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)

The distribution of T lymphocytes expressing the gamma/delta form of the T cell receptor was studied in the liver, intestine, and major lymphoid organs, after bone marrow transplantation (BMT), including cases of graft versus host disease (GvHD). The number of gamma/delta as a proportion of the total number of CD3 positive cells did not differ from that found in normal tissues; the higher percentage normally found in the intestinal epithelium and splenic red pulp was maintained. This, and the results of a previous study undertaken on the skin, provide no evidence that gamma/delta T cells have a particularly important role in T cell regeneration after marrow transplantation or in the pathogenesis of the epithelial lesions associated with GvHD.
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PMID:Immunohistological study of distribution of gamma/delta lymphocytes after allogeneic bone marrow transplantation. 145 77

Graft-versus-host disease is a potential problem following small bowel transplantation. We have previously shown that a two-day intraperitoneal course of polyclonal antilymphocyte serum completely prevents GVHD without impairing allograft function in a unidirectional rat small bowel transplant model. In the present study we sought to determine the optimum route and timing of ALS administration and whether donor pretreatment with the anti-T cell receptor monoclonal antibody R73 would be similarly effective in preventing GVHD. Both intravenous and intraperitoneal injection of ALS effectively prevent GVHD in this model. ALS must be given to donors at least 48 hr prior to graft procurement for maximum effectiveness. Prevention of GVHD correlates with lymphocyte depletion in mesenteric lymph nodes, as opposed to peripheral blood or small bowel lamina propria. Donor pretreatment with the monoclonal antibody R73 significantly delays the onset of GVHD in this small bowel transplant model but appears less effective than polyclonal ALS.
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PMID:Prevention of graft-versus-host disease following small bowel transplantation with polyclonal and monoclonal antilymphocyte serum. The effect of timing and route of administration. 175 80

We have studied T cell receptor (TCR) diversity in a group of six patients with severe combined immunodeficiency (SCID) previously treated by HLA-haploidentical bone marrow transplantation (BMT). At the time of study, all patients had developed stable T cell chimerism and full reconstitution of T cell functions in the absence of acute or chronic graft-versus-host disease. Peripheral blood lymphocytes (PBL) were analysed by immunofluorescence using a panel of monoclonal antibodies (MoAb) against TCR variable (V) region epitopes including V beta 5, V beta 6, V beta 8, V beta 12, and V alpha 2. Our results showed that in each patient studied a low but significant portion of PBL reacted with each anti-TCR V region epitope MoAb used, in a manner that was, on statistical grounds, indistinguishable from results obtained with PBL from healthy controls. We conclude that within the experimental resolution of a limited number of anti-TCR V region epitope MoAb, T cell reconstitution following BMT for SCID, even when performed across a full HLA-haplotype barrier, leads to an apparently normal TCR diversity. These novel findings may be relevant in the evaluation of functional capacities of T cells that have differentiated from transplanted precursor cells in an HLA-haplodifferent environment.
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PMID:T cell receptor diversity in severe combined immunodeficiency following HLA-haploidentical bone marrow transplantation. 176 74

A murine IgG2b monoclonal antibody directed to the constant part of the human alpha/beta T cell receptor (BMA031) was investigated in a pilot study as an initial treatment for acute graft-versus-host disease (aGvHD) after allogeneic bone marrow transplantation. The treatment protocol consisted of 5 mg BMA031 on 5 consecutive days with continuation of the prophylactic baseline immuno suppression using cyclosporin. Seven patients with grades II-III acute graft-versus-host disease were entered on the protocol and six patients completed the full treatment course. Mild to moderate acute adverse reactions to the first BMA031 infusion occurred in three patients. A nearly complete decline of circulating T lymphocytes was observed during BMA031 therapy, but the T cells returned to pretreatment values within 1 week after the last infusion. Serum pharmacokinetics of free antibody best fitted to a two-compartment open model with a mean initial half-life of 6 h and an estimated mean terminal half-life of 40 h. One patient developed antimurine antibodies of the IgM subclass. In five patients a complete and sustained resolution of all disease manifestations was attained, while in one patient a temporary response of skin involvement with aGvHD was noted. These results indicate that BMA031 can be safely administered as initial treatment of aGvHD. The therapeutic responses observed warrant its further clinical evaluation in this setting.
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PMID:Initial treatment of acute graft-versus-host disease with a murine monoclonal antibody directed to the human alpha/beta T cell receptor. 183 76

This report investigates the effects of cyclosporine on the reconstitution of T lymphocytes after syngeneic bone marrow transplantation and its role in the development of a novel T cell-mediated autoimmune disease, syngeneic graft versus host disease. We analyzed the effect of CsA treatment on T lymphocyte differentiation during reconstitution after bone marrow transplantation and correlated the maturation of CD4+ and CD8+ T cell subsets with the onset of syngeneic GVHD. Administration of CsA following syngeneic bone marrow transplantation leads to a developmental arrest of mature CD4+ and CD8+ T lymphocytes in the thymus and a marked reduction in cells expressing the alpha beta T cell receptor. The reduction of CD4+ and CD8+ T cell subsets is also reflected in the peripheral lymphoid compartment with an altered CD4/CD8 ratio. Functional assessment of the cells revealed that CD8+ cells respond normally to mitogenic signalling whereas CD4+ cells exhibit marginal proliferative responses. Both subsets of T lymphocytes respond to syngeneic B lymphoblasts, comparable to the response of T lymphocytes from non-CsA-treated syngeneic BMT recipients, suggesting that autoreactive cells are produced despite CsA treatment. Following discontinuation of CsA, T cell differentiation in the thymus is rapidly restored to normal. However, concurrent with the onset of syngeneic GVHD, a compensatory insurgence of CD4+ T helper cells is observed.
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PMID:Effect of cyclosporine on T lymphocyte development. Relationship to syngeneic graft-versus-host disease. 189 96

This review focuses on the response to foreign major histocompatibility complex (MHC) molecules by T lymphocytes. This phenomenon is characterized by a uniquely strong primary immune reaction, due to a very high precursor frequency of alloreactive T cells. This is manifest in vitro in the mixed lymphocyte reaction (MLR) and in vivo leads to allograft rejection and to graft versus host disease. Understanding this phenomenon requires an understanding of the nature of the ligand recognized by alloreactive T cells. In this review we report evidence in support of the two hypotheses which have been put forward to account for the high precursor frequency of anti-MHC alloreactive T cells. The high determinant hypothesis emphasized the implication of direct contact between the T cell receptor and the MHC molecule; the multiple binary complex hypothesis envisages that alloreactive T cells are specific for self peptide bound by the foreign MHC molecule. With these two lines of apparently contradictory evidence in mind we propose two distinct models to account for the phenomenon of allorecognition and to accommodate it within a self-MHC-restricted T cell repertoire. Which model is most applicable to a particular alloresponse is largely determined by the structural relationship between the responder and the stimulator MHC molecules.
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PMID:The molecular basis of allorecognition of major histocompatibility complex molecules by T lymphocytes. 195 30

We report the immunological characteristics of five patients with Omenn's syndrome, a rare inherited immunodeficiency also known as combined immunodeficiency with hypereosinophilia. The syndrome is characterized by T cell infiltration of skin, gut, liver, and spleen leading to diffuse erythroderma, protracted diarrhea, failure to thrive, and hepatosplenomegaly. Blood T cells as well as those infiltrating the skin and gut were found to express activation markers and were partially activated by mitogens but not by antigens. Although the lesions resembled those in graft-versus-host disease, the blood T cells were shown by DNA haplotype analysis using probes revealing variable number of tandem repeats to belong to the patients as well as the T cells infiltrating the gut and skin in one patient. A given T cell subset (TCR alpha beta+, CD4+/CD8+, or TCR gamma delta+) was predominant in each patient, with a specific distribution in the skin lesions. Moreover, the study of T cell receptor beta, gamma, and delta gene rearrangements in four patients revealed oligoclonality involving C beta 1, C beta 2, or different V gamma J gamma or V delta J delta genes. This indicates that restricted heterogeneity of the T cell repertoire, previously reported in one case, is a major feature of this syndrome. The occurrence of alymphocytosis-type severe combined immunodeficiency in the brother of one of the patients suggests that the restricted heterogeneity of T cell receptor gene usage in Omenn's syndrome may arise from leakiness, within the context of a genetically determined faulty T cell differentiation.
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PMID:Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome). 201 May 48

As part of an ongoing phase-I/II trial, 2 patients received a 5-day treatment course with a murine monoclonal antibody (MAB) directed against the human T cell receptor (BMA031) as primary therapy of acute grade III skin and gastro-intestinal graft-versus-host disease (GvHD) occurring after allogeneic bone marrow transplantation (BMT). All MAB infusions were tolerated without side effects. A complete response of all symptoms of acute GvHD could be attained by MAB therapy under a continued baseline immunosuppression with cyclosporin (CSP), and both patients remain alive and disease-free at 7 and 8 months after therapy without evidence of chronic GvHD. Although the exact treatment scheme has still to be defined, we conclude that this MAB may be useful as primary therapy of acute GvHD. However, the potential hazards of 'in vivo' therapy with MABs directed against T lymphocytes call for a critical evaluation of this treatment modality.
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PMID:Treatment of acute graft-versus-host disease after HLA-partially matched marrow transplantation with a monoclonal antibody (BMA031) against the T cell receptor. First results of a phase-I/II trial. 328 28

We have previously isolated, and characterized in vitro, two subsets of CD4hi T cell receptor (TCR)hi single positive (SP) thymocytes: CD8- and CD8lo. In this report, we have analyzed phenotypic, functional, and developmental characteristics of these "late" CD4hi SP thymocyte subsets. The TCRhi phenotype and the elimination of T cells expressing TCR V beta segments reactive with endogenous mouse mammary tumor virus (MMTV) products suggested that both subsets had undergone positive and negative selection. CD8-4hi thymocytes were functional, as judged by their ability to: (a) induce lethal graft versus host disease (GVHD); (b) survive and expand in peripheral lymphoid organs; and (c) proliferate, rather than undergo apoptosis, in response to in vitro TCR cross-linking. By contrast, CD8lo4hi cells could not induce GVHD, were unable to expand (and perhaps even survive) in peripheral organs and underwent apoptosis upon TCR cross-linking. However, when reintroduced into the thymus, these cells matured into functional, long-lived CD8-4hi lymphocytes. These results document an obligatory requirement for the thymic microenvironment in the final maturation of the majority of CD4hi SP postselection thymocytes, and demonstrate the existence of a previously unrecognized control point in T cell development.
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PMID:The majority of postselection CD4+ single-positive thymocytes requires the thymus to produce long-lived, functional T cells. 752 69

Allogeneic bone marrow transplantation (BMT) has become a therapy of choice for the treatment of certain malignancies and hematopoietic disorders. However, immunodeficiencies following BMT continue to cause significant morbidity and mortality. We have compared the T cell receptor (TCR) repertoire of BMT patients and healthy control individuals by staining peripheral blood mononuclear cells with fluorochrome-labeled TCR-specific antibodies. Several patients exhibited a biased pattern of TCR expression atypical of the healthy controls, yet no particular TCR bias characterized all patients. For example, we found that 2%-8% of T cells from healthy individuals expressed the V beta 19 TCR. One BMT patient exhibited V beta 19 expression on more than 60% of peripheral T cells, while additional patients expressed V beta 19 on less than 1% of T cells. The patients with the most extreme skewing of TCR types suffered from graft-versus-host disease. The causes of skewed TCR V beta expression patterns in BMT patients are not fully understood, yet some researchers have suggested that an oligoclonal expansion of CD8+ T cell populations may be largely responsible. To test this hypothesis, we examined the TCR V beta repertoire of CD4+ and CD8+ T cell populations. We found that biased V beta expression characterized both CD4+ and CD8+ T cell populations, sometimes within a single individual. Thus, therapies directed toward CD8+ T cells alone may not fully correct repertoire abnormalities following BMT.
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PMID:T cell receptor repertoire of CD4+ and CD8+ T cell subsets in the allogeneic bone marrow transplant recipient. 765 69


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