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Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury. Biomed Pharmacother 2018; 103:1127-1136. [DOI: 10.1016/j.biopha.2018.04.169] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 04/20/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
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Tsuruhara A, Aso K, Tokuhara D, Ohori J, Kawabata M, Kurono Y, McGhee JR, Fujihashi K. Rejuvenation of mucosal immunosenescence by adipose tissue-derived mesenchymal stem cells. Int Immunol 2017; 29:5-10. [PMID: 28391291 DOI: 10.1093/intimm/dxx001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 01/05/2017] [Indexed: 02/07/2023] Open
Abstract
Age-associated alterations in the mucosal immune system are generally termed mucosal immunosenescence. The major change seen in the aged mucosa is a failure to elicit an antigen-specific secretory IgA (SIgA) antibody response, which is a central player for host defense from various pathogens at mucosal surfaces. In this regard, it would be a first priority to compensate for mucosal dysregulation in the elderly in order to maintain their health in aging. We have successfully established antigen-specific SIgA antibody responses in aged (2 years old) mice, which provide protective immunity from Streptococcus pneumoniae and influenza virus infections, by using a new adjuvant system consisting of a plasmid encoding Flt3 ligand (pFL) and CpG ODN. In order to explore possible use of current mucosal vaccine strategies for the elderly, we have adoptively transferred adipose tissue-derived mesenchymal stem cells (AMSCs) to aged mice prior to mucosal vaccination. This immune therapy successfully resulted in protective antigen-specific antibody responses in the intestinal mucosa of aged mice that were comparable to those seen in young adult mice. In this regard, we postulate that adoptively transferred AMSCs could augment dendritic cell functions in aged mice. The potential cellular and molecular mechanisms whereby AMSCs restore mucosal immunity in immunosenescence are discussed in this short review. A stem cell transfer system could be an attractive and effective immunologic intervention strategy to reverse mucosal immunosenescence.
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Affiliation(s)
- Akitoshi Tsuruhara
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, 1919 7th Avenue South, SDB 801 A1, Birmingham, AL 35294-0007, USA
| | - Kazuyoshi Aso
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, 1919 7th Avenue South, SDB 801 A1, Birmingham, AL 35294-0007, USA.,Department of Pediatrics, Graduate School of Medicine, Osaka City University, Asahi-cho 1-5-7, Abeno-ku, Osaka, Osaka 545-0051, Japan
| | - Daisuke Tokuhara
- Department of Pediatrics, Graduate School of Medicine, Osaka City University, Asahi-cho 1-5-7, Abeno-ku, Osaka, Osaka 545-0051, Japan
| | - Junichiro Ohori
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, 1919 7th Avenue South, SDB 801 A1, Birmingham, AL 35294-0007, USA.,Department of Otolaryngology, Kagoshima University Faculty of Medicine, Sakuragaoka 8-35-1, Kagoshima, Kagoshima 890-8520, Japan
| | - Masaki Kawabata
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, 1919 7th Avenue South, SDB 801 A1, Birmingham, AL 35294-0007, USA.,Department of Otolaryngology, Kagoshima University Faculty of Medicine, Sakuragaoka 8-35-1, Kagoshima, Kagoshima 890-8520, Japan
| | - Yuichi Kurono
- Department of Otolaryngology, Kagoshima University Faculty of Medicine, Sakuragaoka 8-35-1, Kagoshima, Kagoshima 890-8520, Japan
| | - Jerry R McGhee
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, 1919 7th Avenue South, SDB 801 A1, Birmingham, AL 35294-0007, USA
| | - Kohtaro Fujihashi
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, 1919 7th Avenue South, SDB 801 A1, Birmingham, AL 35294-0007, USA
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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Aso K, Tsuruhara A, Takagaki K, Oki K, Ota M, Nose Y, Tanemura H, Urushihata N, Sasanuma J, Sano M, Hirano A, Aso R, McGhee JR, Fujihashi K. Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice. PLoS One 2016; 11:e0148185. [PMID: 26840058 PMCID: PMC4740412 DOI: 10.1371/journal.pone.0148185] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/14/2016] [Indexed: 12/29/2022] Open
Abstract
It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old) mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA) plus cholera toxin (CT) three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA) and plasma IgG antibody (Ab) responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer's patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice.
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Affiliation(s)
- Kazuyoshi Aso
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Akitoshi Tsuruhara
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, United States of America
| | | | | | - Megumi Ota
- BioMimetics Sympathies Inc., Tokyo, Japan
| | | | | | | | - Jinichi Sasanuma
- Department of Neurosurgery, Shinyurigaoka General Hospital, Kawasaki, Japan
| | | | | | - Rio Aso
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Jerry R. McGhee
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Kohtaro Fujihashi
- Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, United States of America
- * E-mail:
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Peloso A, Katari R, Murphy SV, Zambon JP, DeFrancesco A, Farney AC, Rogers J, Stratta RJ, Manzia TM, Orlando G. Prospect for kidney bioengineering: shortcomings of the status quo. Expert Opin Biol Ther 2015; 15:547-58. [PMID: 25640286 DOI: 10.1517/14712598.2015.993376] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Dialysis and renal transplantation are the only two therapeutic options offered to patients affected by end-stage kidney disease; however, neither treatment can be considered definitive. In fact, dialysis is able to replace only the filtration function of the kidney without substituting its endocrine and metabolic roles, and dramatically impacts on patient's quality of life. On the other hand, kidney transplantation is severely limited by the shortage of transplantable organs, the need for immunosuppressive therapies and a narrow half-life. Regenerative medicine approaches are promising tools aiming to improve this condition. AREAS COVERED Cell therapies, bioartificial kidney, organ bioengineering, 3D printer and kidney-on-chip represent the most appealing areas of research for the treatment of end-stage kidney failure. The scope of this review is to summarize the state of the art, limits and directions of each branch. EXPERT OPINION In the future, these emerging technologies could provide definitive, curative and theoretically infinite options for the treatment of end-stage kidney disease. Progress in stem cells-based therapies, decellularization techniques and the more recent scientific know-how for the use of the 3D printer and kidney-on-chip could lead to a perfect cellular-based therapy, the futuristic creation of a bioengineered kidney in the lab or to a valid bioartificial alternative.
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Affiliation(s)
- Andrea Peloso
- Wake Forest School of Medicine , Winston-Salem, NC , USA
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Lv Y, Xu X, Zhang B, Zhou G, Li H, Du C, Han H, Wang H. Endometrial regenerative cells as a novel cell therapy attenuate experimental colitis in mice. J Transl Med 2014; 12:344. [PMID: 25475342 PMCID: PMC4269937 DOI: 10.1186/s12967-014-0344-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 11/24/2014] [Indexed: 12/16/2022] Open
Abstract
Background Endometrial regenerative cells (ERCs) are mesenchymal-like stem cells that can be non-invasively obtained from menstrual blood and are easily grown /generated at a large scale without tumorigenesis. We previously reported that ERCs exhibit unique immunoregulatory properties in vitro, however their immunosuppressive potential in protecting the colon from colitis has not been investigated. The present study was undertaken to determine the efficacy of ERCs in mediating immunomodulatory functions against colitis. Methods Colitis was induced by 4% dextran-sulfate-sodium (DSS, in drinking water) in BALB/c mice for 7 days. ERCs were cultured from healthy female menstrual blood, and injected (1 million/mouse/day, i.v.) into mice on days 2, 5, and 8 following colitis induction. Colonic and splenic tissues were collected on day 14 post-DSS-induction. Clinical signs, disease activity index (DAI), pathological and immunohistological changes, cytokine profiles and cell populations were evaluated. Results DSS-induced mice in untreated group developed severe colitis, characterized by body-weight loss, bloody stool, diarrhea, mucosal ulceration and colon shortening, as well as pathological changes of intra-colon cell infiltrations of neutrophils and Mac-1 positive cells. Notably, ERCs attenuated colitis with significantly reduced DAI, decreased levels of intra-colon IL-2 and TNF-α, but increased expressions of IL-4 and IL-10. Compared with those of untreated colitis mice, splenic dendritic cells isolated from ERC-treated mice exhibited significantly decreased MHC-II expression. ERC-treated mice also demonstrated much less CD3+CD25+ active T cell and CD3+CD8+ T cell population and significantly higher level of CD4+CD25+Foxp3+ Treg cells. Conclusions This study demonstrated novel anti-inflammatory and immunosuppressive effects of ERCs in attenuating colitis in mice, and suggested that the unique features of ERCs make them a promising therapeutic tool for the treatment of ulcerative colitis.
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Affiliation(s)
- Yongcheng Lv
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| | - Xiaoxi Xu
- Tianjin General Surgery Institute, Tianjin, China.
| | - Bai Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| | | | - Hongyue Li
- Tianjin General Surgery Institute, Tianjin, China.
| | - Caigan Du
- Department of Urologic Sciences, The University of British Columbia, Vancouver, BC, Canada. .,Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
| | - Hongqiu Han
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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Chen T, Cao Q, Wang Y, Harris D. The Role of Dendritic Cells in Renal Inflammation. CURRENT PATHOBIOLOGY REPORTS 2014. [DOI: 10.1007/s40139-014-0059-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Rogers NM, Ferenbach DA, Isenberg JS, Thomson AW, Hughes J. Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat Rev Nephrol 2014; 10:625-43. [PMID: 25266210 PMCID: PMC4922410 DOI: 10.1038/nrneph.2014.170] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Renal dendritic cells (DCs) and macrophages represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune-intelligence activity; they induce and regulate inflammatory responses to freely filtered antigenic material and protect the kidney from infection. Tissue-resident or infiltrating DCs and macrophages are key factors in the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration, regardless of the aetiological and pathogenetic mechanisms. The identification, and functional and phenotypic distinction of these cell types is complex and incompletely understood, and the same is true of their interplay and relationships with effector and regulatory cells of the adaptive immune system. In this Review, we discuss the common and distinct characteristics of DCs and macrophages, as well as key advances that have identified the renal-specific functions of these important phagocytic, antigen-presenting cells, and their roles in potentiating or mitigating intrinsic kidney disease. We also identify remaining issues that are of priority for further investigation, and highlight the prospects for translational and therapeutic application of the knowledge acquired.
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Affiliation(s)
- Natasha M Rogers
- Vascular Medicine Institute and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - David A Ferenbach
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Jeffrey S Isenberg
- Vascular Medicine Institute and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Angus W Thomson
- Vascular Medicine Institute and Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA
| | - Jeremy Hughes
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
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Liu P, Feng Y, Wang Y, Zhou Y. Therapeutic action of bone marrow-derived stem cells against acute kidney injury. Life Sci 2014; 115:1-7. [PMID: 25219881 DOI: 10.1016/j.lfs.2014.08.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 09/02/2014] [Accepted: 08/20/2014] [Indexed: 12/20/2022]
Abstract
Acute kidney injury (AKI) is a frequent clinical disease with a high morbidity rate and mortality rate, while the treatment options for this intractable disease are limited currently. In recent years, bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to hold an effect therapeutic action against AKI by scientists gradually, and the cells are capable to localize to renal compartments and contribute to kidney regeneration though differentiation or paracrine action. Especially, the advantages of BMSCs, such as low toxicity and side effect as well as autologous transplantation, endue the cell with a promising potential in clinical therapy against AKI. In this review, we mainly provide a concise overview of the application of BMSCs in the treatment of AKI, and summarize a series of published data regarding the mechanisms and optimizations of the BMSC-based therapy in renal repair after AKI. Even though some critical points about the BMSC-based therapy model still need clarification, we hope to develop more reliable pharmacological or biotechnical strategies utilizing the stem cell for the eventual treatment of humans with AKI, based on these studies and the understanding of mechanism of renal protection by BMSCs.
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Affiliation(s)
- Pengfei Liu
- Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China; Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China
| | - Yetong Feng
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P.R. China
| | - Yi Wang
- Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China.
| | - Yulai Zhou
- Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China.
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The regulation of inflammatory mediators in acute kidney injury via exogenous mesenchymal stem cells. Mediators Inflamm 2014; 2014:261697. [PMID: 24839354 PMCID: PMC4009277 DOI: 10.1155/2014/261697] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/07/2014] [Accepted: 03/20/2014] [Indexed: 12/31/2022] Open
Abstract
Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is believed to play a major role in the pathophysiology of AKI. Exogenous mesenchymal stem cells (MSCs) are now under extensive investigation as a potential therapy for AKI. Various preclinical studies indicated the beneficial effects of MSCs in alleviating renal injury and accelerating tissue repair. However the mechanisms responsible for these effects are incompletely understood. In the recent years, anti-inflammatory/immunoregulatory properties of MSCs have become one of the important issues in the treatment of AKI. This review will summarize the current literature on the regulation of inflammatory mediators via exogenous MSCs contributing to the recovery from AKI.
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Bedi B, McNair NN, Mead JR. Dendritic cells play a role in host susceptibility to Cryptosporidium parvum infection. Immunol Lett 2013; 158:42-51. [PMID: 24295591 DOI: 10.1016/j.imlet.2013.11.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 11/07/2013] [Accepted: 11/21/2013] [Indexed: 01/08/2023]
Abstract
Our previous studies have described dendritic cells (DCs) to be important sources of Th1 cytokines such as IL-12 and IL-2 in vitro, following stimulation with Cryptosporidium parvum antigens. We further established the role of DCs during cryptosporidiosis using a diphtheria toxin promoter regulated transgenic CD11c-DTR/EGFP mouse model. In vivo depletion of CD11c(+) cells in CD11c-DTR-Tg mice significantly increased susceptibility to C. parvum infection. Adoptive transfer of unstimulated or antigen stimulated DCs into CD11c(+) depleted CD11c-DTR-Tg mice resulted in an early decrease in parasite load at 4 days post infection. However, this response was transient since parasite load increased in mice engrafted with either unstimulated DCs or DCs stimulated with solubilized antigen by 6 days post infection. In contrast, in mice engrafted with DCs stimulated with live sporozoites, parasite load remained low during the entire period, suggesting the development of a more effective and sustained response. A corresponding increase in IFN-γ expression in T cells from spleen and mesenteric lymph nodes was also noted. Consistent with the in vivo engraftment study, DCs that are pulsed with live sporozoites in vitro and co-cultured with CD4(+) and CD8(+) T cells produced higher IFN-γ levels. Our study establishes the importance of DCs in susceptibility to infection by C. parvum and as important mediators of immune responses.
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Affiliation(s)
- Brahmchetna Bedi
- Atlanta VA Medical Center, Decatur, GA 30033, United States; Department of Pediatrics, Emory University, Atlanta, GA 30322, United States
| | - Nina N McNair
- Department of Pediatrics, Emory University, Atlanta, GA 30322, United States
| | - Jan R Mead
- Atlanta VA Medical Center, Decatur, GA 30033, United States; Department of Pediatrics, Emory University, Atlanta, GA 30322, United States.
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