vasoactive-intestinal-peptide and Graft-vs-Host-Disease

Vasoactive intestinal peptide (VIP) is a well-known immunoregulatory neuropeptide produced by the immune system in response to inflammation, autoimmunity or alloantigens as a natural endogenous mechanism of induction of tolerance. VIP has been proven therapeutically effective in various experimental models of autoimmune disorders and recently in human sarcoidosis. Numerous studies clearly show that VIP exerts its immunomodulatory effects by downregulating both inflammatory and Th1 responses. Recent evidences suggest that new actors enter in scene to play a role in this scenario of tolerance. By inducing antigen-specific regulatory T cells and tolerogenic dendritic cells, VIP seems to reinforce/reinstall immune tolerance, especially under autoimmune conditions. Transplantation is also a condition where VIP-related therapies emerge as promising tools for clinical application. Induction of alloantigen-specific tolerance is critical to achieve organ transplant tolerance and to avoid graft-versus-host responses following allogeneic hematopoietic transplantation. This review will focus on describing the capacity of VIP to induce suppressive/regulatory immune cells and how we can manage this cell-based therapeutic strategy to induce transplant tolerance in subjects free of immunosuppressive drugs.

Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immune Tolerance; Organ Transplantation; T-Lymphocytes; Transplantation Immunology; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT.

Topics: Animals; Bone Marrow Transplantation; Dendritic Cells; Graft vs Host Disease; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Mice; Mice, Inbred C57BL; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

Topics: Dendritic Cells; Graft vs Host Disease; Humans; Tissue Donors; Transplantation, Homologous; Vasoactive Intestinal Peptide

Cytomegalovirus (CMV) infection following allogeneic bone marrow transplant (allo-BMT) is controlled by donor-derived cellular immunity. Vasoactive intestinal peptide (VIP) suppresses Th1 immunity. We hypothesized that blocking VIP-signaling would enhance anti-CMV immunity in murine recipients of allo-BMT. Recipients were transplanted with bone marrow (BM) and T-cells from major histocompatibility complex (MHC)-mismatched VIP-knockout (KO) or wild-type donors, and treated with 7 daily subcutaneous injections of VIPhyb (peptidic VIP-antagonist) or phosphate-buffered saline (PBS). Genetic and pharmacological blockade of VIP-signaling protected allo-BMT recipients from lethal murine CMV (mCMV) infection, improving survival without increasing graft-versus-host disease. Mice treated with VIPhyb or transplanted with VIP-KO allografts had significantly lower viral loads, increased numbers of mCMV-M45-peptide-MHC-tetramer(+) CD8(+) T-cells, with lower PD-1 expression, and enhanced primary and secondary cellular immune responses after mCMV infection than did PBS-treated mice. These results demonstrate that administration of a VIP antagonist after allo-BMT is a promising safely therapeutic approach to enhance antiviral cellular immunity.

Topics: Adaptive Immunity; Animals; Bone Marrow Transplantation; Cells, Cultured; Graft vs Host Disease; Herpesviridae Infections; Immunocompromised Host; Mice; Mice, Inbred C57BL; Mice, Knockout; Muromegalovirus; Neurotensin; Recombinant Fusion Proteins; Signal Transduction; Survival Analysis; Transplantation, Homologous; Up-Regulation; Vasoactive Intestinal Peptide; Viral Load

T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25- T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25(high) T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27(kip1). VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

Topics: Acute Disease; Animals; Bone Marrow Transplantation; Cell Cycle; Cell Proliferation; Cells, Cultured; Clonal Anergy; Disease Models, Animal; Down-Regulation; Epitopes, T-Lymphocyte; Graft vs Host Disease; Growth Inhibitors; Humans; Isoantigens; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; T-Lymphocytes, Regulatory; Vasoactive Intestinal Peptide

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) that induce the generation/activation of regulatory T (Tr) cells for the treatment of acute GVHD following allogeneic BMT has been recently established. Therefore, the identification of factors that contribute to the development of tolerogenic DCs is highly relevant. We report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide (VIP), as a new approach to induce tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated in the presence of VIP impair allogeneic haplotype-specific responses of donor CD4(+) cells in mice given transplants by inducing the generation of Tr cells in the graft. VIP-induced tolerogenic DCs did not abrogate the graft-versus-leukemia response presumably by not affecting the cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DCs in future therapeutic regimens may minimize the dependence on nonspecific immunosuppressive drugs used currently as antirejection therapy, and facilitate the successful transplantation from mismatched donors, by reducing the deleterious consequences of acute GVHD and extending the applicability of BMT.

Topics: Acute Disease; Animals; Bone Marrow Transplantation; Dendritic Cells; Female; Graft vs Host Disease; Graft vs Tumor Effect; Immune Tolerance; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; T-Lymphocytes, Regulatory; Transplantation, Homologous; Vasoactive Intestinal Peptide

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation (BMT) for the treatment of leukemia and other immunogenetic disorders. The use of tolerogenic dendritic cells (DCs) with potent immunoregulatory properties by inducing the generation/activation of regulatory T cells (Tr) for the treatment of acute GVHD following allogeneic BMT has been recently established. Here we report the use of the known immunosuppressive neuropeptide, vasoactive intestinal polypeptide (VIP), as a new approach to inducing tolerogenic DCs with the capacity to prevent acute GVHD. DCs differentiated with VIP impair allogeneic haplotype-specific responses of donor CD4+ T cells in transplanted mice by inducing the generation of Tr in the graft. Importantly, VIP-induced tolerogenic DCs did not abrogate the graft versus leukemia response, probably because they do not abrogate cytotoxicity of transplanted T cells against the leukemic cells. Therefore, the inclusion of VIP-induced tolerogenic DC in future therapeutic regimens may facilitate the successful transplantation from mismatched donors, reducing the deleterious consequences of acute GVHD, extending the applicability of BMT.

Topics: Acute Disease; Animals; Bone Marrow Transplantation; Cell Differentiation; Dendritic Cells; Graft vs Host Disease; Leukemia; Mice; Survival Rate; Vasoactive Intestinal Peptide

CD4+CD25+ regulatory T (Treg) cells control the immune response to a variety of antigens, including self-antigens, and several models support the idea of the peripheral expansion of CD4+CD25+ Treg cells. Although hormones such as estrogen and alpha-melanocyte-stimulating hormone have been recently reported to expand the CD4+CD25+ Foxp3-expressing Treg cell compartment, little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+CD25+ Treg cells. In this study, we report on the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, to induce functional Treg cells in vivo. The administration of VIP together with specific antigen to T cell receptor (TCR)-transgenic (Tg) mice results in the expansion of the CD4+CD25+, Foxp-3/neuropilin 1-expressing T cells, which inhibit responder T cell proliferation through direct cellular contact. In addition to the increase in the number of CD4+CD25+ Treg cells, VIP induces more efficient suppressors on a per-cell basis. The VIP-generated CD4+CD25+ Treg cells transfer suppression, inhibit delayed-type hypersensitivity in TCR-Tg hosts, and prevent graft-versus-host disease in irradiated hosts reconstituted with allogeneic bone marrow.

Topics: Animals; CD4-Positive T-Lymphocytes; Cell Communication; Cell Proliferation; Forkhead Transcription Factors; Graft vs Host Disease; Hypersensitivity, Delayed; Immune Tolerance; Immunity, Cellular; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Antigen, T-Cell; Receptors, Interleukin-2; Signal Transduction; T-Lymphocytes, Regulatory; Transplantation, Homologous; Vasoactive Intestinal Peptide