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)

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti-CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC-mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC-mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.
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PMID:Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies. 171 80

Recent observations indicate that stem cells of the murine hair follicle exist exclusively as a subpopulation of relatively undifferentiated outer root sheath cells located in the bulge region at the mid-portion of the follicle. Because it has been hypothesized that stem cells of interfollicular epidermis may represent targets of cytotoxic responses in acute graft-versus-host disease (AGVHD), we studied murine AGVHD and observed sequential skin biopsies for the presence and evolutionary pattern of follicular injury. Highly purified subsets of donor T cells were used to produce AGVHD to multiple minor histocompatibility (H) antigens in two strain combinations of mice matched for the major histocompatibility complex (MHC). In the C3H.SW- greater than B6 strain combination, only CD8+ effector cells produced histologic evidence in skin of AGVHD, which peaked three weeks post-transplant. In the B10.D2- greater than DBA/2 strain combination, CD4+ effector cells, and to a lesser extent, CD8+ cells, mediated disease, which peaked during the fourth week post-transplant. Analysis of skin from both strain/effector cell combinations revealed follicular infiltrates preferentially involving follicular stem cell (FSC) regions (bulge) of anagen follicles between the second and third weeks post-transplant. These infiltrates often preceded infiltration of adjacent interfollicular epidermis and were associated with follicular involution to telogen (resting) phase. By the fourth week post-transplant, greater than 50% of follicles were in telogen phase and residual inflammation was minimal. This provided a unique opportunity to observe follicular recovery from telogen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytotoxic folliculitis in GvHD. Evidence of follicular stem cell injury and recovery. 176 82

The involvement of an auto-immune mechanism has been suggested in the development and/or the maintenance of hypertension in male, genetically hypertensive rats of the Lyon strain (LH). The aim of this study was to determine whether hypertension may be transferred, by lymphoid cells, from hypertensive donors to male, normotensive rats of the Lyon strain (LN). Experiments designed to induce a resistance to hypertension in LH rats by transfer of lymphoid cells from LN animals were also performed. Since LH and LN are mismatched at the major histocompatibility complex, transfers of fetal liver cells (FLC) from fetuses of 13-14 days gestation were performed. These experiments demonstrate the ability of FLC to allow a prolonged survival (over 17 weeks) without graft versus host disease in the rat. As regards the blood pressure level, no LN recipient having received FLC from LH donor became hypertensive, thus showing that hypertension cannot be transferred by lymphoid cells in normotensive animals. Resistance to hypertension was so weakly transferred to hypertensive rats (results being significantly different only at 10 weeks post-grafting) that it may be considered doubtful.
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PMID:Fetal liver cell transplantation fails to transfer hypertension from genetically hypertensive rats to normotensive rats of the Lyon strain. 184 65

The precise identity of effector mononuclear cells capable of eliciting acute graft-versus-host disease (AGVHD) is controversial. In this study, highly purified subsets of donor T cells were used to produce AGVHD to multiple minor histocompatibility (H) antigens in two strain combinations of mice matched for the major histocompatibility complex (MHC). In the C3H.SW- greater than B6 strain combination, only CD8+ effector cells produced histologic evidence of AGVHD in skin and liver, which peaked 3 weeks after transplant. In the B10.D2- greater than DBA/2 strain combination, CD4+ effector cells, and to a lesser extent, CD8+ cells, mediated disease in skin, liver, and intestine, which peaked during the fourth week after transplant. Analysis of skin and liver from both combinations showed target cell injury that was phenotypically similar and resembled that previously described in human disease in other studies. In addition, prominent epithelial injury also was detected in oropharyngeal mucosa, esophagus, hepatobiliary ducts, and seminal vesicle in both transplant settings. These findings indicate that functionally different subsets of donor T cells may be capable of initiating common pathways of cellular injury in selected target sites in AGVHD, and have potential implications for strategies that seek to ablate disease development by manipulation of donor marrow before transplantation.
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PMID:Characterization of target injury of murine acute graft-versus-host disease directed to multiple minor histocompatibility antigens elicited by either CD4+ or CD8+ effector cells. 190 55

We have investigated the effects of the in vitro depletion of LFA1 positive cytolytic T lymphocytes, natural killer (NK) cells, and monocytes on the afferent phase of graft-versus-host disease (GVHD). Lethal GVHD was induced across the murine major histocompatibility complex by injecting C57BL/6 (H-2b) bone marrow (BM) cells (a source of stem cells) and splenocytes (S) (a source of T cells) into lethally irradiated B10.BR (H-2k) recipients. Because anti-LFA1 does not bind complement (C') effectively, we conjugated anti-LFA1 alpha chain monoclonal antibody (MoAb) to ricin toxin A chain (RTA) as a means of facilitating target cell elimination. A 2-hour preincubation of C57BL/6 bone marrow/spleen (BMS) with anti-LFA1-RTA in the presence of ammonium chloride (a potentiator of immunotoxin toxicity), but not a control immunotoxin (IT), reduced CTL activity by greater than 2 logs, significantly reduced NK cell activity, and prevented B10.BR mice from developing GVHD. Depletion of target cells by toxin-labeled-MoAb and not the blockade of the LFA1 molecule by the anti-LFA1 MoAb accounted for our results, because incubating cells with IT in the absence of a potentiator had no effect on GVHD prevention. In contrast, C57BL/6 recipients of C3H BMS grafts only partially benefited from anti-LFA1-RTA preincubation, demonstrating that in this system, different cells not expressing LFA1 were involved in GVHD generation. The same findings observed with anti-LFA1-RTA preincubation were observed with preincubation with L-leucyl-L-leucine methyl ester, a chemical compound eliminating cytolytic cells, providing further support that GVHD induction in the C3H/HeJ into C57BL/6 system is not entirely mediated by classical cytolytic T cells. We next tested anti-LFA1-RTA in a model devised to measure its effect on alloengraftment (B10.BR recipients given lower doses of irradiation). Anti-LFA1-RTA BM preincubation selectively reduced alloengraftment in the model. This observation, combined with experiments showing that LFA1-RTA preincubation, but not anti-Thy 1.2 + C' or control IT preincubation, reduced colony-forming unit-spleen formation, indicates that anti-LFA1 alpha chain IT may remove accessory cells or stem cells critical to engraftment. Still, anti-LFA1-RTA may be useful for clinical GVHD prevention when combined with positive selection techniques designed to enrich for stem cells.
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PMID:Prevention of murine graft-versus-host disease and bone marrow alloengraftment across the major histocompatibility barrier after donor graft preincubation with anti-LFA1 immunotoxin. 195 95

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

Graft-versus-host disease (GVHD) was induced across the murine major histocompatibility complex by injecting C57BL/6 (H-2b) bone marrow and splenocytes into lethally irradiated B10.BR (H-2k) murine recipients. An immunotoxin (IT) composed of a pan T-cell monoclonal antibody called anti-Ly1 (the murine homologue to human anti-CD5) was conjugated to ricin toxin A chain (anti-Ly1-RTA) and used to treat recipient mice. In vitro, IT was as active as free RTA, bound selectively, and inhibited T-cell proliferation even in the absence of potentiators. Mice administered anti-Ly1-RTA in vivo during ongoing GVHD, at a dose of 10 micrograms/d for 5 days, showed lower numbers of splenic Thy1.2+ T cells and significantly improved survival as compared with mice given phosphate-buffered saline (PBS) or irrelevant control RTA IT. Protection was transient because GVHD and weight loss occurred when injections ceased. Survival could not be enhanced by crosslinking RTA30, a low oligosaccharide-containing fraction of purified RTA. Treatment with anti-Ly1-RTA caused a significant elevation in neutrophils, and higher doses were associated with mild hepatotoxicity. In contrast, infusion of identical doses and schedules of another pan T-cell immunotoxin, anti-Thy1.2-RTA, caused a significant decrease in lymphocytes, but not neutrophils; a precipitous increase in weight; a decrease in total plasma protein (TPP); and an increase in pleural and peritoneal effusions reminiscent of vascular leak syndrome (VLS). Although the toxic effects of anti-Thy1.2-RTA were too severe to show a survival advantage in a GVHD model, histopathologic studies showed a definite anti-GVHD effect. The most significant decline in GVHD as compared with the PBS-treated controls was observed in skin, and to a lesser extent, in liver and lung. To investigate the cause of IT toxicity, anti-Thy1.2-RTA was administered intraperitoneally to lethally irradiated B10.BR (H-2k) recipients of syngeneic bone marrow. These recipients showed the same weight gain, hypoproteinuria, and VLS observed in the GVHD model. Death occurred at higher anti-Thy1.2-RTA doses (30 or 50 micrograms/daily injections administered days 8 through 12 posttransplant). Anti-Thy1.2-RTA had a negligible effect on renal function, but histologic studies showed patchy dropout of the renal tubules. Treatment resulted in pulmonary vascular congestion, but there was no pathologic evidence of liver, brain, or colon toxicity. Weight gain was enhanced by irradiation because nonirradiated normal mice did not undergo such a precipitous weight increase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Toxicity and efficacy of anti-T-cell ricin toxin A chain immunotoxins in a murine model of established graft-versus-host disease induced across the major histocompatibility barrier. 198 94

A monoclonal antibody recognizing Ly1, the murine homologue of CD5, was labeled with 90Y. In vivo biodistribution studies showed that 90Y-anti-Ly1 selectively localized in lymphoid tissue. Groups of B10,BR mice (H-2k) were lethally irradiated and given major histocompatibility complex-disparate C57BL/6 (H-2b) bone marrow and spleen cells to induce graft-versus-host disease (GVHD). Eight days later, mice with active GVHD were administered a single i.p. injection of 50 microCi90Y-anti-Ly1. Fifty % of these mice were alive 2 months after treatment. Long term (greater than 4-month) survival was significantly higher than in phosphate-buffered saline-treated mice. Survival was slightly improved in groups of mice receiving control irrelevant antibody labeled with 90Y or mice receiving free 90Y. However, survival in these groups was not significantly different from the phosphate-buffered saline-treated control group. The improved survival was supported by data showing improved mean animal weight. An anti-GVHD effect was confirmed by histopathological analysis. Unlabeled anti-Ly1 monoclonal antibody at comparable doses to 90Y-anti-Ly1 was not effective. Animals that died following 50-microCi treatment did not die of radiation toxicity, since all mice receiving 50 microCi 90Y-anti-Ly1 plus syngeneic bone marrow survived. The window of therapy was narrow in our studies, since 100 microCi 90Y-anti-Ly1 did not confer any survival advantage. Animals that did survive long term were studied for evidence of alloengraftment and found to have high levels of circulating donor mononuclear cells. 90Y-Anti-Ly1 localized in the spleen, thymus, liver, kidney and bone marrow but not in the bowel, lung, muscle, or skin. Animals given similar doses of free 90Y, 90Y-anti-Ly1, or labeled irrelevant antibody eliminated free 90Y fastest, followed by 90Y-anti-Ly1 and then labeled irrelevant antibody. Hematological analysis of peripheral blood from 90Y-anti-Ly1-treated mice showed reduction in total WBC counts, absolute lymphocyte numbers, and absolute neutrophil numbers on day 24 after treatment. Myelosuppression recovered by day 38. These findings indicate that Ly1-positive cells are involved in the effector phase of GVHD and that radiolabeled antibodies may be useful as cell-specific probes for studying the GVHD network. 90Y-Anti-Ly1 protected recipients long term from lethal GVHD, and the fact that it had a rather remarkable inhibitory and selective effect on the lymphoid system of mice suggests that these agents may have broader application in the field of transplantation.
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PMID:Radiotherapy in mice with yttrium-90-labeled anti-Ly1 monoclonal antibody: therapy of established graft-versus-host disease induced across the major histocompatibility barrier. 200 72

An 8-year-old boy with a granulocytic sarcoma of the proximal ileum metastatic to mesenteric lymph nodes was placed into complete remission with surgical excision of the primary tumor and conventional induction chemotherapy with daunorubicin and cytosine arabinoside. He was then treated with high dose cytosine arabinoside, fractionated total body irradiation, and allogeneic marrow transplantation from his 22-month-old brother who was completely matched at the major histocompatibility complex. Methotrexate was given following the transplant to prevent graft-versus-host disease (GVHD). His post-transplantation course was complicated by a transient autoimmune hemolytic anemia related to an ABO blood group incompatibility and hepatic fungal microabscesses which responded to Amphotericin therapy. Four years following the transplant the patient remains in complete remission. The prognosis for patients with granulocytic sarcoma has been poor although, perhaps, improved over the past decade. This is the first published case report of successful treatment of a granulocytic sarcoma of the ileum by allogeneic marrow transplantation.
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PMID:Granulocytic sarcoma of the ileum treated by bone marrow transplantation. 202 76

In a healthy state, the central nervous system (CNS) is believed to be an immunologically privileged site, which does not participate in the immune reactions of the rest of the body, and in which identifiable components of the immune system are rare or non-existent. In this study, an immunohistochemical examination of the CNS of F1 hybrid rats following induction of graft-versus-host disease (GVHD) was carried out to determine whether specific immune reactions in the normal CNS could occur during a systemic immune reaction. The results revealed extensive parenchymal and vascular expression of class I and II major histocompatibility complex (MHC) encoded cell surface molecules. The strongest expressors of class I and II molecules were endothelial cells and parenchymal cells, respectively, the latter being apparently activated microglia, in the cerebrum and cerebellum of rats with GVHD. In addition, occasional scattered lymphocytes were detected in the CNS of GVHD rats without blood-brain barrier disruption. Thus, evidence was obtained for the presence of immune responses such as MHC antigen expression and lymphocyte infiltration in the CNS during a strong systemic immune response such as GVHD, microglia and endothelial cells apparently playing an important role.
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PMID:Major histocompatibility complex expression in brain of rats with graft-versus-host disease. 203 16


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