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)

Three different types of anti-T cell antibody were used in patients undergoing haematopoietic stem cell transplantation (HSCT) with an HLA-A, -B and -DR compatible unrelated donor: ATG-Fresenius (ATG-F) (n = 26), Thymoglobuline (TMG) (n = 61) and OKT-3 (n = 45). The groups were comparable regarding diagnosis, stage, age, conditioning and GVHD prophylaxis, Adverse events were less frequent after ATG-F treatment. Levels of IL-2, IL-6, IFN-gamma, TNF-alpha and GM-CSF were increased after OKT-3 infusion. In multivariate analysis OKT-3 treatment (P = 0.01), G-CSF treatment (P = 0.02) and a cell dose >/=2.7 x 108/kg (P = 0.03) gave a faster engraftment. Acute GVHD grades II-IV occurred in 25% of the ATG-F patients, 12% of the TMG-patients and 43% (P < 0.001 vs TMG) of the OKT-3 patients. OKT-3 was associated with acute GVHD in multivariate analysis. TRM was 26% using TMG as compared to 43% in the OKT-3 group (P = 0.03). Patient survival at 4 years was 63%, 50% and 45% in the ATG-F, TMG and OKT-3-treated patients, respectively (NS). Relapses were 8%, 49% and 34%, respectively (ATG-F vs TMG, P = 0.03). Relapse-free survivals were 61%, 40% and 37% (NS). Among CML patients the probability of relapse was 61% in TMG-treated patients, while no patients relapsed in the other two groups. To conclude, the type of anti-T cell antibody affects GVHD and relapse after HSCT using unrelated donors.
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PMID:Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. 1051 91

The use of unrelated donors for bone marrow transplantation is associated with an increased morbidity and mortality when compared with HLA identical siblings. We have demonstrated previously that matching of unrelated donors and recipients for TNFa microsatellites is correlated with lower CTLp frequencies. Matching of unrelated donors and recipients for other non-HLA sequences in the major histocompatibility complex has been reported to result in less graft-versus-host disease and improved survival. It has been argued that matching for non-HLA sequences in the MHC in addition to the HLA genes themselves results in matching for the entire MHC and is therefore the equivalent of providing an HLA identical sibling donor. In order to test this hypothesis we have examined TNFa microsatellites of unrelated donor recipient pairs in whom matching for HLA loci, non-HLA sequences near HLA B (beta-block markers) and non-HLA sequences near DRB1 (delta-block markers) had been determined. All 17 patients who were matched for HLA and non-HLA markers were also matched for TNF microsatellites. This data supports the idea that matching for HLA genes and non-HLA markers results in matching at all other loci in the MHC.
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PMID:Matching for TNF microsatellites is strongly associated with matching for other non-HLA MHC sequences in unrelated bone marrow donor-recipient pairs. 1052 94

Recent data suggests that graft-versus-host disease (GVHD) is initiated by host APCs. Blockade of CD40:CD154 interactions between APCs and T cells in vivo induces T cell tolerance to host alloantigen and dramatically reduces GVHD. Because allogeneic cord blood (CB) transplantation results in a lower incidence and severity of acute GVHD compared with bone marrow transplantation, we have investigated whether CB T cells can express CD154 in response to stimulation by allogeneic monocyte-derived dendritic cells (MDDC) and have used 5- (and 6-)carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling in combination with intracellular cytokine analysis to assess the proliferation and cytokine profiles of alloantigen-responsive cells. CB T cells stimulated with allogeneic MDDC showed stronger proliferation than adult blood T cells. Surface CD154 expression was detected in the actively dividing CFSElow populations of both the CD4+ and CD4- subsets and was brightest in cells that had divided the most. Assessment of supernatants from MDDC-stimulated CB and adult blood T cells showed no significant difference in the levels of either IFN-gamma or TNF-alpha, but CB T cell supernatants did show a significant lack of detectable IL-2. Intracellular cytokine analysis revealed that dividing CB T cells had been primed to produce IFN-gamma, TNF-alpha, and IL-2 on restimulation. Further phenotype analysis showed that 75% of CB T cells producing IFN-gamma were CD8+. These data suggest that MDDC-stimulated CB T cells express functional CD154 and provide enough costimulation for dendritic cells to prime naive CD8+ CB T cells and induce type 1 cytokine production.
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PMID:Sustained expression of CD154 (CD40L) and proinflammatory cytokine production by alloantigen-stimulated umbilical cord blood T cells. 1084 72

Tumor necrosis factor (TNF) and Fas ligand (FasL) have been implicated in the pathogenesis of graft-versus-host disease (GVHD). Several recent studies have shown that some metalloproteinase mediates TNF-alpha and FasL processing. We examined the ameliorating effect of a hydroxamic acid-based metalloproteinase inhibitor (KB-R7785) that inhibits TNF-alpha and FasL release in a lethal acuteGVHD model in mice. The ameliorating effect of KB-R7785 was superior to that of anti-TNF-alpha antibody. We also examined the effect of KB-R7785, which we previously demonstrated a potent ameliorating effect on acute GVHD, on graft-versus-leukemia (GVL) effect of allogeneic bone marrow transplantation (BMT). Administration of KB-R7785 without bone marrow cells and spleen cells (BMS). significantly prolonged the survival of IgE-producing B53 hybridoma cell-inoculated (C57BL/6 x BALB/c) F1 (CBF1) mice by inhibiting the infiltration of B53 cells into the liver and spleen. Transplantation of B6 BMS without KB-R7785 resulted in the death of most recipients due to acute GVHD while efficiently eliminating B53 cells. Administration of KB-R7785 along with B6 BMS resulted in 50% survival of B53-inoculated CBF1 mice over 50 days without histological manifestations of acute GVHD or residual B53 cells. These results suggest that KB-R7785 could be a potent therapeutic agent for GVHD, and indicate the beneficial effects of KB-R7785 that inhibit tumor infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.
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PMID:A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation. 1095 77

Cytokine levels in sera from 14 patients undergoing allogeneic bone marrow transplantation (alloBMT) or donor lymphocyte infusion (DLI) were sequentially measured to evaluate the roles of cytokines in clinical graft-versus-host disease (GVHD). In clinical courses, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay. Among the evaluable cases, 6 patients developed acute GVHD. Serum IL-5 levels increased to more than 100 pg/mL in 5 of the 6 patients before, or simultaneously with, the clinical manifestation of acute GVHD. Elevation of IL-5 was transient in 3 patients. In the other 2 patients who showed regimen-related toxicity and/or thrombotic microangiopathy as well as acute GVHD, remarkable and sustained elevation of the serum IL-5 level was observed. In 7 patients without acute GVHD, IL-5 levels remained below 100 pg/mL. An association of acute GVHD was less prominent with TNF-alpha than with IL-5 in our study. Elevation of IL-6 was associated with infections. In 2 patients with severe extensive chronic GVHD, serum IL-10 was elevated in parallel with exacerbation of clinical symptoms. Our findings suggest that an elevated serum IL-5 level may be a marker of acute GVHD.
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PMID:Kinetics of serum cytokines after allogeneic bone marrow transplantation: interleukin-5 as a potential marker of acute graft-versus-host disease. 1097 16

Scleroderma (SSc) is a fibrosing connective tissue disease that is poorly responsive to any treatment, including immune suppression. SSc shares many characteristics with chronic graft-versus-host disease (GVHD). Because the immunomodulatory drug thalidomide has proven beneficial in chronic GVHD, we studied the immune response and clinical effects of thalidomide in SSc patients. We treated 11 SSc patients with thalidomide in an open label, dose escalating, 12 week study. Histologic comparison of skin biopsies showed changes in skin fibrosis and an increase in epidermal and dermal infiltrating CD8(+) T cells with thalidomide treatment. In thalidomide-treated SSc patients, plasma levels of IL-12 and TNF-alpha increased, while plasma IL-5 and IL-10 levels remained unchanged. These changes were associated with clinical effects, including dry skin, dermal edema, transient rashes, decreased gastroesophageal reflux symptoms, and healing of digital ulcers. When SSc PBMCs activated by anti-CD3 mAb were exposed to thalidomide, increases in both production of IL-2, IL-3, GM-CSF, and IFN-gamma and T cell expression of CD40L were observed. Thalidomide therefore appears to induce immune stimulation in SSc patients in association with clinical changes. However, it remains to be shown whether long-term enhancement of immune responses in SSc patients is clinically beneficial.
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PMID:Immune stimulation in scleroderma patients treated with thalidomide. 1102 51

We have shown previously that increased levels of hsp70, and antibodies reactive with hsp70 parallel the onset and severity of graft-versus-host disease (GVHD) in a parent --> (DA x LEW)F1 rat model. In this study we have assessed the effect of reducing the levels of the 70 kDa heat shock protein (hsp70), on the morbidity and mortality of acute GVHD in (DA x LEW)F1 rats. The reduction was accomplished by the administration of 15-deoxyspergualin (DSG), an immunosuppressive agent which binds to a constitutively expressed member of the 70 kDa heat shock protein family. DSG administered via three different protocols reduced GVHD-associated morbidity. One of the regimens, which consisted of intermittent DSG administration, also significantly reduced GVHD associated mortality. This DSG treatment reduced hsp70 levels in spleen and lymph nodes, inhibited anti-hsp70 antibody production, and diminished the serum levels of IL-2, IFN-gamma, TNF-alpha, and IL-10. IL-4 levels in the serum did not change during GVHD and were not effected by DSG. These results show that the mechanism of DSG immunosuppressive effect in rat GVHD may involve DSG's capacity to bind to hsp70, which in turn may lead to a decrease in levels of circulating anti-hsp70 antibodies, and reduced production of cytokines.
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PMID:Reduced levels of Hsp70 result in a therapeutic effect of 15-deoxyspergualin on acute graft-versus-host disease in (DA x LEW)F1 rats. 1104 61

Some cytokines are believed to play a role in the development of acute and chronic GVHD after allo-hematopoietic stem cell transplantation. It has been reported that TNF-alpha and IL-10 gene polymorphisms are associated with the production of those cytokines and the development of graft failure after organ transplantation and systemic lupus erythematosus. We examined whether TNF-alpha and IL-10 gene polymorphisms affect the severity of acute GVHD (aGVHD) and chronic GVHD (cGVHD). Sixty-two and 54 patients were available for the analysis of aGVHD and cGVHD, respectively. We analyzed the gene polymorphisms derived from pre- and post-transplant blood cells. Donor-derived TNF2 allele (A) was more frequently detected in patients with aGVHD III/IV than those aGVHD 0-II (2/6 vs 2/56) (P = 0.04). The donors of the patients with cGVHD more frequently possessed a greater number of alleles (allele 13 or more which contain 26 or more CA repeats) in IL-10.G than those without (13/26 vs 5/28) (P = 0.02), and the patients with cGVHD had more CA repeats in donor-derived IL-10.G than those without (mean = 25.2 vs 23.4) (P = 0.01). Donor-derived TNF-308 and IL-10.G alleles may contribute to severe aGVHD and cGVHD, respectively, and will help us distinguish those patients at high risk for GVHD.
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PMID:Contribution of TNF-alpha and IL-10 gene polymorphisms to graft-versus-host disease following allo-hematopoietic stem cell transplantation. 1122 72

It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this study we differentiated peripheral blood AML cells in vitro into functional dendritic cells (DCs), as demonstrated by cell morphology, immunophenotype and functional activity, in the presence of GM-CSF, IL-4, TNF-alpha and FLT3 ligand. Such DCs could be differentiated from 77% of AML patients, irrespective of their FAB classification and clinical status and, in all cases tested, the DCs were shown to derive from the leukemic clone by FISH analysis. Importantly, from >60% of AML patients, autologous T lymphocytes stimulated with these in vitro generated leukemic DCs displayed specific cytotoxic activity against AML blasts but low reactivity against autologous non-leukemic targets and HLA-matched normal PBMNCs therefore suggesting that the CTLs were AML-specific. The use of FLT3 ligand in our system resulted in a significantly higher number of leukemic DCs as compared to cultures from which FLT3 ligand was omitted which is obviously advantageous if large numbers of specific CTLs are to be generated in the shortest possible time.
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PMID:Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia. 1123 40

Patients who receive a donor lymphocyte infusion (DLI) for the treatment of relapsed leukemia after allogeneic BMT (alloBMT) often developed GVHD. To determine whether cytokines might have a role in GVHD, an intensive kinetic analysis of in vivo cytokine gene expression was performed on PBMC from three such patients. Expression of IL-1beta, IL-2, IFN-gamma, IL-4, IL-5, IL-8, IL-10, IL-12, TNF-alpha, and IL-2Ralpha was examined using a sensitive semi-quantitative reverse transcription (RT)-PCR assay system. Six normal controls were also analyzed for comparison. Expression of type 1 T helper (Th1) cytokines, IL-2 and IFN-gamma was greatly increased in all three patients. In particular, the changes in IL-2 gene expression correlated well with disease progression, suggesting that IL-2 has a critical role in the development of GVHD. Although the pattern of type 2 T helper (Th2) cytokine gene expression differed in each patient, the expression of IL-4 was inversely related to expression of Th1 cytokines. These results suggest that Th1 dominates in the development of human clinical GVHD.
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PMID:Kinetic analysis of cytokine gene expression in patients with GVHD after donor lymphocyte infusion. 1131 66


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