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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 main issue addressed at the Fifth International Workshop on Bone Marrow Transplantation for Leukaemia was the importance of the major histocompatibility complex (MHC) and of minor histocompatibility (minor H) systems in allogeneic bone marrow transplantation (BMT) in humans. It is well established that mismatching for either HLA or minor antigens increases the risks of graft-versus-host disease (GVHD) and graft failure. In HLA-identical sibling transplants minor antigen differences may be responsible for these problems, which might be reduced by matching for minor antigens and improving methods for immunosuppression in vivo. If a suitable family member is not available, then a 'matched' unrelated donor (MUD) may be an alternative. At present MUD transplants have greater risks of GVHD and graft failure and consequently poor survival than HLA-identical sibling transplants; this may be due to unrecognized MHC polymorphisms or to multiple minor H differences. Possible strategies to improve the results of MUD transplants include better HLA matching, new in vitro functional tests for optimizing donor selection and better immunosuppression. Approaches for improving HLA typing include isoelectric focusing for class I and RFLP/allogenotyping or oligonucleotide typing for class II antigens. One obvious disadvantage of exploiting more precise methods for donor matching is the possibility of excluding donors with biologically unimportant histocompatibility differences, which would increase rather than reduce the proportion of patients without donors in a given panel. Functional assays could help in selecting donors on the basis of 'intelligent mismatching' within the HLA system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:How important is histocompatibility in bone marrow transplantation? 267 65

Twenty-six bone marrow transplant recipients, 14 of whom had evidence of acute graft versus host disease at autopsy, were studied. The pancreas in four of these patients exhibited changes thought to be due to acute graft versus host disease. Pathognomonic findings were in exocrine ducts which showed marked epithelial cellular atypia associated with a mild lymphocytic infiltrate. This was accompanied by ulceration and intraluminal haemorrhage in severe cases. In three of these four cases ductal epithelium showed marked hyperexpression of class I and class II major histocompatibility complex molecules. By contrast islets were not inflamed, showed no evidence of endocrine cell damage and no abnormalities of major histocompatibility complex expression were seen.
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PMID:The pancreas in acute graft versus host disease in man. 270 48

Ex vivo T cell depletion of donor marrow grafts in humans and mice has virtually eliminated severe graft-versus-host disease (GVHD). However, as a consequence of T cell depletion, sustained donor cell engraftment is likely compromised. Since the majority of T cell depletion techniques also deplete natural killer (NK) cells, we investigated the role of donor NK cells in engraftment and GVHD in a murine model. Using a monoclonal antibody directed against an NK-specific epitope, we have selectively depleted NK cells while preserving donor marrow T cells. In an established model of engraftment, selective NK depletion demonstrated that removal of donor NK cells did not impair the engraftment process under conditions in which donors and recipients are major histocompatibility complex-disparate. In contrast, recipients of anti-Thy 1.2 plus complement (C')-treated marrow grafts had a significantly higher incidence of either partial engraftment or graft rejection as compared with recipients of selective NK-depleted donor grafts or control grafts. In addition, we have observed that NK-specific depletion of donor marrow/splenocyte inocula does not alter the incidence of GVHD. Recipients of NK-depleted donor grafts developed lethal acute GVHD, whereas recipients of anti-Thy 1.2-depleted donor grafts did not (P less than 0.0001). Interestingly, NK 1.1-depleted donor graft recipients had a significantly increased mortality in comparison with control groups receiving C'-treated grafts (P = 0.04) or anti-Thy 1.2 plus C'-treated grafts (P less than 0.05). Thus, NK depletion may reduce immunosurveillance, thereby increasing the risk of posttransplant infection. We conclude from these results that donor NK cells play an insignificant role in engraftment as well as in the afferent phase of GVHD, but may be important in immunosurveillance when murine bone marrow is transplanted across the major histocompatibility barrier.
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PMID:Absence of a facilitory role for NK 1.1-positive donor cells in engraftment across a major histocompatibility barrier in mice. 289 41

The current studies were designed to evaluate the effectiveness of marrow transplantation within and outside the major histocompatibility complex (MHC) on the long-term survival and occurrence of spontaneous leukemia in AKR mice. AKR mice, which were lethally irradiated and received MHC-matched marrow from CBA/J mice (CBA----AKR), never developed leukemia and were alive and remained healthy for up to 280 days post-transplant. These long-term surviving chimeras possessed substantial immune vigor when both cell-mediated and humoral responses were tested. Lethally irradiated AKR mice, which had received MHC-mismatched marrow (anti-Thy-1.2 treated or nontreated) from C57BL/6J mice (B6----AKR), never developed leukemia and survived up to 170 days post-transplant. However, both groups of these chimeras began dying 180 to 270 days post-transplant due to a disease process which could not be readily identified. Histological analysis of B6----AKR chimeras revealed severe lymphoid cell depletion in thymus and spleen; however, none of these chimeras exhibited classical features of acute graft versus host disease. Concanavalin A mitogenesis, primary antibody responses to sheep red blood cells and the production of interleukin 2 (IL-2) were suppressed in B6----AKR chimeras. IL-2 treatment of B6----AKR chimeras was shown to partially correct these deficiencies without stimulating mixed lymphocyte responsiveness to donor or host lymphocytes. These studies indicate that the use of MHC-mismatched marrow for the prevention of spontaneous AKR leukemia may rely on augmentative IL-2 therapy for complete immune reconstitution of leukemia-free chimeras.
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PMID:Leukemia prevention and long-term survival of AKR mice transplanted with MHC-matched or MHC-mismatched bone marrow. 294 11

Cloned natural suppressor (NS) cell lines derived from the spleens of TLI-treated adult BALB/c or neonatal BALB/c mice were assayed for their ability to inhibit acute GVHD in vivo. Two assay systems were used to measure GVHD: spleen enlargement of F1 hybrid neonates, and mortality of sublethally irradiated homozygous weanling mice after the i.p. injection of fresh allogeneic spleen cells. Both lines of NS cells significantly reduced GVHD, but the control HT-2 cell line (T cell line of BALB/c origin) did not affect GVHD. The NS cells reduced GVHD regardless of the strain combination of the donor and recipient. Thus, suppression occurred without restriction by the major histocompatibility complex, and without antigenic specificity.
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PMID:Cloned natural suppressor cells prevent lethal graft-vs-host disease. 294 6

Implantation of either major histocompatibility complex (MHC)-disparate thymus to 7-day thymectomized (Tx) Xenopus in late larval life, or allogeneic skin to perimetamorphic controls, routinely induces tolerance towards implant-strain skin grafts applied in adult life. To characterize this allotolerance further, additional in vivo approaches were attempted. Injection of gamma-irradiated (5000 rads) implant-strain splenocytes into frogs bearing tolerant skin grafts revealed (within 3 days) significantly elevated tritiated thymidine uptake by host spleen cells, compared to siblings injected with isogeneic cells. Although this in vivo 'mixed leucocyte reaction' proved to be thymus dependent, the identity of the cells involved awaits clarification. When non-restored Tx Xenopus are injected with live MHC-disparate splenocytes, graft-versus-host (GVH)-induced mortality ensued within 2 weeks. Such GVH disease also occurred (albeit more chronically) when Tx allothymus-implanted animals were given MHC-incompatible splenocytes, but only when these came from the thymus donor strain. Splenocytes from thymus-implanted animals failed to achieve GVH-induced splenomegaly when transferred to appropriate hosts (bearing MHC antigens of the thymus donor strain). Overall, the experiments indicate that alloreactivity against donor cells is impaired but not completely inhibited in Xenopus following perimetamorphic implantation.
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PMID:In vivo studies on allotolerance perimetamorphically induced in control and thymectomized Xenopus. 296 Jun 13

Simplified-in vitro system was developed to examine the contribution of host's cells in graft-versus-host (GVH)-disease-associated immunodeficiencies. In analogy with major histocompatibility complex (MHC)-matched GVH-reaction, (BALB/c x DBA/2)F1 (H-2d) hybrid spleen cells were co-cultured with irradiated BALB/c (H-2d) spleen cells, so that cellular activities to be generated are ascribable to F1 cells. In vitro development of anti-allo-specific cytotoxic T cells of the F1 origin was dramatically suppressed by coexistence of the irradiated parental cells and by the addition of F1 cells precultured once with the parental cells, suggesting the generation of suppressor cells in the F1 (host) cells activated by the parental cells. Thus generated suppressor cells are Thy.1-, weakly or nonadherent and radiosensitive. Interestingly, in the same reactions there also developed Thy.1- cytotoxic cells for autologous macrophage targets. An involvement in immunodeficiencies in GVH disease of the host-derived cytotoxic and/or immunosuppressive, non-T cells was discussed.
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PMID:Generation of self-macrophage-toxic non-T cells in the MHC-homozygous F1 spleen cells co-cultured with parental cells: possible involvements of host cells in impaired immunity in GVH disease. 297 70

The graft-versus-host reaction (GVHR) in both mice and humans can lead to the development of a broad spectrum of clinical and pathological symptoms. These symptoms are strikingly similar to those of a number of diseases of proven or presumed immunological origin, such as systemic lupus erythematosus (SLE), other collagen vascular diseases, lymphoproliferative disease, and aplastic anemia. The purpose of our investigation was to describe the immunological and pathological events that take place in the course of graft-versus-host disease (GVHD) and to gain insight into the cellular mechanisms underlying these events. To this end, a model was employed in which nonirradiated F1 mice were used as recipients of parental lymphoid cells. By pathological manifestations, 2 basic forms of GVHD can be distinguished in such non-irradiated F1 recipients: One is acute GVHD which is often lethal. It is characterized by a variety of suppressive (hypoplastic) pathological symptoms, including a severe hypoplasia of the lymphohemopoietic system accompanied by aplastic anemia and hypogammaglobulinemia. The other basic form is characterized by stimulatory symptoms, such as persistent lymphoid hyperplasia, formation of autoantibodies, and development of pathological symptoms reminiscent of SLE and other collagen vascular diseases. The suppressive pathological graft-versus-host (GVH) symptoms are caused by T suppressor/killer (TS/K) cells of the donor which react towards allogeneic class-I-structures of the F1 recipient's major histocompatibility complex (MHC). The stimulatory pathological GVH symptoms, by contrast, are caused by donor T helper (TH) cells which react toward the recipient's allogeneic class-II-MHC structures. The possible implications of these observations for the pathogenesis of a number of GVH-like diseases in humans are discussed. The hypothesis is advanced that some of these GVH-like conditions, which arise either e causa ignota or after exposure to certain viruses or drugs, are caused by T lymphocytes reacting against self-MHC structures on lymphohemopoietic cells that were rendered "foreign". By analogy to GVHD, it is conceivable that the development of either stimulatory or suppressive GVH-like symptoms in individuals exposed to a given virus or sensitizing drug depends not on the etiologic agent per se, but on whether the predominant response is made by the individual's TH or TS@K cells. This, in turn, might depend on whether the agent becomes immunogenic in combination with class-II or class-I alloantigens.
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PMID:Pathogenesis of graft-versus-host reactions (GVHR) and GVH-like diseases. 315 4

We have been studying the mitogen hyporesponsiveness and immunosuppression induced in chronic murine graft-vs.-host disease (GVHD) induced across minor histocompatibility (MiHA) barriers. In this system, donor and recipient mice are major histocompatibility complex- and mls-identical, and are nonreactive in primary mixed leukocyte reactions. Spleen cells from B10.D2 (H-2d, mls b) mice were injected into irradiated (600 rad) BALB/c (H-2d, mls b) recipients. Recipient spleen cells are hyporesponsive to mitogens, and contain natural suppressor (NS) cells. We investigated the cellular requirements for both the in vivo induction and the in vitro expression of this GVH suppression. T cells are required in the graft, but they are not sufficient to induce suppression, and a non-T cell population is also required for maximum induction in vivo. T cells are also required for the maximum expression of NS cell suppressive ability in vitro. Early in the course of GVH, the suppressor cells are able to suppress the Con A and LPS response of all mouse strains tested (except for the relative difficulty in suppressing the B10.D2 LPS response). Later, they become almost completely unable to suppress the B10.D2 LPS response; while still being able to suppress the Con A and LPS response of all other strains tested (including the B10.D2 Con A response). This inability to suppress a B10.D2 LPS response can be brought back to almost complete suppression by the addition of concanavalin A supernatant (CAS). We present a hypothesis to explain what may be a common mechanism for GVH-induced suppression, total lymphoid irradiation-induced suppression, and neonatal tolerance. These situations all include rapidly proliferating lymphohematopoietic stem cell populations, and also have large numbers of NS cells. NS cells can suppress proliferating lymphoid populations, and their development and activity are greatly enhanced by T cell signals such as are supplied by donor T cells in chronic GVHD. Thus, NS cells may feed back on and downregulate self-reactive T cells or T cells responding to introduced foreign antigens.
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PMID:Synergism between T and non-T cells in the in vivo induction and in vitro expression of graft-vs.-host disease-induced natural suppressor cells. 316 77

Occurrence of acute graft-versus-host reactivity-like (GvHR) syndromes has been shown in at least 3 and possibly in 4 further cases of 9 patients with bone marrow transplants from identical twin donors. The diagnosis of GvHR-like syndromes is based on clinical, immunologic, and histologic features indistinguishable from those observed in graft-versus-host disease (GvHD) grades I-III of patients receiving allogeneic major histocompatibility complex (MHC) matched bone marrow transplants. Induction of GvHR-like symptoms appeared to be correlated with reactivated viral infections after bone marrow transplantation (BMT) or, like in animal models, was due to specific conditioning therapy with cyclophosphamide. The high incidence of acute GvHR-like syndromes in the first months after syngeneic BMT suggests inability of the immune system to discriminate appropriately self from nonself antigens during a normal tolerance induction period after grafting.
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PMID:High frequency of graft-versus-host-like syndromes following syngeneic bone marrow transplantation. 327 84


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