Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

Dendritic cells (DCs) derive from CD34+ cells or monocytes and stimulate alloimmune responses in transplantation. We hypothesized that the interaction between CD34+ cells and allogeneic T cells would influence the function of hematopoietic stem cells (HSCs). Cord blood (CB) CD34+ cells proliferated briskly in response to allogeneic, but not autologous, T cells when mixed with irradiated T cells for 6 days in vitro. This proliferation was significantly inhibited by an anti-HLA class II monoclonal antibody (mAb), by an anti-TNFalpha mAb, or by CTLA4-Ig. Allogeneic T cells induced the differentiation of CD34+ progenitors into cells with the morphology of dendritic monocytic precursors and characterized by the expression of HLA-DR, CD86, CD40, CD14, and CD11c, due to an endogenous release of TNFalpha. Cotransplantation of CD34+ cells with allogeneic T cells into nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mice resulted in a greater engraftment of myeloid CD1c+ dendritic cells compared with cotransplantation with autologous T cells. In vitro, CD34+ cell-derived antigen-presenting cells (APCs) were functionally capable of both direct and indirect presentation of alloantigens. Based on these findings, we hypothesize that in HSC transplantation the initial cross talk between allogeneic T cells and CD34+ cells may result in the increased generation of APCs that can present host alloantigens and possibly contribute to the development of graft-versus-host disease.
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PMID:Allogeneic T cells induce rapid CD34+ cell differentiation into CD11c+CD86+ cells with direct and indirect antigen-presenting function. 1647 83

The immunosuppressive properties of mesenchymal stem cells (MSC) make them particularly attractive to manipulate graft-versus-host disease (GVHD). So far, the experience of using MSC to treat GVHD is limited to a few cases, controversial results come from preclinical models and several issues remain to be clarified. The present studies were designed to address these questions in a xenogenic model testing the ability of umbilical cord blood-derived MSC (UCB-MSC) to prevent and/or treat GVHD. Sublethally irradiatiated non-obese diabetic/severe combined immunodeficiency NOD/SCID mice transplanted with human peripheral blood mononuclear cells (huPBMC) showed extensive human T-cell proliferation in the peripheral blood, lymphoid and non-lymphoid tissues, which evolved in extensive GVHD (wasting, ruffled hair and hunched back). The mice treated with a single dose of UCB-MSC did not behave differently form the controls. However, when UCB-MSC were given at weekly intervals, there was a marked decrease in human T-cell proliferation and none of the mice developed GVHD. No therapeutic effect was obtained if UCB-MSC were administered at onset of GVHD. This work supports the clinical use of MSC in stem cell transplantation as a prophylaxis rather than treatment of GVHD.
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PMID:Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. 1762 9

Although adoptive transfer of donor lymphocytes protects from infections and relapse after allogeneic hematopoietic stem cell transplantation in both mice and in men, it is associated with a high risk of graft versus host disease (GvHD) which rises with HLA mismatching and the number of T lymphocytes that are infused. Elimination/reduction of alloreactive donor T lymphocytes is an appealing approach and several strategies have been proposed. Here we describe generation of anti-3rd party T lymphocytes under conditions of IL-2 deprivation and their effects in a pre-clinical murine model. Our results clearly indicated that anti-3rd party T lymphocytes generated on a large scale by means of IL-2 deprivation maintain a broad T cell repertoire, do not proliferate in a mixed lymphocyte reaction and do not cause GvHD in NOD-SCID mice. These anti-3rd party lymphocytes contain a large adaptive T regulatory cell subset which might contribute to in vitro and in vivo immune modulation.
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PMID:Large-scale generation of human allodepleted anti-3rd party lymphocytes. 1793 16

Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model.
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PMID:Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice. 1797 28

NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice are immune deficient mice which are made by backcross of severe combined immunodeficient mice with non-obese diabetic mice strains. NOD/SCID mice are both innate immune deficiencies and lack of T and B lymphocytes. Various tumor cells can be implanted in this kind of mice, the rejection and graft-versus-host disease (GVHD) occur fewer. Therefore, NOD/SCID mice gradually become a useful tool for the study on Experimental Hematology. This paper comprehensively reviews the biological characteristics of NOD/SCID mice, the establishment of human leukemia model, stem cell transplantation, drug research, deficiency and improvement of NOD/SCID mice in application for study.
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PMID:[Application of NOD/SCID mice in research of experimental hematology - review]. 1871 1

Mouse studies demonstrated that infusion of CD4+CD25+ regulatory T cells (Tregs) prevented graft versus host disease (GVHD) lethality after bone marrow transplantation (BMT). But the potential impact of human Tregs on GVHD has not been well demonstrated. In this study, we demonstrated that human Tregs enriched from peripheral blood of healthy donors could be expanded ex vivo to clinically relevant cell numbers in 2-3 weeks while maintaining Foxp3, CD25, CTLA-4, and CD62L expression as well as in vitro suppressive function. Furthermore, injection of human PBL into NOD/SCID mice induced lethal xenogenic GVHD, but co-transfer of expanded human Tregs with human PBL significantly enhanced survival, reduced GVHD symptoms, and inhibited human IgG/IgM production in the NOD/SCID mice. These results demonstrated that ex vivo expanded human Tregs retained their in vivo suppressive activity and prevented lethal xenogeneic GVHD, revealing the therapeutic potential of expanded human Tregs for GVHD.
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PMID:Ex vivo expanded human CD4+CD25+Foxp3+ regulatory T cells prevent lethal xenogenic graft versus host disease (GVHD). 1941 Feb 43

Allogeneic hematopoietic cell transplantation represents an important therapy for certain malignant and nonmalignant diseases. However, graft-versus-host disease (GVHD) is a major cause of mortality and morbidity. The search for agents that can efficiently suppress GVHD has been going on for more than half a century. GVHD is particularly strong in xenogeneic donor-recipient combinations, given the unlimited number of potentially immunogenic antigens donor lymphocytes encounter in the host. Using a hu-nonobese diabetic/severe combined immunodeficiency (hu-NOD/SCID) gamma-null model of xenogeneic GVHD, we have demonstrated that treatment with recombinant immunoglobulin-like transcript 3-Fc protein induces the differentiation of CD8(+) T suppressor cells and blocks the cellular and humoral arm of the GVH reaction.
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PMID:Suppression of xenogeneic graft-versus-host disease by treatment with immunoglobulin-like transcript 3-Fc. 1950 24

The use of umbilical cord blood (UCB) grafts for hematopoietic stem cell transplantation (HSCT) is a promising technique that permits a degree of human leukocyte antigen mismatch between the graft and the host without the concomitant higher rate of graft-versus-host disease that would be observed between an adult marrow graft and a mismatched host. A disadvantage to the use of UCB for HSCT is that immune reconstitution may be significantly delayed because of the low stem cell dose available in the graft. Ex vivo expansion of UCB CD34 cells would provide a greater number of stem cells; however, there are persistent concerns that ex vivo-expanded CD34 cells may lose pluripotency and the ability to contribute meaningfully to long-term engraftment. To address this issue, we transduced CD34-selected UCB cells with a lentiviral construct expressing luciferase, and determined homing and engraftment patterns in vivo by noninvasive bioluminescent imaging in sublethally irradiated NOD/SCID/IL-2Rgamma(-/-) (NSG) mice. Graft contribution to multilineage commitment was also confirmed by analysis of primary and secondary transplants by flow cytometry and immunohistochemistry. Our results demonstrate that, other than a mild delay at the onset of engraftment, there were no significant differences in lineage repopulation or in long-term or secondary engraftment between culture-expanded and unexpanded UCB CD34-selected cells. The results suggest that multipotent stem cells can be expanded ex vivo and can contribute meaningfully to long-term hematopoietic engraftment.
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PMID:Noninvasive bioluminescent imaging demonstrates long-term multilineage engraftment of ex vivo-expanded CD34-selected umbilical cord blood cells. 1954 39

Nucleotide-binding oligomerization domain 2 (NOD2) polymorphisms are independent risk factors for Crohn's disease and graft-versus-host disease (GVHD). In Crohn's disease, the proinflammatory state resulting from NOD2 mutations have been associated with a loss of antibacterial function of enterocytes such as paneth cells. NOD2 has not been studied in experimental allogeneic bone marrow transplantation (allo-BMT). Using chimeric recipients with NOD2(-/-) hematopoietic cells, we demonstrate that NOD2 deficiency in host hematopoietic cells exacerbates GVHD. We found that proliferation and activation of donor T cells was enhanced in NOD-deficient allo-BMT recipients, suggesting that NOD2 plays a role in the regulation of host antigen-presenting cells (APCs). Next, we used bone marrow chimeras in an experimental colitis model and observed again that NOD2 deficiency in the hematopoietic cells results in increased intestinal inflammation. We conclude that NOD2 regulates the development of GVHD through its inhibitory effect on host APC function.
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PMID:NOD2 regulates hematopoietic cell function during graft-versus-host disease. 1973 67

Immunodeficient mice have been used as recipients of human peripheral blood mononuclear cells (PBMC) for in vivo analyses of human xeno-graft-versus-host disease (GVHD). This xeno-GVHD model system in many ways mimics the human disease. The model system is established by intravenous or intraperitoneal injection of human PBMC or spleen cells into unconditioned or irradiated immunodeficient recipient mice. Recently, the development of several stocks of immunodeficient Prkdc ( scid ) (scid) and recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rgamma) have been reported. The addition of the mutated IL2rgamma gene onto an immunodeficient mouse stock facilitates heightened engraftment with human PBMC. Stocks of mice with mutations in the IL2rgamma gene have been studied in several laboratories on NOD-scid, NOD-Rag1 ( null ), BALB/c-Rag1 ( null ), BALB/c-Rag2 ( null ), and Stock-H2(d)-Rag2 ( null ) strain backgrounds. Parameters to induce human xeno-GVHD in H2(d)-Rag2 ( null ) IL2rgamma ( null ) mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rgamma ( null ) stock that engrafts more readily with human PBMC than does the Stock-H2(d)-Rag2 ( null ) IL2rgamma ( null ) stock should lead to a more reproducible humanized mouse model of GVHD and for the use in drug evaluation and validation. Furthermore, GVHD in human PBMC-engrafted scid mice has been postulated to result predominately from a human anti-mouse major histocompatibility complex (MHC) class II reactivity. Our recent development of NOD-scid IL2rgamma ( null ) beta2m ( null ) and NOD-scid IL2rgamma ( null ) Ab ( null ) stocks of mice now make it possible to investigate directly the role of host MHC class I and class II in the pathogenesis of GVHD in humanized mice using NOD-scid IL2rgamma ( null ) stocks that engraft at high levels with human PBMC and are deficient in murine MHC class I, class II, or both classes of MHC molecules.
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PMID:Development of novel major histocompatibility complex class I and class II-deficient NOD-SCID IL2R gamma chain knockout mice for modeling human xenogeneic graft-versus-host disease. 2001 95


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