• Cytokine production
• Dendritic cells
• Immune regulation
• Sema-3E and PlexinD1
• Therapeutic potential

• Dendritic Cells/immunology
• Humans
• Semaphorins/metabolism
• Semaphorins/immunology
• Animals
• Signal Transduction
• Phenotype
• Antigen Presentation
• Cell Differentiation/immunology
• Nerve Tissue Proteins/metabolism
• Nerve Tissue Proteins/immunology
• Nerve Tissue Proteins/genetics
• Immunomodulation
• Cytokines/metabolism
• Membrane Glycoproteins
• Intracellular Signaling Peptides and Proteins

• integrin
• plasmacytoid dendritic cell
• toll-like receptor
• type i interferon
• sle

• Animals
• Mice
• Dendritic Cells/immunology
• Integrin alphaVbeta3/immunology
• Integrin alphaVbeta3/metabolism
• Autoimmunity/immunology
• Mice, Knockout
• Toll-Like Receptor 7/immunology
• Toll-Like Receptor 7/metabolism
• Toll-Like Receptor 7/genetics
• Lupus Erythematosus, Systemic/immunology
• Signal Transduction/immunology
• Mice, Inbred C57BL
• Cytokines/metabolism
• Cytokines/immunology
• Toll-Like Receptor 9/immunology
• Toll-Like Receptor 9/metabolism
• B-Lymphocytes/immunology
• Autoantibodies/immunology
• Membrane Glycoproteins/immunology
• Membrane Glycoproteins/metabolism
• Lymphocyte Activation/immunology
• Disease Models, Animal

• R56AI148785 HHS | National Institutes of Health (NIH)
• T32 AI106677 NIAID NIH HHS
• R56 AI148785 NIAID NIH HHS
• R01 AI150178 NIAID NIH HHS
• 4T32AI106677-05 HHS | National Institutes of Health (NIH)

• Treg differentiation
• antigen cross-presentation
• apoptotic cell
• dendritic cell
• efferocytosis
• immune regulation

• Dendritic Cells/immunology
• Humans
• Phagocytosis/immunology
• Animals
• Macrophages/immunology
• Apoptosis/immunology
• Immune Tolerance
• Efferocytosis

Tumour onset and development occur because of specific immune support. The immune system, which is originally able to perceive and eliminate incipient cancer cells, becomes suppressed and hijacked by cancer. For these purposes, tumour cells use extracellular vesicles (TEVs). Specific molecular composition allows TEVs to reprogram immune cells towards tumour tolerance. Circulating TEVs move from their site of origin to other organs, preparing “a fertile soil” for metastasis formation. This implies that TEV molecular content can provide a valuable tool for cancer biomarker discovery and potential targets to reshape the immune system into tumour recognition and eradication.

Control of the immune response is crucial for tumour onset and progression. Tumour cells handle the immune reaction by means of secreted factors and extracellular vesicles (EV). Tumour-derived extracellular vesicles (TEV) play key roles in immune reprogramming by delivering their cargo to different immune cells. Tumour-surrounding tissues also contribute to tumour immune editing and evasion, tumour progression, and drug resistance via locally released TEV. Moreover, the increase in circulating TEV has suggested their underpinning role in tumour dissemination. This review brings together data referring to TEV-driven immune regulation and antitumour immune suppression. Attention was also dedicated to TEV-mediated drug resistance.

• cell-to-cell communication
• exosomes
• extracellular vesicles
• tumour antigens
• tumour immune editing
• tumour immune suppression

Vitamin D3 (VD3) is a potential adjuvant for use in tolerogenic vaccine formulations that target dendritic cells (DCs) for the treatment of chronic inflammatory disorders, e.g., autoimmune diseases. These disorders are often associated with enhanced activity of IL-17-producing T helper 17 (Th17) cells which develop in a DC-driven and neutrophil-dependent fashion. Here, we investigated the effect of VD3 on Candida albicans-specific human T-cell differentiation, since C. albicans is a model pathogen for Th17 cell development. VD3 priming of DCs restricted neutrophil-dependent Th17 cell development and neutrophil-independent Th1 cell formation from naive CD4⁺ T cells. In line with this, the production of Th1/Th17-polarizing cytokines IL-12 and IL-23 by DCs was reduced by VD3 priming. Development of both FoxP3⁺CD127_lowCD25⁺ Tregs and IL-10-producing T cells was significantly enhanced in VD3-primed conditions, even in the presence of neutrophils. ICOS⁺ Tregs, major IL-10 producers, CD69⁺FoxP3⁺, and TIGIT⁺FoxP3⁺ Tregs were significantly induced by VD3 priming as well. Our data support the potential use of VD3 as an adjuvant to induce tolerance in the treatment of autoimmune disorders, including those in which neutrophils are involved in pathogenesis, since we show that Treg development is enhanced by VD3 even in the presence of neutrophils, while Th17 cell development is restricted.

• Autoimmune Diseases/metabolism
• Cholecalciferol/metabolism
• Cholecalciferol/pharmacology
• Dendritic Cells
• Forkhead Transcription Factors/metabolism
• Humans
• Interleukin-10
• Neutrophils
• T-Lymphocytes, Regulatory
• Th17 Cells

The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A distinct characteristic of ICD is the release of danger-associated molecular patterns (DAMPs) by dying and/or dead cells. Thus, several members of the DAMP family, such as the well-characterized heat shock proteins (HSPs) HSP70 and HSP90, the high-mobility group box 1 protein and calreticulin, and the thymic polypeptide prothymosin α (proTα) and its immunoreactive fragment proTα(100–109), are being studied as potential diagnostic tools and/or possible therapeutic agents. Here, we present the basic aspects and mechanisms of both ICD and other immunogenic RCD forms; denote the role of DAMPs in ICD; and further exploit the relevance of human proTα and proTα(100–109) in ICD, highlighting their possible clinical applications. Furthermore, we present the preliminary results of our in vitro studies, which show a direct correlation between the concentration of proTα/proTα(100–109) and the levels of cancer cell apoptosis, induced by anticancer agents and γ-radiation.

Neutrophils are involved in the initial host responses to pathogens. Neutrophils can activate T cell responses either independently or through indirect involvement of Dendritic cells (DCs). Recently we have demonstrated direct neutrophil-T cell interactions that initiate adaptive immune responses following immunization with live attenuated Leishmania donovani centrin deleted parasite vaccine (LdCen^-/-). However, neutrophil-DC interactions in T cell priming in vaccine immunity in general are not known. In this study we evaluated the interaction between neutrophils and DCs during LdCen^-/- infection and compared with wild type parasite (LdWT) both in vitro and in vivo.

LdCen^-/- parasite induced increased expression of CCL3 in neutrophils caused higher recruitment of DCs capable of inducing a strong proinflammatory response and elevated co-stimulatory molecule expression compared to LdWT infection. To further illustrate neutrophil-DCs interactions in vivo, we infected LYS-eGFP mice with red fluorescent LdWT/LdCen^-/- parasites and sort selected DCs that engulfed the neutrophil containing parasites or DCs that acquired the parasites directly in the ear draining lymph nodes (dLN) 5d post infection. The DCs predominantly acquired the parasites by phagocytosing infected neutrophils. Specifically, DCs containing LdCen^-/- parasitized neutrophils exhibited a proinflammatory phenotype, increased expression of costimulatory molecules and initiated higher CD4⁺T cell priming ex-vivo. Notably, potent DC activation occurred when LdCen^-/- parasites were acquired indirectly via engulfment of parasitized neutrophils compared to direct engulfment of LdCen^-/- parasites by DCs. Neutrophil depletion in LdCen^-/- infected mice significantly abrogated expression of CCL3 resulting in decreased DC recruitment in ear dLN. This event led to poor CD4⁺Th1 cell priming ex vivo that correlated with attenuated Tbet expression in ear dLN derived CD4⁺ T cells in vivo.

Collectively, LdCen^-/- containing neutrophils phagocytized by DC markedly influence the phenotype and antigen presenting capacity of DCs early on and thus play an immune-regulatory role in shaping vaccine induced host protective response.

Visceral Leishmaniasis (VL), caused by the protozoan parasites of the genus Leishmania is a neglected tropical disease. Leishmania donovani is the principal causative agent of VL in East Africa and the Indian subcontinent whereas in Europe, North Africa, and Latin America VL is mainly caused by Leishmania infantum. No licensed vaccine exists against VL. We have reported previously that live attenuated centrin gene-deleted L. donovani (LdCen^-/-) parasite vaccine induced strong innate immunity which leads to a protective Th1 response in animal models. We recently demonstrated that neutrophils play an indispensable role following immunization with LdCen^-/- parasites in inducing protective Th1 immune response. However, neutrophils also secrete chemokines that attract other innate cells such as dendritic cells and regulate their activities. In the current study we analyzed the interplay between neutrophils and DCs, and its effects on T cell activation during LdCen^-/- infection and compared with wild type parasite (LdWT) infection. We observed that higher recruitment of DCs occurred in LdCen^-/- infected mice ear draining lymph nodes compared to LdWT. This recruitment is facilitated by increased secretion of the chemokine CCL3 by neutrophils. A markedly decreased DC recruitment was observed in LdCen^-/- infected mice following CCL3 neutralization indicating the key role of neutrophils in DC recruitment. Further, we demonstrated that DCs that ingest LdCen^-/- infected neutrophils are better activated than those that acquire the parasites independent of neutrophils. Notably neutrophil depletion in LdCen^-/- infected mice also attenuated activation of DCs in the ear dLN that resulted in poor CD4⁺T cell priming. Our results reveal that interaction between neutrophils and DCs play an important role in shaping proinflammatory immune response induced by a live attenuated Leishmania vaccine.

• Animals
• Cell Communication
• Dendritic Cells
• Leishmania donovani/physiology
• Leishmaniasis Vaccines
• Leishmaniasis, Visceral/parasitology
• Mice
• Neutrophils
• Vaccines, Attenuated

• U.S. Food and Drug Administration

The clearance of apoptotic cells is known to be a critical step in maintaining tissue and organism homeostasis. This process is rapidly/promptly mediated by recruited or resident phagocytes. Phagocytes that engulf apoptotic cells have been closely linked to the release of anti-inflammatory cytokines to eliminate inflammatory responses. Defective clearance of apoptotic cells can cause severe inflammation and autoimmune responses due to secondary necrosis of apoptotic cells. Recently accumulated evidence indicates that apoptotic cells and their clearance have important physiological roles in addition to immune-related functions. Herein, we review the current understanding of the mechanisms and fundamental roles of apoptotic cell clearance and the beneficial roles of apoptotic cells in physiological processes such as differentiation and development.

• apoptosis
• apoptotic cell clearance
• development
• differentiation
• inflammation
• phagocyte

• EDCI-SP
• apoptosis
• cell-based therapies
• tolerance
• transplantation

In the mammalian gut CD103+ve myeloid DCs are known to suppress inflammation threatened by luminal bacteria, but stimuli driving DC precursor maturation towards this beneficial phenotype are incompletely understood. We isolated CD11+ve DCs from mesenteric lymph nodes (MLNs) of healthy mice; CD103+ve DCs were 8–24 fold more likely than CD103-ve DCs to exhibit extensive of prior phagocytosis of apoptotic intestinal epithelial cells. However, CD103+ve and CD103-ve MLN DCs exhibited similar ex vivo capacity to ingest apoptotic cells, indicating that apoptotic cells might drive immature DC maturation towards the CD103+ve phenotype. When cultured with apoptotic cells, myeloid DC precursors isolated from murine bone marrow and characterised as lineage-ve CD103-ve, displayed enhanced expression of CD103 and β8 integrin and acquired increased capacity to induce T regulatory lymphocytes (Tregs) after 7d in vitro. However, DC precursors isolated from α_v-tie2 mice lacking α_v integrins in the myeloid line exhibited reduced binding of apoptotic cells and complete deficiency in the capacity of apoptotic cells and/or latent TGF-β1 to enhance CD103 expression in culture, whereas active TGF-β1 increased DC precursor CD103 expression irrespective of α_v expression. Fluorescence microscopy revealed clustering of α_v integrin chains and latent TGF-β1 at points of contact between DC precursors and apoptotic cells. We conclude that myeloid DC precursors can deploy α_v integrin to orchestrate binding of apoptotic cells, activation of latent TGF-β1 and acquisition of the immunoregulatory CD103+ve β8+ve DC phenotype. This implies that a hitherto unrecognised consequence of apoptotic cell interaction with myeloid phagocytes is programming that prevents inflammation.

• Animals
• Antigens, CD/metabolism
• Apoptosis
• Dendritic Cells/cytology
• Dendritic Cells/immunology
• Dendritic Cells/metabolism
• Female
• Gene Expression Regulation
• Immunomodulation
• Integrin alpha Chains/metabolism
• Integrin alphaV/metabolism
• Mice, Inbred C57BL
• Myeloid Cells/cytology
• Phagocytosis
• T-Lymphocytes, Regulatory/immunology
• Transforming Growth Factor beta1/metabolism

• G0802069 Medical Research Council
• U19 AI125378 NIAID NIH HHS
• Medical Research Council United Kingdom
• National Institutes of Health

Intratracheal instillation of apoptotic cells enhances resolution of experimental lung inflammation by incompletely understood mechanisms. We report that this intervention induces functional regulatory T lymphocytes (Tregs) in mouse lung experimentally inflamed by intratracheal administration of lipopolysaccharide. Selective depletion demonstrated that Tregs were necessary for maximal apoptotic cell–directed enhancement of resolution, and adoptive transfer of additional Tregs was sufficient to promote resolution without administering apoptotic cells. After intratracheal instillation, labeled apoptotic cells were observed in most CD11c⁺CD103⁺ myeloid dendritic cells migrating to mediastinal draining lymph nodes and bearing migratory and immunoregulatory markers, including increased CCR7 and β8 integrin (ITGB8) expression. In mice deleted for αv integrin in the myeloid line to reduce phagocytosis of dying cells by CD103⁺ dendritic cells, exogenous apoptotic cells failed to induce transforming growth factor-β1 expression or Treg accumulation and failed to enhance resolution of lipopolysaccharide-induced lung inflammation. We conclude that in murine lung, myeloid phagocytes encountering apoptotic cells can deploy αv integrin–mediated mechanisms to induce Tregs and enhance resolution of acute inflammation.

• C-type lectin
• T cell priming
• apoptotic extracellular vesicles
• cancer vaccine
• dendritic cell
• glycan modification

• CD80
• CTLA-4
• apoptosis
• autoimmunity
• coinhibitory pathway
• costimulatory pathway
• immune evasion
• immunotolerance

• APC
• ECP
• GVHD
• PD-L1
• extracorporeal photopheresis

• DC
• cancer combination therapies
• cancer vaccines
• human dendritic cells
• mo-DC
• monocyte-derived dendritic cells

• Atherosclerosis
• Dendritic cells
• Immune tolerance
• Selectins

• Animals
• Antigen Presentation
• Cells, Cultured
• Female
• Forkhead Transcription Factors/metabolism
• Humans
• Immune Tolerance
• Immunity, Mucosal
• Lactation
• Mammary Glands, Animal/physiology
• Mammary Glands, Human/physiology
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
• Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
• T-Lymphocytes, Regulatory/immunology

• F31 CA196052 NCI NIH HHS
• P30 CA076292 NCI NIH HHS
• R01 CA169175 NCI NIH HHS

Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulated by a balance of costimulatory signaling (mediated by the costimulatory receptor CD28 on T cells) and coinhibitory signaling (mediated by the coinhibitory ligands CD80 and PD-L1 and -2 on Antigen-Presenting Cells). Here, we found that ACs specifically upregulated the coinhibitory ligand CD80 on macrophages. Conversely, ACs did not exhibit a robust regulation of the other coinhibitory ligands on macrophages or the costimulatory receptor CD28 on T cells. We show that the robust positive regulation of CD80 by ACs requires phagocytosis of ACs by macrophages. We also demonstrate that CD80 modulation by dead cells is a specific effect of ACs, but not necrotic cells (which stimulate immune responses). These results indicate that ACs modulate the coinhibitory pathway of T cell activation via CD80, and suggest a role for CD80 in suppressing T cell responses by ACs. Understanding a mechanism of regulating adaptive immune responses to ACs, which harbor an abundance of self-antigens, may advance our understanding of mechanisms of regulating autoimmunity and facilitate future therapy development for autoimmune disorders.

• Immune tolerance
• Molecular biomarkers
• Regulatory T cells
• Regulatory dendritic cells
• Tolerant footprint

Massive turnover of cells occurs through apoptosis during the constant remodeling of our tissues at homeostasis, from the shedding of cells at exposed barrier surfaces to the elimination of autoreactive lymphocytes. However, a surge of apoptotic cells also accompanies tissue damage, infection, and inflammation. A salient feature of apoptosis in either scenario is the exposure of phosphatidylserine (PtdSer) on the outer leaflet of the plasma membrane. In response to this cue, a range of phagocytes are charged with the sizeable task of engulfing apoptotic bodies and disposing of the billions of cells that perish each day. The presence of apoptotic cells in the remarkably distinct immunological settings described above, therefore, raises the question of how phagocytes are able to coordinate appropriate responses to apoptotic cells—from their silent removal to the production of growth factors or tissue repair molecules—following such a ubiquitous signal as PtdSer exposure. Here, we consider several emergent properties of phagocytes and apoptotic cell clearance that may facilitate specification among this suite of potential responses.

• apoptosis
• homeostasis
• phagocytic receptors
• signal integration
• tissue repair

Inefficient and abnormal clearance of apoptotic cells (efferocytosis) contributes to systemic autoimmune disease in humans and mice, and inefficient chromosomal DNA degradation by DNAse II leads to systemic polyarthritis and a cytokine storm. By contrast, efficient clearance allows immune homeostasis, generally leads to a non-inflammatory state for both macrophages and dendritic cells (DCs), and contributes to maintenance of peripheral tolerance. As many as 3 × 10⁸ cells undergo apoptosis every hour in our bodies, and one of the primary “eat me” signals expressed by apoptotic cells is phosphatidylserine (PtdSer). Apoptotic cells themselves are major contributors to the “anti-inflammatory” nature of the engulfment process, some by secreting thrombospondin-1 (TSP-1) or adenosine monophosphate and possibly other immune modulating “calm-down” signals that interact with macrophages and DCs. Apoptotic cells also produce “find me” and “tolerate me” signals to attract and immune modulate macrophages and DCs that express specific receptors for some of these signals. Neither macrophages nor DCs are uniform, and each cell type may variably express membrane proteins that function as receptors for PtdSer or for opsonins like complement or opsonins that bind to PtdSer, such as protein S and growth arrest-specific 6. Macrophages and DCs also express scavenger receptors, CD36, and integrins that function via bridging molecules such as TSP-1 or milk fat globule-EGF factor 8 protein and that differentially engage in various multi-ligand interactions between apoptotic cells and phagocytes. In this review, we describe the anti-inflammatory and pro-homeostatic nature of apoptotic cell interaction with the immune system. We do not review some forms of immunogenic cell death. We summarize the known apoptotic cell signaling events in macrophages and DCs that are related to toll-like receptors, nuclear factor kappa B, inflammasome, the lipid-activated nuclear receptors, Tyro3, Axl, and Mertk receptors, as well as induction of signal transducer and activator of transcription 1 and suppressor of cytokine signaling that lead to immune system silencing and DC tolerance. These properties of apoptotic cells are the mechanisms that enable their successful use as therapeutic modalities in mice and humans in various autoimmune diseases, organ transplantation, graft-versus-host disease, and sepsis.

• TAM receptors
• clearance of apoptotic cells
• inflammasome
• lipid-activated nuclear receptors
• nuclear factor kappa B
• signal transducer and activator of transcription 1
• suppressor of cytokine signaling
• toll-like receptor

Neuropilins (NRPs) are non-tyrosine kinase cell surface glycoproteins expressed in all vertebrates and widely conserved across species. The two isoforms, such as neuropilin-1 (NRP1) and neuropilin-2 (NRP2), mainly act as coreceptors for class III Semaphorins and for members of the vascular endothelial growth factor family of molecules and are widely known for their role in a wide array of physiological processes, such as cardiovascular, neuronal development and patterning, angiogenesis, lymphangiogenesis, as well as various clinical disorders. Intriguingly, additional roles for NRPs occur with myeloid and lymphoid cells, in normal physiological as well as different pathological conditions, including cancer, immunological disorders, and bone diseases. However, little is known concerning the molecular pathways that govern these functions. In addition, NRP1 expression has been characterized in different immune cellular phenotypes including macrophages, dendritic cells, and T cell subsets, especially regulatory T cell populations. By contrast, the functions of NRP2 in immune cells are less well known. In this review, we briefly summarize the genomic organization, structure, and binding partners of the NRPs and extensively discuss the recent advances in their role and function in different immune cell subsets and their clinical implications.

• dendritic cells
• immune cells
• macrophages
• neuropilin-1
• neuropilin-2
• regulatory T cells
• tolerance

In the human body, billions of cells die by apoptosis every day. The subsequent clearance of apoptotic cells by phagocytosis is normally efficient enough to prevent secondary necrosis and the consequent release of cell contents that would induce inflammation and trigger autoimmunity. In addition, apoptotic cells generally induce an anti-inflammatory response, thus removal of apoptotic cells is usually immunologically silent. Since the first discovery that uptake of apoptotic cells leads to transforming growth factor (TGF)-β and interleukin (IL)-10 release by engulfing macrophages, numerous anti-inflammatory mechanisms triggered by apoptotic cells have been discovered, including release of anti-inflammatory molecules from the apoptotic cells, triggering immediate anti-inflammatory signaling pathways by apoptotic cell surface molecules via phagocyte receptors, activating phagocyte nuclear receptors following uptake and inducing the production of anti-inflammatory soluble mediators by phagocytes that may act via paracrine or autocrine mechanisms to amplify and preserve the anti-inflammatory state. Here, we summarize our present knowledge about how these anti-inflammatory mechanisms operate during the clearance of apoptotic cells.

• anti-inflammatory
• apoptotic cell
• phagocytosis
• phosphatidylserine
• pro-resolving lipid mediators

• Dendritic cell
• Experimental autoimmune encephalomyelitis
• Immune tolerance
• Multiple sclerosis

• Adaptive Immunity
• Animals
• Annexins/metabolism
• Antigen-Presenting Cells/cytology
• Antigen-Presenting Cells/immunology
• Antigen-Presenting Cells/metabolism
• Apoptosis
• Humans
• Phagocytosis

• apoptosis/autophagy
• autoimmunity
• dendritic cells
• monocytes/macrophages
• phagocytosis
• toll-like receptors/pattern recognition receptors

• Animals
• Apoptosis
• Atherosclerosis/immunology
• Cholesterol/metabolism
• Dendritic Cells/immunology
• Fatty Acids/metabolism
• Homeostasis
• Humans
• Immune Tolerance
• Inflammatory Bowel Diseases/immunology
• Lupus Erythematosus, Systemic
• Nucleotides/metabolism
• Phagocytes/physiology
• Phagocytosis

• P01 DK072201 NIDDK NIH HHS
• R01 AI123284 NIAID NIH HHS
• R01 AI127658 NIAID NIH HHS
• R01 DK111862 NIDDK NIH HHS

• Listeria monocytogenes
• apoptosis
• cell death
• immunotherapy
• inflammasome

Apoptotic cell-based therapies have been proposed to treat chronic inflammatory diseases. The aim of this study was to investigate the effect of intravenous (i.v.) apoptotic cell infusion in ongoing collagen-induced arthritis (CIA) and the interaction of this therapy with other treatments used in rheumatoid arthritis (RA), including methotrexate (MTX) or anti-TNF therapy.

The effects of i.v. apoptotic cell infusion were evaluated in a CIA mouse model in DBA/1 mice immunized with bovine type II collagen. The number and functions of antigen-presenting cells (APC), regulatory CD4⁺ T cells (Treg), and circulating anti-collagen auto-antibodies were analyzed in CIA mice.

Treatment of arthritic mice with i.v. apoptotic cell infusion significantly reduced the arthritis clinical score. This therapeutic approach modified T cell responses against the collagen auto-antigen with selective induction of collagen-specific Treg. In addition, we observed that APC from apoptotic-cell-treated animals were resistant to toll-like receptor ligand activation and favored ex vivo Treg induction, indicating APC reprogramming. Apoptotic cell injection-induced arthritis modulation was dependent on transforming growth factor (TGF)-β, as neutralizing anti-TGF-β antibody prevented the effects of apoptotic cells. Methotrexate did not interfere, while anti-TNF therapy was synergic with apoptotic-cell-based therapy.

Overall, our data demonstrate that apoptotic-cell-based therapy is efficient in treating ongoing CIA, compatible with current RA treatments, and needs to be evaluated in humans in the treatment of RA.

This study evaluates the ability of Lactobacillus rhamnosus GG (LGG) to activate DC and neutrophils and modulate T cell activation and the impact of bacterial dose on these responses. Murine bone marrow derived DC or neutrophils were stimulated with LGG at ratios of 5 : 1, 10 : 1, and 100 : 1 (LGG : cells) and DC maturation (CD40, CD80, CD86, CD83, and MHC class II) and cytokine production (IL-10, TNF-α, and IL-12p70) were examined after 2 h and 18 h coculture and compared to the ability of BCG (the present immunotherapeutic agent for bladder cancer) to stimulate these cells. A 2 h exposure to 100 : 1 (high dose) or an 18 h exposure to 5 : 1 or 10 : 1 (low dose), LGG : cells, induced the highest production of IL-12 and upregulation of CD40, CD80, CD86, and MHC II on DC. In DCs stimulated with LGG activated neutrophils IL-12 production decreased with increasing dose. LGG induced 10-fold greater IL-12 production than BCG. T cell IFNγ and IL-2 production was significantly greater when stimulated with DC activated with low dose LGG. In conclusion, DC or DC activated with neutrophils exposed to low dose LGG induced greater Th1 polarization in T cells and this could potentially exert stronger antitumor effects. Thus the dose of LGG used for immunotherapy could determine treatment efficacy.

• Drug delivery
• Imaging
• Immune response
• Leukocytes
• Liposomes
• Phagocytes
• Phosphatidylserine

• Animals
• Diagnostic Imaging
• Drug Carriers/administration & dosage
• Drug Therapy
• Humans
• Immunity, Innate
• Pharmaceutical Preparations/administration & dosage
• Phosphatidylserines/administration & dosage

• K01 DK099475 NIDDK NIH HHS
• 5 K01 DK099475 NIDDK NIH HHS

• Apoptotic cells
• Dendritic cells
• Graft versus host disease
• Immunological tolerance
• Transplantation

Neutrophils are the predominant recruited and infected cells during the early stages of Leishmania major infection in the skin, and depletion of neutrophils promotes immunity to infection transmitted by sand fly bite. In order to better understand how the acute neutrophilic response suppresses immunity, we assessed the consequences of the interaction between neutrophils recovered from the skin-inoculation site and bone marrow-derived dendritic cells (DCs) in vitro. The capture of infected, apoptotic neutrophils by the DCs completely inhibited their cross-presentation function that was dependent on engagement of the receptor tyrosine kinase Mer on the DCs. The capture of uninfected neutrophils, or neutrophils infected with Toxoplasma gondii, had only slight immunomodulatory effects. These studies define the clearance of infected, apoptotic neutrophils by DCs and Mer receptor signaling as central to the early immune evasion strategies of L. major, with relevance to other vector-borne pathogens delivered by bite to the skin.

• Autoimmune diseases
• Immune therapy
• Immune tolerance
• Innate immunity
• Regulatory dendritic cells

Leishmania spp. are intracellular parasitic protozoa responsible for a group of neglected tropical diseases, endemic in 98 countries around the world, called leishmaniasis. These parasites have a complex digenetic life cycle requiring a susceptible vertebrate host and a permissive insect vector, which allow their transmission. The clinical manifestations associated with leishmaniasis depend on complex interactions between the parasite and the host immune system. Consequently, leishmaniasis can be manifested as a self-healing cutaneous affliction or a visceral pathology, being the last one fatal in 85–90% of untreated cases. As a result of a long host–parasite co-evolutionary process, Leishmania spp. developed different immunomodulatory strategies that are essential for the establishment of infection. Only through deception and manipulation of the immune system, Leishmania spp. can complete its life cycle and survive. The understanding of the mechanisms associated with immune evasion and disease progression is essential for the development of novel therapies and vaccine approaches. Here, we revise how the parasite manipulates cell death and immune responses to survive and thrive in the shadow of the immune system.

• Leishmania
• acquired immunity
• apoptosis
• immunomodulation
• innate immunity

Immunosuppression therapy is the key to successful post-transplantation outcomes. The need for ideal immunosuppression became durable maintenance of long-term graft survival. In spite of current immunosuppressive therapy regimens advances, surgical procedures, and preservation methods, organ transplantation is associated with a long-term poor survival and significant mortality. This has led to an increased interest to optimize outcomes while minimizing associated toxicity by using alternative methods for maintenance immunosuppression, organ rejection treatment, and monitoring of immunosuppression. T regulatory (Treg) cells, which have immunosuppressive functions and cytokine profiles, have been studied during the last decades. Treg cells are able to inhibit the development of allergen-specific cell responses and consequently play a key role in a healthy immune response to allergens. Mature dendritic cells (DCs) play a crucial role in the differentiation of Tregs, which are known to regulate allergic inflammatory responses. Advance in long-standing allograft outcomes may depend on new drugs with novel mechanisms of action with minimal toxicity. Newer treatment techniques have been developed, including using novel stem cell-based therapies such as mesenchymal stem cells, phagosomes and exosomes. Immunoisolation techniques and salvage therapies, including photopheresis and total lymphoid irradiation have emerged as alternative therapeutic choices. The present review evaluates the recent clinical advances in immunosuppressive therapies for organ transplantation.

• exosomes
• immune rejection
• immunoisolation
• immunosuppression
• mesenchymal stem cells
• transplantation

• Apoptotic cells
• CD4+ T-cell responses
• Dendritic cells

• dendritic cell vaccination
• dendritic cell loading
• apoptotic tumor cells
• blebs
• t cell priming
• anti-tumor immunity

• Antigen Presentation
• Antigens, Neoplasm/immunology
• Antigens, Neoplasm/isolation & purification
• Apoptosis/drug effects
• Apoptosis/immunology
• Cancer Vaccines/immunology
• Cell Movement
• Cell-Derived Microparticles/immunology
• Cells, Cultured
• Dendritic Cells/immunology
• HL-60 Cells
• Humans
• Immunophenotyping
• Interferon-gamma Release Tests
• Leukemia, Promyelocytic, Acute/immunology
• Leukemia, Promyelocytic, Acute/pathology
• Lymphocyte Culture Test, Mixed
• Mitoxantrone/therapeutic use
• Monocytes/drug effects
• T-Lymphocyte Subsets/immunology
• T-Lymphocytes, Cytotoxic/immunology