC class II expression was increased 10- to 20-fold, and microglial cell recoveries were enhanced substantially. Immunohistologic analysis revealed CD4+αβTCR+CD2+ T cells scattered infrequently throughout the CNS parenchyme, 90% of which were blast cells of donor origin. An unusual clustering of activated microglia expressing strongly enhanced levels of CD11b/c and MHC class II was a feature of the GvHD-affected CNS, and despite the paucity of T lymphocytes present, activated microglial cell clusters were invariably intimately associated with these T cells. Moreover, 70% of T cells in the CNS were associated with single or clustered MHC class II+ microglia, and interacting cells were predominantly deep within the tissue parenchyme. Approximately 3.7% of the microglia that were freshly isolated from the GvHD-affected CNS were cycling, and proliferating cell nuclear Ag-positive microglia were detected in situ. Microglia from GvHD-affected animals sorted to purity by flow cytometry and cultured, extended long complex processes, exhibited spineous processes, and were phagocytic and highly motile. These outcomes are consistent with direct tissue macrophage-T cell interactions in situ that lead to activation, proliferation, and expansion of the responding tissue-resident cell.
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Affiliation(s)
- Jonathon D. Sedgwick
- Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia
| | - Andrew L. Ford
- Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia
| | - Eléna Foulcher
- Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia
| | - Rhonda Airriess
- Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Camperdown, Sydney, Australia
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Abstract
Graft-versus-host reactions frequently produce cutaneous and systemic complications in patients receiving bone marrow transplants. Characteristic skin involvement typically heralds graft-versus-host reactions and significantly contributes to the morbidity associated with marrow transplants. Familiarity with these reactions and their treatment is important to dermatologists involved in the care of marrow transplant recipients.
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Affiliation(s)
- M L Johnson
- Department of Dermatology, Keesler Medical Center, Keesler Air Force Base, Biloxi, Mississippi, USA
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Li J, Farthing PM, Thornhill MH. Cytokine regulation of major histocompatibility complex antigen expression by human oral and skin keratinocytes. Arch Oral Biol 1996; 41:533-8. [PMID: 8937643 DOI: 10.1016/0003-9969(96)00026-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The expression, and cytokine modulation, of major histocompatibility complex (MHC) class I and class II molecules on oral and skin keratinocytes were compared in cell culture. Both cell types expressed class I, but not class II, constitutively. However, stimulation with interferon-gamma, but not interleukin-1 alpha, and -1 beta, tumour necrosis factor-alpha or lymphotoxin, induced increased expression of class I and de-novo expression of HLA-DR on both cell types. Oral keratinocytes differed from skin keratinocytes in that they exhibited greater sensitivity to interferon-gamma stimulation and higher stimulated expression of both class I and HLA-DR. In addition, interferon-gamma stimulated oral, but not skin, keratinocytes to express HLA-DP and -DQ. These observations suggest that, like skin keratinocytes, under certain conditions, oral keratinocytes may be able to act as antigen-presenting cells. This may be important in the initiation and progression of some immune-mediated mucocutaneous diseases. Moreover, differences in MHC expression may help to explain differences in the presentation of these diseases on the skin and oral mucosa.
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Affiliation(s)
- J Li
- Clinical Academic Group of Oral Medicine and Dental Diagnostic Science, University Dental Hospital of Manchester, UK
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21
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Nasir A, Gaspari AA. Contact dermatitis. Clinical perspectives and basic mechanisms. Clin Rev Allergy Immunol 1996; 14:151-84. [PMID: 8727021 DOI: 10.1007/bf02780197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- A Nasir
- Medical Services, Massachusetts General Hospital, Harvard Medical School, Boston, USA
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22
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Tsuji S, Char D, Bucy RP, Simonsen M, Chen CH, Cooper MD. Gamma delta T cells are secondary participants in acute graft-versus-host reactions initiated by CD4+ alpha beta T cells. Eur J Immunol 1996; 26:420-7. [PMID: 8617313 DOI: 10.1002/eji.1830260223] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
To examine the role of T cell subpopulations in an acute graft-versus-host (GVH) reaction, gamma delta T cells and alpha beta T cells expressing one of the two prototypic V beta families were negatively isolated from adult blood samples and injected into allogeneic chick embryos. CD4+ alpha beta T cells expressing either V beta 1 or V beta 2 receptors were equally capable of inducing acute GVH reactions, consistent with the idea that alpha beta T cell alloreactivity is determined by CDR3 variability. By themselves, the gamma delta T cells were incapable of inducing GVH reactions. However, host gamma delta T cells were recruited into the donor alpha beta T cell-initiated lesions, where they were activated and induced to proliferate. The data suggest that gamma delta T cells may play a secondary role in GVH reactions.
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Affiliation(s)
- S Tsuji
- Division of Developmental and Clinical Immunology, Department of Medicine, University of Alabama at Birmingham 35294-3000 USA
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23
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Müller CA, Hebart H, Roos A, Roos H, Steidle M, Einsele H. Correlation of interstitial pneumonia with human cytomegalovirus-induced lung infection and graft-versus-host disease after bone marrow transplantation. Med Microbiol Immunol 1995; 184:115-21. [PMID: 8577311 DOI: 10.1007/bf00224347] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
In a retrospective analysis lung biopsy specimens obtained postmortem from 30 consecutive allogeneic bone marrow transplant recipients who had died of either either interstitial pneumonitis (IP; 18/30 patients) or various other causes (12/30 patients) were studied for the local presence of human cytomegalovirus (HCMV) by culture, in situ hybridization, polymerase chain reaction (PCR) and immunohistochemistry for HCMV proteins. All patients suffering from IP were found to be HCMV positive in the lung biopsy. PCR revealed the highest sensitivity for HCMV detection in lung biopsies, but in 15/18 PCR-positive samples local HCMV infection could be confirmed by at least one additional technique. All the lung biopsies obtained from the 12 patients without IP were negative for HCMV by all techniques applied, except one with a weak HCMV-DNA signal in the PCR assay. The severity of the clinical, as well as histological and immunohistological alterations in the lung did not correlate with the amount of HCMV-DNA or the number of HCMV-positive cells detected in the biopsy. An increase of HLA-class II antigen and of ICAM-1 expression on the alveolar epithelium, as well as presence of activated CD8+ or CD4+ lymphocytes infiltrating only HCMV-positive lung biopsies revealed T cell-mediated immune reactions to be involved in the pathogenesis of IP. Since all analyzed patients presented with severe acute or extensive chronic graft-versus-host disease (GvHD), but only those with pulmonary HCMV infection developed IP, dissemination of HCMV appears to be the primary requirement for the initiation of IP. GvHD, however, may interfere with normal control of subsequent antiviral immune response and, thus, provoke the immunopathology of IP.
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Affiliation(s)
- C A Müller
- Abteilung II mit Sektion für Transplantationsimmunologie und Immunhämatologie, Universität Tübingen, Germany
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24
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Weller FR, De Jong MC, Weller MS, Heeres K, De Monchy JG, Jansen HM. HLA-DR expression is induced on keratinocytes in delayed hypersensitivity but not in allergen induced late-phase reactions. Clin Exp Allergy 1995; 25:252-9. [PMID: 7788573 DOI: 10.1111/j.1365-2222.1995.tb01037.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
In view of increasing evidence suggesting an active immunoregulatory role of the skin keratinocytes and the observation that the differentiation of allergen specific T lymphocytes is critical in the development of allergy, we evaluated epidermal expression of HLA-DR antigen in skin reactions induced with an atopen (house dust mite) and with an non-atopic antigen (Hemocyanin). Two groups of patients with house dust mite (Dermatophagoides pteronyssinus [Der p]) allergy were compared, one group was skin tested with Der p, the other group was immunized and subsequently skin tested with Helix pomatia Hemocyanin (HPH). Biopsy specimens taken at 48 h after the HPH (n = 11) and Der p (n = 11) tests were analysed immunohistologically. Reactions in both groups were comparable in size. Immunohistological analysis showed domination by CD4+ lymphocytes. Expression of HLA-DR antigen by epidermal keratinocytes was observed in six out of 11 of the HPH induced reactions, but in none of the Der p induced reactions. Eosinophils were spotted only throughout the Der p induced reactions, showing a good correlation with the number of CD4 positive lymphocytes. The lack of HLA-DR expression by keratinocytes during the allergen-induced reaction, compared with the Hemocyanin induced reaction can be the result of a difference in cytokine profile of the lymphocytes dominating the dermal infiltrate. On the other hand evidence exists that defective HLA-DR expression by keratinocytes enhances antigen induced lymphocyte activation, and may thus contribute to the development of allergen-specific T-lymphocytes.
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Affiliation(s)
- F R Weller
- Department of Pulmonology, University of Amsterdam, the Netherlands
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25
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Suda T, Sato A, Sugiura W, Chida K. Induction of MHC class II antigens on rat bronchial epithelial cells by interferon-gamma and its effect on antigen presentation. Lung 1995; 173:127-37. [PMID: 7715254 DOI: 10.1007/bf02981472] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Recent studies have found aberrant expression of class II antigens by bronchial epithelial cells (BECs), suggesting that these cells may also be involved in airway mucosal immunity. However, the regulation of class II antigen expression on BECs by cytokines and the functional capacity of such cells bearing class II molecules remain unknown. We investigated the effect of IFN-gamma on class II antigen expression by cultured rat BECs, as well as the ability of these cells to present intact protein antigens to specifically sensitized T cells. Although primary BECs did not express class II antigens, IFN-gamma readily induced their expression in a dose-dependent manner. More than 85% of the BECs treated with 1000 U/ml of IFN-gamma were positive for class II antigens. In addition, when IFN-treated BECs bearing class II molecules were pulsed with ovalbumin (OVA), they significantly stimulated the proliferation of OVA-sensitized T cells, whereas cells that were not treated with IFN-gamma but were pulsed with OVA did not do so. Our findings indicate that BECs bearing class II molecules are capable of presenting OVA to OVA-sensitized T cells. These results suggest that various pathological conditions causing the local production of IFN-gamma may increase class II antigen expression on BECs, which in turn may modulate the airway mucosal immune response by the presentation of antigens to T cells.
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Affiliation(s)
- T Suda
- Department of Internal Medicine, Hamamatsu University School of Medicine, Japan
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26
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Strange P, Skov L, Baadsgaard O. Interferon gamma-treated keratinocytes activate T cells in the presence of superantigens: involvement of major histocompatibility complex class II molecules. J Invest Dermatol 1994; 102:150-4. [PMID: 7906285 DOI: 10.1111/1523-1747.ep12371753] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
During inflammation in the skin keratinocytes can express major histocompatibility complex class II molecules but are unable to present nominal antigens to resting T cells. Certain bacteria including staphylococci produce a new class of antigens termed superantigens that are very potent T-cell activators. Using an in vitro model with cultured normal human keratinocytes and purified allogeneic T cells, we demonstrated that major histocompatibility complex class II+ keratinocytes can activate T cells in the presence of the superantigen staphylococcal enterotoxin B. Major histocompatibility complex class II+ keratinocytes activated T cells at concentrations of staphylococcal enterotoxin B as low as 100 pg/ml. The activation required contact between keratinocytes and T cells, was inhibited with a monoclonal antibody to human leukocyte antigen DR, -DQ, and was not affected by fixation of the keratinocytes. These data show that major histocompatibility complex class II+ keratinocytes activate T cells in the presence of the superantigen staphylococcal enterotoxin B.
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Affiliation(s)
- P Strange
- Department of Dermatology, Gentofte Hospital, University of Copenhagen, Denmark
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27
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Osawa J, Kitamura K, Saito S, Ikezawa Z, Nakajima H. Immunohistochemical study of graft-versus-host reaction (GVHR)-type drug eruptions. J Dermatol 1994; 21:25-30. [PMID: 7908910 DOI: 10.1111/j.1346-8138.1994.tb01405.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Skin biopsies of graft-versus-host reaction (GVHR)-type drug eruptions in the acute phase were compared immunohistochemically with those in the chronic phase and also with non-GVHR type drug eruptions in the acute phase. Predominance of CD8+ T cells in the epidermal infiltrates, reduction in the number of epidermal OKT6+ dendritic cells (Langerhans cells), and increased expression of HLA-DR and ICAM-1 on keratinocytes were observed in the acute phase of GVHR-type, but not in either the chronic phase of GVHR-type or the acute non-GVHR type. These findings were similar to those of previous reports on skin lesions of acute GVH disease (GVHD) seen after bone marrow transplantation. Therefore, immunohistochemistry is not useful for differential diagnosis between acute GVHR-type drug eruptions and acute cutaneous GVHD. These findings also indicate that similar immunomechanisms may be involved in the pathogenesis of both GVHR-type drug eruptions and cutaneous GVHD.
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Affiliation(s)
- J Osawa
- Department of Dermatology, Yokohama City University School of Medicine, Urafune Hospital, Japan
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28
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Cesbron A, Moreau P, Muller JY. [Immunologic aspects of bone marrow transplantation]. REVUE FRANCAISE DE TRANSFUSION ET D'HEMOBIOLOGIE : BULLETIN DE LA SOCIETE NATIONALE DE TRANSFUSION SANGUINE 1993; 36:339-73. [PMID: 8357446 DOI: 10.1016/s1140-4639(05)80239-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Allogeneic bone marrow transplantation is concerned by immunology by at least two aspects: the first one is the acceptance of the graft by the host and reciprocally and the second one is that it constitutes an unique human model of immune reconstitution. In this review of the immunological aspects, we deal with the selection of the bone marrow donor (related or not) especially on the base of HLA compatibility and the graft-versus-host disease (GVH) with the clinical manifestations, the usual treatments, the supposed cellular mechanisms and the risk factors of developing such complications. The graft versus leukemia effect (GVL) which may be linked to the GVH disease and the mechanisms of rejection and take of the graft are also reviewed as well as the immune reconstitution following the immune deficiency due to the conditioning treatment and the occurrence of a GVH disease.
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Affiliation(s)
- A Cesbron
- Laboratoire HLA, CRTS BP 349, Nantes
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29
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Rowbottom AW, Norton J, Riches PG, Hobbs JR, Powles RL, Sloane JP. Cytokine gene expression in skin and lymphoid organs in graft versus host disease. J Clin Pathol 1993; 46:341-5. [PMID: 8496391 PMCID: PMC501216 DOI: 10.1136/jcp.46.4.341] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
AIM To determine if human graft versus host disease (GvHD) is associated with any detectable change in cytokine gene expression in the skin and lymphoid organs. METHODS Reverse transcriptase and the polymerase chain reaction were used to amplify mRNA for interleukins-1 (IL-1), -2 (IL-2), -4 (IL-4) and -6 (IL-6), IL-2 receptor (IL-2R), tumour necrosis factors alpha (TNF-alpha) and beta (TNF-beta), gamma interferon (IFN gamma) and granulocyte macrophage colony stimulating factor (GM-CSF) in frozen punch biopsy specimens of skin and necropsy samples of skin, lymph node, and spleen. RESULTS No cytokine mRNA was detected in the punch biopsy specimens except weak signals for IL-6 and IL-1 and GM-CSF in two normal donors and IL2-R in one patient with GvHD. In samples of skin taken at necropsy, however, significant quantities of mRNA for TNF-alpha, TNF-beta, and IL-4 were detected in patients who had or had had GvHD in contrast to those without the disease whose skin lacked mRNA for these products but contained detectable quantities of IL-1, IL2-R, IL-6 and GM-CSF. There seemed to be a reciprocal relation between TNF-alpha and IL-4. In necropsy samples of lymph node and spleen a pattern of cytokine production similar to that in the skin was observed with a preponderance of TNF-alpha, TNF-beta and IL-4 in patients with GvHD and GM-CSF and IL-6 in those without the disease. CONCLUSIONS The local synthesis of these molecules would explain many of the morphological and immunohistological features of GvHD. The failure to detect TNF-alpha, TNF-beta, and IL-4 in skin biopsy specimens exhibiting GvHD is probably due to their small size but further investigations are required.
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Affiliation(s)
- A W Rowbottom
- Department of Immunology, Charing Cross and Westminster Medical School, London
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30
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Abstract
The pathological complications of bone marrow transplantation are complex and may affect any organ in the body. The causes are often multifactorial and include the effects of chemotherapy, the conditioning regimen, drugs used in the post-transplant period such as immunosuppressants and antibiotics, graft-versus-host disease (GvHD) and the effects of the primary disease itself. Infections are common and result from the immunosuppressive effects of cytotoxic drugs and irradiation, GvHD and marrow failure. Haemorrhage is not infrequent. Graft-versus-host disease remains a significant problem and can be difficult to diagnose. Some of its histological features simulate the effects of chemoradiation and the diagnostic lesions may not be present early in the disease, when treatment is most effective. Evidence has accumulated that inflammatory cytokines have a key role in the pathogenesis of GvHD. It can be prevented by eliminating T-cells from the donor marrow but this procedure adversely affects marrow engraftment, increases the changes of rejection and results in a higher incidence of leukaemic relapse. Immunohistochemical staining for various cytokine-inducible molecules has led to some improvement in early diagnosis.
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Affiliation(s)
- J P Sloane
- Department of Histopathology, Royal Marsden Hospital, Sutton, UK
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31
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Khan IU, Boehm KD, Elmets CA. Modulation of interferon-gamma-induced HLA-DR expression on the human keratinocyte cell line SCC-13 by ultraviolet radiation. Photochem Photobiol 1993; 57:285-90. [PMID: 8451291 DOI: 10.1111/j.1751-1097.1993.tb02288.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Cell surface expression of major histocompatibility determinants on epidermal keratinocytes is a characteristic feature of a number of inflammatory dermatoses and in all likelihood is caused by diffusion of human leukocyte antigen (HLA)-DR-inducing cytokines from cells present in the dermal mononuclear cell infiltrate. Many of these same disorders respond to ultraviolet (UV) radiation phototherapy. Using the human SCC-13 keratinocyte cell line as a model, UV radiation was found to inhibit interferon-gamma-induced HLA-DR expression. Inhibition correlated closely with decreased steady-state levels of HLA-DR mRNA. These findings provide evidence that the therapeutic effect of UV radiation phototherapy may be mediated by its capacity to down-regulate cytokine-induced keratinocyte HLA-DR expression.
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Affiliation(s)
- I U Khan
- Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106
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32
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Lin YL, Borenstein LA, Selvakumar R, Ahmed R, Wettstein FO. Progression from papilloma to carcinoma is accompanied by changes in antibody response to papillomavirus proteins. J Virol 1993; 67:382-9. [PMID: 7677955 PMCID: PMC237374 DOI: 10.1128/jvi.67.1.382-389.1993] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Cottontail rabbit papillomavirus induces benign tumors, papillomas, in rabbits which progress at a high frequency to malignant tumors, carcinomas. Cottontail rabbit papillomavirus therefore provides an experimental model for oncogenic human papillomaviruses. The nature of the antigens recognized by the host has not been identified at any stage of tumor development. Here, we characterized the humoral immune response to viral antigens in cottontail and domestic rabbits at the papilloma stage, in domestic rabbits at the carcinoma stage, and in animals in which papillomas had regressed. Antibodies to linear epitopes were identified by Western blotting (immunoblotting) with bacterial fusion proteins, and evidence for recognition of conformational epitopes was obtained by immunoprecipitation. An immune response to the early proteins E1, E2, E6, and E7 was detected only in a fraction of the animals, and all animals were negative for E4 and E5. The response to E6 and E7 peaked around 7 months and then decreased, while that to E1 and E2 remained level after an initial raise. The antibody response to structural proteins was low at the papilloma stage, and antibodies to L1 recognized predominantly conformational epitopes. As papillomas progressed to carcinomas, there was a drastic increase in the response to L1 and L2, suggesting a change in interaction between virus-infected host cells and the host's immune system.
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Affiliation(s)
- Y L Lin
- Department of Microbiology and Immunology, School of Medicine, University of California, Los Angeles 90024
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33
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Norton J, Sloane JP. Epidermal damage in skin of allogeneic marrow recipients: relative importance of chemotherapy, conditioning and graft v. host disease. Histopathology 1992; 21:529-34. [PMID: 1468751 DOI: 10.1111/j.1365-2559.1992.tb00440.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The relative importance of previous chemotherapy, conditioning and graft v. host disease in producing the epidermal damage associated with allogeneic bone marrow transplantation was investigated by enumerating individually necrotic cells. A small number was seen in many pre-transplant biopsies and was related to the time interval between biopsy and the last dose of chemotherapy. Their presence did not predispose patients to develop graft v. host disease in the post-transplant period. In post-transplant patients without rashes the degree of epidermal damage at 14 days was similar to that seen in the pre-transplant period indicating that the effects of the conditioning regime were insignificant. In patients with rashes clinically classical of graft v. host disease, necrotic cells were increased above the pre-transplant levels even in the absence of a lymphocytic infiltrate. Lymphocytic infiltration was seen more frequently in biopsies taken later after transplantation and after the onset of the rash and was associated with the maximal amount of epidermal damage. Comparison of the degree of epidermal damage in pre- and post-transplantation specimens lacking a lymphocytic infiltrate resulted in the correct identification of the majority of patients with clinical evidence of graft v. host disease. This approach may, thus, be useful in diagnosing early graft v. host disease especially if combined with keratinocyte HLA-DR staining.
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Affiliation(s)
- J Norton
- Department of Histopathology, Royal Marsden Hospital, Sutton, Surrey, UK
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34
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Abstract
Although once thought to play a purely structural role, there is increasing evidence that keratinocytes are actively involved in epidermal immune responses, including allergic contact dermatitis (ACD). In vitro studies demonstrate that both urushiol and nickel sulphate induce cytokine production in cultured keratinocytes including molecules responsible for endothelial cell activation and lymphocyte chemotaxis and adhesion. In vivo, these same molecules are expressed in experimentally induced patch test reactions to a variety of allergens. Furthermore, such expression precedes the onset of the inflammatory phase of ACD. Taken together, these studies suggest a role complementary to that of Langerhans cells for keratinocytes in the initiation and propagation of ACD.
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Affiliation(s)
- J N Barker
- Department of Dermatology, Guy's Hospital, London, UK
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35
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Abstract
The results of a number of investigations have proved that human keratinocytes (HKs) possess the ability to synthesize and express cell surface moieties characteristic of effector and/or accessory cells of the immune system. The present paper summarizes the known immune cell surface features of HKs, reflecting their stage of activation and differentiation. The surface and functional characteristics of HKs suggest their monocyte/macrophage behavior, which fits in well with the presumed active involvement of HKs in the skin immune system.
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Affiliation(s)
- J Hunyadi
- Department of Dermatology, Albert Szent-Györgyi Medical University, Szeged, Hungary
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36
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Okabayashi M, Angell MG, Christensen ND, Kreider JW. Morphometric analysis and identification of infiltrating leucocytes in regressing and progressing Shope rabbit papillomas. Int J Cancer 1991; 49:919-23. [PMID: 1660041 DOI: 10.1002/ijc.2910490620] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Spontaneous regressions of papillomavirus lesions frequently occur in both human and animal infections. The mechanism by which this occurs is currently unknown. Mononuclear infiltrates are found in regressing human and rabbit papillomas. To assess the potential functional role of these infiltrates in regression, we have characterized and quantitated the cell types present in regressing rabbit lesions. Forty New Zealand white rabbits were inoculated with cottontail rabbit papillomavirus (CRPV) at 2 sites on the dorsal skin. All tumors on 6 rabbits markedly decreased in volume within 6 to 8 weeks of inoculation. Tumors on 4 of these 6 regressor rabbits were studied by immunohistochemistry. Regressor papillomas had conspicuous leucocytic infiltrates, most concentrated at the epithelial basement membrane, and often obliterating the basal cells of the germinal layer. Infiltrating leucocytes were also concentrated in the subjacent dermis immediately beneath the basement membrane. The infiltrates gradually lessened at increased depths in the dermis. In contrast, progressor papillomas contained fewer leucocytes, which were randomly distributed in the dermis. The phenotype of the infiltrating leucocytes was examined in 4 regressing and 12 progressing papillomas. In regressing papillomas, infiltrating leucocytes were predominantly T cells (68.0%), with relatively few B cells (7.4%). Progressing papilloma dermis contained fewer T cells and B cells than regressing papillomas. Most of the infiltrating T cells in regressing papillomas were labelled with a rabbit MHC-class-II-specific monoclonal antibody (MAb) (2C4), in contrast to only a small number in progressing papillomas. In addition to the leucocytic infiltrates, keratinocytes in regressing, but not in progressing, papillomas, frequently exhibited strong 2C4 staining. These results demonstrate that infiltration with T cells expressing rabbit class II is characteristic of regressing Shope papillomas and strengthens the assertion that cell-mediated immunity is the mechanism of Shope papilloma regression.
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Affiliation(s)
- M Okabayashi
- Department of Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033
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37
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Stringer CP, Hicks R, Botham PA. The expression of MHC class II (Ia) antigens on mouse keratinocytes following epicutaneous application of contact sensitizers and irritants. Br J Dermatol 1991; 125:521-8. [PMID: 1760356 DOI: 10.1111/j.1365-2133.1991.tb14788.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The expression of MHC class II (Ia) antigens on mouse keratinocytes was studied following both the induction and elicitation of contact sensitivity, and after primary irritant reactions. IA+ and IE+ keratinocytes were detected, using an indirect immunofluorescence assay on epidermal sheets, only after the induction and elicitation of contact sensitivity with the sensitizers oxazalone, picryl chloride and 2,4-dinitrochlorobenzene but not with formaldehyde. Ia+ keratinocytes were not detected after epicutaneous application of the non-sensitizing irritants croton oil, SDS and anthralin, or following attempted sensitization of nude mice, suggesting that the expression of Ia antigen on keratinocytes during contact sensitivity reactions is T-cell mediated. Because Ia antigen expression on keratinocytes could be detected only several days after induction or elicitation of contact sensitivity, and contact sensitization could also be demonstrated to occur independently of aberrant Ia expression, Ia+ keratinocytes cannot be involved in the initiation of these reactions. However, they might be important in exerting an immunomodulatory influence during the later stages of the responses to certain sensitizers.
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Affiliation(s)
- C P Stringer
- ICI Central Toxicology Laboratories, Alderley Park, Macclesfield, U.K
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38
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Beaudoin AR, Grondin G. Shedding of vesicular material from the cell surface of eukaryotic cells: different cellular phenomena. BIOCHIMICA ET BIOPHYSICA ACTA 1991; 1071:203-19. [PMID: 1958687 DOI: 10.1016/0304-4157(91)90014-n] [Citation(s) in RCA: 105] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- A R Beaudoin
- Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Canada
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39
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Gilhar A, Etzioni A, Pillar T, Assy B, Eidelman S. Effect of cyclosporine A on the regulation of Ia antigen keratinocytes expression. CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY 1991; 60:349-55. [PMID: 1650656 DOI: 10.1016/0090-1229(91)90092-o] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Since many skin diseases characterized by positive Ia keratinocytes show improvement with cyclosporine therapy, the purpose of this study was to determine whether cyclosporine A (CyA) alters the expression of Ia keratinocytes. Nude mice were injected with normal mouse serum (NMS) to induce keratinocyte expression of the Ia antigen. The injected mice were then divided into four groups: one was treated with oral CyA; the second was treated topically with CyA twice a day; the third was treated topically with olive oil; and the fourth was injected with nude mouse serum. The third and fourth groups served as Ia positive and Ia negative controls, respectively. The mice were treated during the first 10 days after the injections. On Day 10, epidermal sheets were analyzed for Ia expression. Analysis was made by an indirect immunoperoxidase staining method using monoclonal antibodies specific for Ia determinants. Quantitation of the number of Langerhans cells was analyzed on epidermal sheets using immunodiagnostic reagents, anti-MHC-Ia, and surface ectoenzyme, ATPase. A significant reduction of Ia-positive keratinocytes was noted in the oral CyA group vs topical and olive oil groups (64.9 +/- 29.9% vs 20.1 +/- 18.7%, respectively, P less than 0.01). In a second set of experiments mice were injected with NMS, but treatment was started only on Day 10 after injections, for 10 days. The results showed that CyA failed to down-regulate Ia expression. Topical and systemic CyA did not modify Langerhans cell population. The present study showed that systemic administration of CyA significantly reduced Ia induction by keratinocytes of nude mice that were injected with NMS.
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Affiliation(s)
- A Gilhar
- Skin Research Laboratory, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa
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40
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Abstract
Lichen planus is a mucocutaneous disease of unknown etiology which, according to current knowledge, may represent a cell-mediated immunological response to induced antigenic changes in the skin and mucosa. Oral lichen planus (OLP) is a disease of adulthood and as one of the most prevalent diseases affecting the oral mucosa it has been the subject of intensive research during recent years. Ultrastructural and immunohistochemical studies particularly dealing with the subepithelial inflammatory cell infiltrate and its relations to epithelial pathology, the basal cell region and the intraepithelial antigen presenting Langerhans' cells, have contributed vastly to our knowledge of the pathogenesis of OLP. However, the treatment of OLP still remains largely symptomatic because many as yet unknown factors, active in the disease process, still remain to be elucidated.
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Affiliation(s)
- P Jungell
- Department of Oral Surgery, University of Helsinki, Finland
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41
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Partridge M, Chantry D, Turner M, Feldmann M. Production of interleukin-1 and interleukin-6 by human keratinocytes and squamous cell carcinoma cell lines. J Invest Dermatol 1991; 96:771-6. [PMID: 2022885 DOI: 10.1111/1523-1747.ep12471723] [Citation(s) in RCA: 57] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Cultured human keratinocytes and squamous cell carcinoma (SCC) cell lines were analyzed for the presence of ribonucleic acid (RNA) transcripts for the cytokines interleukin-1 and interleukin-6 and for these proteins. This study demonstrates that both cytokines are synthesized and secreted by both normal keratinocytes and SCC lines. The rate of secretion of these cytokines can be augmented in response to a variety of stimuli including tumor necrosis factor-alpha, granulocyte-macrophage colony stimulating factor, transforming growth factor-beta and the combination of lipopolysaccharide and phorbol myristate acetate. Interleukin-1 and interleukin-6 have been reported to influence the proliferation of cultured human fibroblasts. However, these cytokines had no significant effect on the proliferation of human keratinocytes or the SCC lines tested. Although it seems unlikely that interleukin-1 or interleukin-6 could directly influence keratinocyte proliferation in vivo, the capacity of these cells to synthesize and release these cytokines supports earlier observations that keratinocytes may play an important role in augmenting an immune or inflammatory response.
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Affiliation(s)
- M Partridge
- Charing Cross Sunley Research Centre, London, U.K
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42
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Willis CM, Stephens CJ, Wilkinson JD. Selective expression of immune-associated surface antigens by keratinocytes in irritant contact dermatitis. J Invest Dermatol 1991; 96:505-11. [PMID: 1706746 DOI: 10.1111/1523-1747.ep12470213] [Citation(s) in RCA: 60] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The expression of three immunoregulatory surface antigens by epidermal keratinocytes was studied in irritant contact dermatitis (ICD), in order to assess whether keratinocytes have a modulatory role in the pathogenesis of this disorder. Biopsies were taken from 48-h patch test reactions to six structurally unrelated irritants, and frozen sections immunolabeled with monoclonal antibodies to the major histocompatibility complex class II antigen, HLA-DR, intercellular adhesion molecule-1 (ICAM-1), and the 88-Kd glycoprotein CD36 (OKM5), as well as to the CD3 (T cells) and CD11a (lymphocyte function associated antigen-1, LFA-1) antigens. We found that there was very limited expression of HLA-DR by keratinocytes, with no correlation between the extent of HLA-DR positivity and the degree of T cell infiltration into the epidermis and dermis, suggesting that interferon gamma may not be a significant mediator of ICD at 48 h. In contrast, keratinocytes showed extensive upregulation of ICAM-1, with an excellent spatial association between ICAM-1 expression and LFA-1 positive leucocytes in the epidermis. This indicates that keratinocyte ICAM-1 induction is not restricted to diseases in which antigen presentation is pivotal, but that it has a generalized role in cutaneous inflammatory reactions, promoting the infiltration of leucocytes into the epidermis. Immunolabeling with OKM5 revealed that CD36 is present to a variable degree on keratinocytes in normal skin. Differential changes in the pattern of keratinocyte expression occurred between irritants, in a manner that suggested that the CD36 antigen does not act as an adhesion molecule in ICD, but rather that its expression is related to the proliferative state of the epidermis. The results of this study demonstrate that immune-associated antigens are selectively expressed on the surface of keratinocytes in 48-h ICD biopsies, implying that these cells play an important regulatory role in the development of the inflammatory response to irritant chemicals.
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Affiliation(s)
- C M Willis
- Department of Dermatology, Wycombe General Hospital, Buckinghamshire, U.K
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43
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Kaneko F, Suzuki M, Takiguchi Y, Itoh N, Minagawa T. Immunohistopathologic studies in the development of psoriatic lesion influenced by gamma-interferon and the producing cells. J Dermatol Sci 1990; 1:425-34. [PMID: 2126953 DOI: 10.1016/0923-1811(90)90012-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Immunological studies on psoriasis have been done using monoclonal antibodies (MoAbs) to elucidate the relation between gamma-interferon (IFN-gamma) secreted from inflammatory infiltrate, and the expression of HLA-DR molecule on epidermal keratinocytes in the lesion. In highly inflamed psoriatic lesions, IFN-gamma producing cells were found in the inflammatory infiltrate of the dermal papillae, while keratinocytes located near IFN-gamma+ cells expressed HLA-DR molecules on the surface. In fully developed psoriatic lesions, HLA-DR+ keratinocytes were mainly found in the thin epidermis over the elongated dermal papillae where IFN-gamma deposited not only at infiltrates but also in teh dermal components. The IFN-gamma+ cells were activated T cells which exhibited HLA-DR and interleukin 2 receptor. Munro's microabscess under the horny layer also included IFN-gamma producing cells. A radioimmunoassay by the sandwich method with anti-human IFN-gamma and anti-recombinant IFN-gamma MoAbs found that extracts from psoriatic scales contained IFN-gamma. The results suggest that HLA-DR+ keratinocytes are due to the effect of IFN-gamma secreted by activated T cells in psoriatic lesions. The proliferation of keratinocytes over the dermal papillae in fully developed lesions seemed to be inhibited by IFN-gamma from the inflammatory infiltrate. We consider that cell-mediated immune reaction plays an important role in the development of psoriatic eruption.
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Affiliation(s)
- F Kaneko
- Department of Dermatology, Fukushima Medical College, Japan
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44
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Affiliation(s)
- J P Sloane
- Department of Histopathology, Royal Marsden Hospital, Sutton, Surrey, UK
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45
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Tokuda N, Kasahara M, Levy RB. Differential regulation and expression of major histocompatibility complex (MHC) and Ly-6 gene products on mouse testicular Leydig and Sertoli cell lines. J Autoimmun 1990; 3:457-71. [PMID: 2222751 DOI: 10.1016/s0896-8411(05)80013-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The expression and regulation of Class I and Class II major histocompatibility complex (MHC) and Ly-6 antigens were examined in BALB/c testicular cells. Studies were performed utilizing differentiated murine Leydig (TM3) and Sertoli (TM4) cell lines. Neither Class I (Dd) nor Class II (IA/Ed) MHC antigens were detectable on untreated TM3 cells. However, concanavalin-A activated spleen cell supernatant (Con-A sup) or interferon-gamma (IFN-gamma) treatment resulted in the marked induction of both Class I and Class II MHC antigens on virtually all of the Leydig cells. MHC Class II mRNA, which was not detected in resting cells, was clearly induced following IFN-gamma incubation. Sertoli cells were found to constitutively express low levels of Class I (Dd) but not Class II (IA/Ed) antigens. However, in contrast to the enhanced MHC expression in TM3 cells, Con-A sup or IFN-gamma treatment of TM4 cells resulted in marked augmentation of Class I, but not Class II, MHC antigens. Northern blot analysis failed to detect Class II mRNA in either the resting or IFN-gamma treated TM4 populations. Neither ethanol nor tumor necrosis factor (TNF) alone, or together with IFN-gamma head significant effects on MHC expression by TM3 and TM4 cells. Ly-6 antigens, predominantly expressed on hematopoietic cells, were found to be present on both TM3 and TM4 cells. Expression of this non-MHC encoded product was also shown to be markedly enhanced by IFN-gamma treatment on both testicular cell lines. In total, these findings demonstrated that cytokines can differentially affect discrete cell populations arising from a particular tissue with respect to the un-regulation of MHC and non-MHC gene products. These findings are discussed in the context of autoimmune responses directed against this tissue.
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Affiliation(s)
- N Tokuda
- Department of Microbiology and Immunology, University of Miami School of Medicine, Florida 33101
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46
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Abstract
Liver transplantation is performed successfully across major HLA differences between donor and recipient. This may be influenced by the organ specific expression of major histocompatibility complex (MHC) molecules which determine the local immune reactivity and rejection response. The tissue expression of MHC molecules on parenchymal and infiltrating cells has been studied in transplanted human liver using monoclonal antibodies and immunohistological methods. A strong induction of class I (HLA-A,B,C; beta 2-microglobulin) and class II (HLA-DR,DQ,DP) MHC antigens was demonstrated on hepatocytes, bile duct epithelium and endothelial cells during rejection episodes and viral and bacterial infections. The massive induction of donor antigens on hepatocytes, bile ducts and endothelia forms part of, and may also augment, the rejection response. During quiescent states without infection or rejection after transplantation, however, a rather restricted expression of class I and class II donor MHC antigens is present. In addition, the donor Kupffer cells and interstitial dendritic cells are gradually replaced by recipient accessory cells expressing self-MHC molecules. The changes in antigen density and distribution of donor MHC alloantigens as the replacement of accessory cells capable of presenting antigens to T-lymphocytes may influence the course of immune reactivity and the rejection response in the liver. This may partly explain the favourable clinical course long after transplantation. Preliminary clinical investigations of the effect of HLA matching have shown a dualistic effect of the matching of class I or class II HLA antigens. The role of HLA matching in liver transplants in large clinical studies, with specific immunological testing however, remains to be investigated. This may lead to prospective HLA matching with wider organ availability and improved preservation time in the future.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- G Steinhoff
- Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Federal Republic of Germany
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47
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Esteban F, Ruiz-Cabello F, Concha A, Pérez-Ayala M, Sánchez-Rozas JA, Garrido F. HLA-DR expression is associated with excellent prognosis in squamous cell carcinoma of the larynx. Clin Exp Metastasis 1990; 8:319-28. [PMID: 2350918 DOI: 10.1007/bf01810678] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We studied class II antigen expression and tumor-infiltrating leukocytes (TIL) in tissue sections of 69 squamous cell carcinomas of the larynx and 24 lymph node metastases in the neck. HLA-DR expression was found only in eight well-differentiated, highly keratinizing squamous cell carcinomas comprising seven of the verrucous variety and one ventriculosaccular tumor. None of the metastases was positive for DR antigen. Neither primary tumors nor autologous metastases stained for DP or DQ antigens. DR-positive tumors shared a peculiar pattern of TIL composed mainly of T cells, most of which belonged to the cytotoxic/suppressor subset, and B cells. These neoplasms had in common a slow rate of growth, and are considered low-grade carcinomas in the literature. We conclude from our study that HLA-DR expression seems to characterize tumors with a prominent infiltrate and an excellent prognosis.
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Affiliation(s)
- F Esteban
- Servicio de Otorrinolaringología, Hospital Virgen de las Nieves, Universidad de Granada, Spain
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48
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Detmar M, Orfanos CE. Tumor necrosis factor-alpha inhibits cell proliferation and induces class II antigens and cell adhesion molecules in cultured normal human keratinocytes in vitro. Arch Dermatol Res 1990; 282:238-45. [PMID: 2115318 DOI: 10.1007/bf00371643] [Citation(s) in RCA: 53] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The effects of recombinant human tumor necrosis factor-alpha (TNF) on cell proliferation, cell morphology, and on the expression of class II alloantigens and intercellular adhesion molecule-1 (ICAM-1) were assessed in human keratinocytes cultured in serum-free medium. TNF inhibited cell proliferation in a time- and dose-dependent manner with a minimum effective dose of 10 U/ml and a 50% inhibitory dose of 100 U/ml. However, TNF did not induce cell death, and the growth inhibition induced by TNF was completely reversible after its withdrawal. In vitro combination of TNF with interferon-alpha (IFN-alpha) and IFN-beta resulted in additive growth inhibitory effects, while IFN-gamma enhanced the TNF mediated growth inhibition in a synergistic way. Furthermore, TNF altered the morphology of the growing keratinocytes inducing the appearance of a fusiform, fibroblast-like population. Also, treatment with TNF over 6 days markedly induced the expression of ICAM-1 on the cultured keratinocytes with a minimal effective dose of 10 U/ml, while HLA-DR was only moderately expressed after 1,000 U/ml. TNF did not induce HLA-DQ, but reduced the IFN-gamma induced expression of HLA-DR and HLA-DQ. By immunoelectron microscopy, an intense membrane-bound labeling for ICAM-1 was found after treatment with TNF, clearly pronounced in areas of microvillous membrane protrusions. These results indicate that epidermal keratinocytes are a major target for various biological effects of TNF. We also found that TNF differentially modulates IFN-gamma-induced effects, thus suggesting its potential role in the regulation of inflammatory skin disorders.
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Affiliation(s)
- M Detmar
- Department of Dermatology, University Medical Center Steglitz, Free University of Berlin
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Cuvelier C, Mielants H, De Vos M, Veys E, Roels H. Major histocompatibility complex class II antigen (HLA-DR) expression by ileal epithelial cells in patients with seronegative spondylarthropathy. Gut 1990; 31:545-9. [PMID: 2351304 PMCID: PMC1378571 DOI: 10.1136/gut.31.5.545] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Major histocompatibility complex molecules act as non-specific receptors for antigenic proteins and present them to T-cells. Presented antigen together with class II molecules activates antigen specific T-helper cells and may trigger a cellular immune response. The expression of HLA-DR antigens by epithelial cells was examined with an indirect peroxidase technique in ileal biopsies from 38 patients with seronegative spondylarthropathy and features of acute or chronic gut inflammation on biopsy, 14 patients with chronic inflammatory bowel disease, 10 rheumatic and 10 non-rheumatic controls. In acute ileitis, there was more HLA-DR expression in villous and crypt epithelial cells than in non-inflamed controls (p less than 0.01). In chronic inflammation and in chronic inflammatory bowel disease, class II antigens were more expressed in villus (p less than 0.02) and crypt epithelium (p less than 0.01). Strong HLA-DR expression in crypt epithelial cells was connected with active inflammation (p less than 0.02). These findings suggest binding of unknown enterobacterial or nutritional luminal antigens to HLA-DR antigens normally present in enterocytes. The enterocytes act as antigen presenting cells causing a local increase of targets for activated T-cells and trigger the gut inflammation responsible for the clinical symptoms of the seronegative spondylarthropathy.
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Affiliation(s)
- C Cuvelier
- Department of Pathology, University Hospital, Ghent, Belgium
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50
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Franco A, Barnaba V, Ruberti G, Benvenuto R, Balsano C, Musca A. Liver-derived T cell clones in autoimmune chronic active hepatitis: accessory cell function of hepatocytes expressing class II major histocompatibility complex molecules. CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY 1990; 54:382-94. [PMID: 2302841 DOI: 10.1016/0090-1229(90)90052-r] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Thirty T cell clones were generated from T cell blasts, infiltrating the liver of autoimmune chronic active hepatitis (CAH) patients, stimulated with autologous hepatocytes expressing class II major histocompatibility complex (MHC) molecules and interleukin 2 (IL2). Sixteen clones were CD4+ and 14 were CD8+; all were CD25+ and WT31+, revealing that all cell lines expressed the alpha/beta chains of T cell receptor. Five CD4+ and 4 CD8+ T clones proliferated in response to hepatocytes expressing both class I and class II antigens. The hepatocyte recognition was MHC restricted because only class II MHC-matched hepatocytes were able to stimulate the CD4+ T clones, while only class I-matched hepatocytes stimulated CD8+ T clones, and because MoAbs to monomorphic determinants of class II antigens or to class I antigens appeared to block the response of the CD4+ and CD8+ T clones, respectively. These findings, together with the observation that autologous irradiated peripheral blood mononuclear cells (iPBMC) were unable to stimulate the clones, indicate that the response of these clones was directed to a liver membrane antigen in association with class II or class I MHC molecules on the surface of the hepatocytes. All the CD8+ T clones and 5 CD4+ T clones expressed high cytotoxic activity in a lectin-dependent cell-mediated cytotoxicity assay; 10 CD8+ and 3 CD4+ T clones also showed natural killer (NK)-like function. The cytolytic machinery was also present in those clones (both CD8 and CD4) recognizing the HLA-matched hepatocytes. All liver-derived T clones were able to produce high amounts of interferon (IFN)-gamma, as well as being capable of secreting IL2, following PHA stimulation.
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Affiliation(s)
- A Franco
- Fondazione Andrea Cesalpino, Università La Sapienza, Roma, Italy
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