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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of the bone marrow culture technique was studied as a means to prepare donor marrow for bone marrow transplantation to avoid lethal graft-versus-host disease (GVHD). Preliminary experiments demonstrated the rapid loss of theta-positive cells in such cultures, so that theta-positive cells were not detected after 6 days. Initial experiments in C3H/HeJ (H-2k, Hbbd) recipients prepared with 900 rad demonstrated improved survival when 3-day cultured C57BL/6 (H-2b, Hbbs) donor cells were used in place of hind limb marrow for transplantation. However, hemoglobin typing of recipient animals revealed only short-term donor engraftment, with competitive repopulation of recipient marrow occurring. Subsequent experiments were done in 1,200-rad prepared recipients, with long-term donor engraftment demonstrated. The majority of 1,200-rad prepared animals receiving cultured allogeneic cells died of GVHD, but animals receiving 28-day cultured cells had an improved 90-day survival and a delay in GVHD development over animals receiving hind limb marrow or marrow from shorter times in culture. In addition, animals receiving anti-theta-treated, 3-day nonadherent cells had an improved survival (44%) over animals receiving anti-theta-treated hind limb marrow (20%). These experiments demonstrate modest benefit for the use of cultured cells in bone marrow transplantation across major H-2 histocompatibility complex differences.
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PMID:Lethal graft-versus-host disease: modification with allogeneic cultured donor cells. 614 77

Nonmajor histocompatibility complex (non-MHC) antigens are important targets of graft rejection and graft-versus-host disease in clinical transplantation. Little is known regarding immunity to non-MHC antigens. To study this problem we evaluated the effect of antihuman thymocyte globulin (ATG) on reactivity in autologous and allogeneic mixed lymphocyte cultures and activity in a model of immunity to non-MHC antigens, the response to trinitrophenyl (TNP)-modified autologous cells. Primary proliferative responses to autologous B lymphocytes, allogeneic cells, and TNP-modified autologous cells were all inhibited by ATG treatment. Secondary proliferative responses and cytotoxicity to TNP-modified autologous cells were also inhibited as was cross-reactive cytotoxicity to TNP-modified allogeneic cells. These data indicate that both MHC-restricted and MHC-nonrestricted immune responses to modified self-antigens and possibly to non-MHC antigens are sensitive to ATG treatment. ATG may be useful in clinical situations where the objective of immunosuppression is to inhibit immunity to non-MHC antigens such as after HLA-matched kidney grafting or bone marrow transplantation.
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PMID:Effect of antithymocyte globulin on histocompatibility antigen recognition in man. 616 30

Increased understanding of minor histocompatibility complex (MiHC) antigen presentation to donor T cells may permit methods to modulate graft-versus-host disease (GVHD), a major complication of allogeneic bone marrow transplantation (BMT). Previously, we described the importance of B cells as antigen presenting cells in T cell responses to a virally induced murine leukemia. Using a B cell deficient mouse model in which mice receive either control rabbit immunoglobulin (RIgG) or rabbit anti-IgM mu chain from birth (B cell deficient), we evaluated whether B cells were necessary for T cell responses to MiHC and the induction of GHVD. Normal and B cell deficient C57BL/6 (H-2b) mice were primed with BALB.B (H-2b; MiHC incompatible) spleen cells and evaluated > 4 weeks later in vitro. While splenic or lymph node T cells obtained from BALB.B primed control C57BL/6 mice demonstrated strong in vitro proliferative responses to MiHC mismatched targets, B cell deficient hosts were markedly reduced to 14-42% of controls. Similarly, a strong MiHC specific cytolytic T cell response was observed in control C57BL/6 mice (53-100% specific cytotoxicity) whereas B cell depleted recipients had no activity (< or = 5% specific lysis). The role of B cells in GVHD was evaluated using a MiHC disparate mouse model (LP/J donor into C57BL/6 recipient). We found that 12% of B cell depleted recipient mice receiving B cell depleted donor cells developed GVHD compared to 50% of RIgG control mice. B cell depletion of donor cells only, resulted in a similar result with 0% of mice receiving B cell depleted donor cells developing GVHD compared to 38% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Requirement for B cells in T cell priming to minor histocompatibility antigens and development of graft-versus-host disease. 758 Nov 50

The morbidity and mortality associated with sickle cell disease (SCD) is caused by hemolytic anemia, vaso-occlusion, and progressive multiorgan damage. Bone marrow transplantation (BMT) is currently the only curative therapy; however, toxic myeloablative preconditioning and barriers to allotransplantation limit this therapy to children with major SCD complications and HLA-matched donors. In trials of myeloablative BMT designed to yield total marrow replacement with donor stem cells, a subset of patients developed mixed chimerism. Importantly, these patients showed resolution of SCD complications. This implies that less toxic preparative regimens, purposefully yielding mixed chimerism after transplantation, may be sufficient to cure SCD without the risks of myeloablation. To rigorously test this hypothesis, we used a murine model for SCD to investigate whether nonmyeloablative preconditioning coupled with tolerance induction could intentionally create mixed chimerism and a clinical cure. We applied a well-tolerated, nonirradiation-based, allogeneic transplantation protocol using nonmyeloablative preconditioning (low-dose busulfan) and costimulation blockade (CTLA4-Ig and anti-CD40L) to produce mixed chimerism and transplantation tolerance to fully major histocompatibility complex-mismatched donor marrow. Chimeric mice were phenotypically cured of SCD and had normal RBC morphology and hematologic indices (hemoglobin, hematocrit, reticulocyte, and white blood cell counts) without evidence of graft versus host disease. Importantly, they also showed normalization of characteristic spleen and kidney pathology. These experiments demonstrate the ability to produce a phenotypic cure for murine SCD using a nonmyeloablative protocol with fully histocompatibility complex-mismatched donors. They suggest a future treatment strategy for human SCD patients that reduces the toxicity of conventional BMT and expands the use of allotransplantation to non-HLA-matched donors.
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PMID:A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex-mismatched bone marrow transplantation. 1186 3

The effect of allogeneic versus syngeneic killer cells derived from normal or severe combined immunodeficiency disease (SCID) mice was evaluated for induction of antitumor reaction in a murine model of mammary carcinoma. Tumor cells of H-2d origin were injected intravenously into H-2(d/b) mice 24 hours after total body irradiation (4 Gy). On the following day, lymphokine-activated killer (LAK) splenocytes, derived from either minor (H-2d) or major (H-2b) histocompatibility complex (MHC)-mismatched parental normal mice or MHC (H-2b)-mismatched SCID mice, were given intravenously. LAK cells of H-2d normal or SCID mice, syngeneic to the tumor, were inoculated in parallel. The results show that LAK cells derived from minor histocompatibility complex-mismatched or MHC-mismatched parental normal mice improved the probability of tumor-free survival as compared with LAK cells syngeneic to the tumor cells, but they aggravated the severity of graft-versus-host disease. SCID splenocytes serving as a source of natural killer (NK) cells were expanded and activated in vitro by rIL-2 to obtain a sufficient number of DX5+ CD3- CD8- NK cells (SCID-LAK). H-2b SCID-LAK cells did not cause graft-versus-host disease and significantly delayed tumor growth compared with syngeneic H-2d SCID-LAK cells, as indicated by tumor colony assays in vitro and adoptive transfer experiments. However, the graft-versus-tumor effect was not long lasting, and treated mice finally died of tumor. Our results show an advantage of allogeneic over syngeneic cell therapy for achieving a graft-versus-tumor effect by rIL-2-activated T cells and NK cells. Periodic repetition of NK treatments may be required to achieve more durable antitumor effects.
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PMID:Allogeneic versus syngeneic killer splenocytes as effector cells for the induction of graft-versus-tumor effect. 1475 78

Graft-versus-host disease occurs when transplanted donor-derived T lymphocytes recognize major or minor histocompatibility complex proteins and their associated peptides expressed by recipient antigen-presenting cells. A widely accepted paradigm for the pathophysiology of acute GVHD is based on the existence of 3 sequential steps: (1) injury to the host environment (as would occur during conditioning regimens); (2) donor T-cell activation, proliferation, and differentiation; and (3) damage to the target tissue caused by either cytotoxicity or indirectly by inflammatory cytokines. In order to reduce the incidence of GVHD, recent studies have focused on methods of prophylaxis as well as novel treatments for established GVHD. We review each phase in the development of acute GVHD and discuss recently developed interventions aimed to prevent or treat GVHD by interfering with these pathways.
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PMID:Graft-versus-host disease: how to translate new insights into new therapeutic strategies. 1557 Feb 50

Prophylactic approaches to graft versus host disease (GvHD) have employed both phenotypic reduction of T cells and selective elimination of host-primed donor T cells in vitro and in vivo. An additional approach to GvHD prophylaxis by functional depletion of apoptosis-sensitive donor T cells without host-specific sensitization ex vivo showed remarkable reduction in GHD incidence and severity. We address the role and significance of antigen-specific sensitization of donor T cells and discuss the mechanisms of functional T cell purging by apoptosis for GvHD prevention. Host-specific sensitization is dispensable because migration is antigen-independent and donor T cell sensitization is mediated by multiple and redundant mechanisms of presentation of major and minor histocompatibility complex and tissue antigens by donor and host antigen-presenting cells. Our data suggest that potential murine and human GvH effectors reside within subsets of preactivated T cells susceptible to negative regulation by apoptosis prior to encounter of and sensitization to specific antigens.
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PMID:Antigen-Specific Priming is Dispensable in Depletion of Apoptosis-Sensitive T Cells for GvHD Prophylaxis. 2490 71

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an increasingly important treatment for conditions including hematopoietic malignancies and inherited hematopoietic disorders, and is considered to be the most effective form of tumor immunotherapy available to date. However, graft-versus-host disease (GVHD) remains a major source of morbidity and mortality following allo-HSCT, and understanding the mechanisms of GVHD has been highlighted as a key research priority. During development of GVHD, activation of various immune cells, especially donor T cells, leads to damage of target organs including skin, liver, hematopoietic system, and of particular clinical importance, gut. In addition to histocompatibility complex differences between the donor and recipient, pretransplant conditioning with chemotherapy and irradiation also contributes to GVHD by damaging the gut, resulting in systemic exposure to microbial products normally confined to the intestinal lumen. The intestinal microbiota is a modulator of gastrointestinal immune homeostasis. It also promotes the maintenance of epithelial cells. Recent reports provide growing evidence of the impact of intestinal microbiota on GVHD pathophysiology. This review summarizes current knowledge of changes and effects of intestinal microbiota in the setting of allo-HSCT. We will also discuss potential future strategies of intestinal microbiota manipulation that might be advantageous in decreasing allo-HSCT-related morbidity and mortality.
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PMID:Intestinal microbiota-related effects on graft-versus-host disease. 2581 38