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)

We compared the findings in the wasting syndrome seen in [MRL lpr/lpr--> MRL +/+] chimeras with those of chronic graft versus host disease (GVHD) in [B10.D2-->BALB/c] chimeras. BALB/c mice were lethally irradiated and administered B10.D2 spleen and bone marrow cells. These mice are identical to MHC and Mls but differ as to genetic background. As a result of chronic GVHD, these [B10.D2-->BALB/c] chimeras showed hair loss, weight loss and atrophy of lymph nodes and spleen beginning 5 weeks after the transplantation. MRL lpr/lpr mice carry the lpr gene and spontaneously develop generalized lymph node swelling and lupus-like autoimmune disease, while congenic MRL +/+ mice lack the lpr gene. The [MRL lpr/lpr-->MRL +/+] chimeras showed wasting and the same symptoms as in [B10.D2-BALB/c] chimeras beginning 16 weeks after cell transfer. Skin biopsy from both chimeras showed very similar changes on HE staining and on immunoperoxidase staining for Ia and Thy-1. Our data suggest that very small differences in minor histocompatibility may induce GVHD which produces severe wasting with lethal consequences. Finally, we succeeded in transferring the wasting syndrome seen in the [MRL lpr/lpr--> MRL +/+] chimera to other MRL +/+ mice by transplanting spleen cells from the [MRL lpr/lpr-->MRL +/+] chimera to lethally irradiated MRL +/+ mice.
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PMID:Comparison of wasting syndrome in [MRL lpr/lpr-->MRL +/+] chimera and graft versus host disease in [B10.D2-->BALB/c] chimera and an attempt to transfer the wasting syndrome in [MRL lpr/lpr-->MRL +/+] to MRL +/+ mice. 791 43

In this study reconstitution of lymphoid tissues under the influence of subclinical graft versus host reaction (GVHR) was investigated. Lethally irradiated recipient mice (AKR: H-2k, Mls-1a) were reconstituted with donor (B10: H-2b, Mls-1b) bone marrow (BM) cells treated with anti-Thy 1 antibody alone without complement (GVHR chimeras). When their immunological reconstitution was analysed and compared with that of AKR recipients which had been reconstituted with B10 BM treated with anti-Thy 1 and complement (Control chimera), both of these chimeras all survived more than 100 days without showing clinical signs of GVHD. Full donor chimerism was accomplished at an early stage after BM transplantation (BMT) in GVHR chimeras, whereas substantial number of recipient T cells persisted in Control chimeras during the entire observation period. No significant difference was observed in the reconstitution of the thymus and spleen between the Control and GVHR chimeras. By contrast, the reconstitution of lymph nodes (LN) in GVHR chimeras was inhibited. The apparent failure of LN reconstitution was attributed to damage of LN structure involved in homing of lymphocytes, but not attributable to damage of lymphocytes themselves. Since donor CD8+ T cells caused the damage, target antigens of this damage appeared to be H-2 class I molecules in the present system. Furthermore, clonal deletion of V beta 6+T cells that are reactive to recipient Mls-1a antigen was induced in Control chimeras but abrogated in the GVHR chimeras. The latter abrogation of clonal deletion of V beta 6+T cells appeared to result from the early disappearance of recipient T cells in these GVHR chimeras.
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PMID:[The influence of subclinical level of graft versus host reaction on reconstitution of host lymphoid tissues]. 792 74

IL-10 is a regulatory cytokine of both T cells and monocytes. We have investigated the ability of IL-10 to regulate responses to alloantigens in vitro and in vivo. Addition of IL-10 to mixed lymphocyte cultures profoundly decreased the proliferation and IL-2 production by donor B10.BR cells stimulated with CBA cells expressing minor histocompatibility antigens. Administration of IL-10 for a period of 2 weeks after bone marrow transplantation decreased the expansion of CD4+ and CD8+ donor T cells. In addition, splenocytes from BMT mice treated with IL-10 secreted less IFN-gamma after stimulation with Con A in vitro. The suppression of the mitogen-driven proliferative response of lymphocytes from the IL-10-treated group could also be reversed with significantly less anti-IFN-gamma antibody than for saline-treated controls. However, treatment with IL-10 was not sufficient to alter significantly the clinical course of graft-versus-host disease in CBA recipient mice as assessed by survival, weight loss, and splenomegaly. The results suggest that exogenous IL-10 suppresses the afferent Th1 response in a graft-versus-host reaction but does not significantly diminish the effector stage of graft-versus-host disease.
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PMID:Effects of exogenous interleukin-10 in a murine model of graft-versus-host disease to minor histocompatibility antigens. 799 70

Treatment of lethally irradiated mice with a short course of high-dose interleukin (IL)-2 markedly inhibits acute and chronic graft-versus-host disease (GVHD), while preserving a graft-versus-leukemia (GVL) effect of allogeneic T-cells. We recently demonstrated that this GVL effect, observed with the EL4 leukemia/lymphoma in the A/J-->B10 strain combination, was mediated by CD8+ A/J T-cells in a CD4-independent fashion. IL-2 inhibited only the activity of CD4+ cells, and not that of CD4-independent CD8+ T-cells in A/J spleen cell inocula. This inhibition of CD4 function was sufficient to markedly inhibit GVHD, thus explaining the dissociation of GVHD and GVL in IL-2-treated mice. We have now performed studies to determine the capacity of IL-2 to inhibit GVHD induced across a variety of different histocompatibility barriers. IL-2 significantly delayed GVHD mortality in three of four additional fully major histocompatibility complex (MHC) plus minor-disparate strain combinations when CD4+ T-cells were given. Numbers of CD8+ T-cells comparable to those that might contaminate human marrow demonstrated a relatively poor capacity to produce acute GVHD when given without CD4+ cells in all of three additional strain combinations evaluated. In one of these strain combinations (B10-->BALB/c), IL-2 protected against acute but not chronic GVHD mortality when CD4+ cells were given with or without CD8+ cells. In one fully allogenic strain combination, B10-->A/J, IL-2 did not inhibit the GVHD produced by CD4+ cells given with or without CD8+ cells. IL-2 was unable to inhibit CD8-mediated GVHD in strain combinations differing at isolated class I MHC loci. In a strain combination differing only at multiple minor histocompatibility antigen (HA) loci, B10-->C3H.SW, GVHD was largely CD8-dependent, but IL-2 did not inhibit the small CD4-mediated component of GVHD. Together, these results suggest that IL-2 inhibits a restricted subset of CD4 cells or functions, and that the type of CD4 activities mediating GVHD is determined by the particular histoincompatibilities between donor and host.
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PMID:Strain dependence of interleukin-2-induced graft-versus-host disease protection: evidence that interleukin-2 inhibits selected CD4 functions. 811 Jul 26

The possibility, conditions, and quantitative aspects of eliciting GVHD in CBA (H-2k) mice made neonatally tolerant to the alloantigens of the donor A (H-2a) strain were studied. The intravenous injection of different doses (10(7)-2 x 10(8)) of A spleen cells caused a severe, often fatal, systemic GVHD in 12-month-old tolerant mice. The GVHD was found to be specific: spleen cells of a third party strain (B10) did not induce any disease. The intensity and the mortality of the GVHD depended on the cell dose and on the age of the recipients. In contrast, unirradiated (CBA x A)F1 recipients proved to be resistant to the lethal disease. In spite of their different susceptibility to the systemic GVHD, the tolerant and F1 hybrid recipients showed equally strong local GVH reactivity in the popliteal lymph node enlargement assay. Neonatally tolerant mice offer a new, sensitive model for the induction of lethal GVHD without the need of immunosuppression or irradiation.
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PMID:Lethal systemic graft-vs-host disease in neonatally tolerant, but not in F1 hybrid mice. 817 81

The intensity of graft-versus-leukemia (GVL) effect was studied using several radiation-induced leukemia cell lines (designated 8027, 8313, 9107, 7929) in MHC-compatible and -incompatible allogeneic bone marrow transplantation (BMT) of leukemia-bearing C3H mice. The results indicated that BMT from MHC-incompatible allogeneic (B10, B10.D2) donors consistently improved the survival of the treated mice compared with that in syngeneic (C3H) donors. However, BMT from MHC-compatible allogeneic (B10.BR, CBA, AKR) donors failed to improve the survival of 8027-bearing recipients. On the other hand, a remarkable improvement in survival of 8313, 9107 or 7929-bearing recipients was observed in MHC-compatible allogeneic (B10.BR, AKR) BMT but there was only a marginal GVL effect in MHC-compatible BMT from CBA donors. There was no clear correlation between the intensity of GVL effect and the amount of class I MHC molecules expressed on leukemic cell lines. The activity of donor lymph node cells for the induction of lethal graft-versus-host disease (GVHD) correlated with the intensity of GVL effect induced by intact donor bone marrow. The results indicate that GVL effect against radiation-induced leukemias could be consistently induced in MHC-incompatible allogeneic BMT whereas the intensity of GVL effect induced in MHC-compatible allogeneic BMT varied among different leukemias and the donor-host strain combinations used.
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PMID:Graft-versus-leukemia effect in allogeneic bone marrow transplantation in mice against several radiation-induced leukemias. 820 78

Acute graft-versus-host-disease is classically described as reactivity of donor lymphocytes to recipient alloantigens. To date there is debate as to whether GVHD can be induced across a species barrier. We recently reported the induction of stable xenogeneic chimerism (rat-->mouse) and donor-specific transplantation tolerance using the transplantation of untreated rat bone marrow cells into B10 mouse recipients. Survival of chimeras was excellent, and there was no evidence of GVHD. We now describe the induction of xenogeneic GVHD by transplanting large numbers of donor rat spleen cells with the bone marrow inoculum. All chimeras that received bone marrow and untreated spleen cells developed an external appearance compatible with GVHD and had a median survival time of 14 days. Mice that received equivalent numbers of untreated rat bone marrow alone appeared healthy, had no evidence for GVHD, and survived > 90 days. The usual epithelial target tissues for allogeneic GVHD in those mice that received xenogeneic bone marrow and spleen cells showed the presence of tissue injury and histologic features compatible with GVHD. Donor rat MHC class I and class II positive cells were prominent cell types present in the tongues of mice that developed features of GVHD, and this was accompanied by a significant inflammatory tissue response with loss of the dermal-epidermal architecture. In contrast, fully xenogeneic chimeras without GVHD had no evidence for tissue injury or pathologic cellular infiltrates when examined by immunohistochemical analysis. These data suggest that although fully xenogeneic chimeras resist GVHD, GVHD can be induced across a species barrier if sufficient numbers of donor rat spleen cells are added to the bone marrow inoculum. Further comparisons of these models may provide an approach to study the mechanisms responsible for xenoreactivity in vivo.
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PMID:Cross-species graft-versus-host-disease is accompanied by a donor-derived cellular immune response. 821 20

A murine model of bone marrow (BM) transplantation in which donor (B10.D2) and recipient (BALB/c) mice were major histocompatibility complex (MHC) (H-2d) and Mls-1 identical, but incompatible at multiple non-MHC minor histocompatibility (H) antigens, and at Mls-2,3 was used to examine regeneration of B-cell development during the minor H antigen graft-versus-host reaction (GVHR). Mice that received T-cell-depleted allogeneic BM regained significant pre-B cells (sIg- 14.8+) in their BM. Mice undergoing GVHR after transplantation with allogeneic BM + T cells had less than 2% pre-B cells in their BM at day 7 and only 12% to 14% pre-B cells at days 21 and 28 compared with greater than 20% pre-B cells in the allogeneic controls. After partial recovery, the pre-B cells in the BM of GVH mice again decreased to less than 3% by day 42. This abnormal pattern of pre-B cell development in mice undergoing GVHR was associated with a reduced response to interleukin-7 (IL-7) in vitro. The delay in B-lineage cell reconstitution in mice with GVHR correlated with the expansion of donor V beta 3+ T cells in both the spleen and BM. BM T cells from mice with GVHR as well as isolated V beta 3+ T cells inhibited IL-7 colony-forming units from normal BM in co-culture assays. This inhibition could be reversed with anti-interferon gamma (IFN gamma) antibody. These data suggest that the delay in appearance and the reduction in proportion and number of pre-B cells observed early during the GVH reaction in this model is caused, in part, by the inhibitory actions of IFN gamma derived from donor V beta 3+ T cells on B-lineage cell development.
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PMID:Suppression of B-cell development as a result of selective expansion of donor T cells during the minor H antigen graft-versus-host reaction. 821 28

The role of TNF in the expression of GVHD and GVHD-related immunodeficiency was studied in a well-established murine GVHD model of bone marrow transplantation across minor histocompatibility barriers (B10.BR-->GBA/J) both in vitro and in vivo. Splenocytes from animals with GVHD profoundly inhibited the proliferation of normal spleen cells in response to a wide range of stimuli in an MHC-nonrestricted fashion. Neutralizing mAbs to TNF reversed the ability of splenocytes from animals with GVHD to suppress the proliferation of normal splenocytes stimulated by the mitogen concanavalin A. Addition of rTNF enhanced the degree of suppression. This reversal was similar to that previously reported for IFN gamma and leucine methyl ester treatment of the GVHD populations. All three components are necessary for suppression to occur because addition of rTNF to cultures in which suppression had been reversed by anti-IFN gamma or leucine methyl ester treatment did not reconstitute suppression. Neutralization of endogenous TNF production in vivo resulted in an amelioration of clinical GVHD, but neutralization of endogenous IFN gamma resulted in a more severe course. However, in vivo neutralization of either TNF or IFN gamma post-BMT resulted in a decreased ability of splenocytes from animals with GVHD to suppress mitogen responses but did not affect the generation of the suppressor cell population. These findings support multiple roles for TNF and IFN gamma in the pathophysiology of GVHD, including terminal cellular differentiation and/or regulation of effector cell function.
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PMID:The role of tumor necrosis factor and interferon gamma in graft-versus-host disease and related immunodeficiency. 831 May 20

Murine graft versus host (GVH) disease takes two forms depending on the parental/F1 strain combination employed. In an accompanying paper (Singh et al., Clin. Immunol. 151, 1993) many of the clinical features of these two forms of GVH disease are described. In addition to these clinical characteristics, acute lethal GVH (ALGVH) disease is characterized by diminished natural killer cell activity, whereas chronic GVH disease is characterized by normal or increased natural killer cell activity. Previously we have reported that this marked disparity in disease expression can be attributed to radiosensitive host cells which protect the F1 mouse from parental anti-F1 cytotoxicity (CTX) in mice undergoing chronic GVH (CGVH) disease. These cells fail to functionally emerge in mice undergoing ALGVH disease. We now report that the background genome, presumably the minor lymphocyte stimulatory loci, of the donor cells determines whether these host cells emerge and thereby dictates the form of GVH disease which is induced. C57BL/6 (B6) cells (H-2b, minor lymphocyte stimulatory locus (Mls)b) and B10.D2 cells (H-2d, Mlsb) were found to induce ALGVH disease when adoptively transferred to [C57BL/6xDBA/2]F1 (B6D2) (H-2b/d, Mls-1a/b, Mls-2a/b) recipient mice. DBA/2 cells (H-2d, Mls-1a, Mls-2a) and Balb/c cells (H-2d, Mls-1a, Mls-2b) induced CGVH disease in B6D2 mice. Using Mls congenic strains we have demonstrated that donor cell reactivity against Mls-2a was necessary and sufficient to induce ALGVH disease as determined by anemia, lymphopenia, anti-F1 cytotoxicity, and loss of cytotoxicity against allogeneic targets. Such Mls-2a reactivity correlated with the impaired induction of a host protective cell capable of vetoing self-directed CTX. Failure of this host protective cell to emerge in turn correlated with donor anti-host CTX and the emergence of ALGVH disease.
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PMID:The host response in graft versus host disease. II. The emergence of host protective cells is in part determined by background genomic compatibility. 840 30


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