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)

Hyperacute graft-versus-host disease (GVHD), which progresses severely and rapidly, was observed in three patients with acute leukemia transplanted with bone marrow cells from human leukocyte antigens (HLA)-identical and mixed leukocyte reactions (MLR)-negative siblings. Hyperacute GVHD developed in these patients within 7 days after bone marrow transplantation (BMT) and was rapidly aggravated inspite of cyclosporin A (CyA) and short-term methotrexate (MTX) prophylaxis and treatment with bolus methylprednisolone (mPSL). These patients showed markedly increased serum interleukin-6 (IL-6) levels after BMT, whereas other cytokines such as interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), and IL-2 were not increased compared with pretreatment levels. These findings suggest that markedly increased IL-6 levels may be related to hyperacute GVHD.
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PMID:Hyperacute graft-versus-host disease accompanied by increased serum interleukin-6 levels. 791 41

In patients with acute graft-versus-host disease (GVHD), IL-6 gradually increased > 14 days before clinical onset of acute GVHD and decreased when acute GVHD disappeared. Interferon-gamma (IFN gamma) levels increased < 14 days before clinical acute GVHD and decreased at the disappearance of acute GVHD. Tumor necrosis factor-alpha (TNF alpha) levels increased almost simultaneously with the onset of acute GVHD and also decreased when it disappeared. However, these results do not necessarily mean that the increased levels of IL-6, IFN gamma and TNF alpha induced acute GVHD; they merely show that acute GVHD is observed more frequently in patients with increased IL-6, IFN gamma and TNF alpha levels than in those with normal levels. Although increased IL-6 levels were also observed in patients without acute GVHD, concomitant increase of IFN gamma and TNF alpha was not detected in such cases, showing that IL-6 can be increased by even graft-versus-host reaction (GVHR) which may not develop into clinical acute GVHD. Taken together, acute GVHD appeared to be induced by synergistic interaction of IL-6, IFN gamma and TNF alpha, consistent with a cytokine cascade. A similar interaction of IL-6 and TNF alpha was also observed in chronic GVHD. Although IFN gamma levels were slightly increased in chronic GVHD and sometimes aggravated the disease status, IL-6 and TNF alpha appeared to be more closely involved in the induction of chronic GVHD. In autologous BMT, increased cytokine levels were not observed unless IL-2 was administered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum cytokine levels in bone marrow transplantation: synergistic interaction of interleukin-6, interferon-gamma, and tumor necrosis factor-alpha in graft-versus-host disease. 792 Mar 9

We have investigated cytokine gene expression in the two-way mixed lymphocyte cultures (MLC) enhanced by concanavalin A to assess whether this is a useful predictive method for severe graft-versus-host disease (GVHD) and graft failure in nine allogeneic bone marrow transplantation (allo-BMT) patients. Our present study revealed that increased IL-2, IL-5 and IFN-gamma mRNA expression and IL-2 and IFN-gamma production in the MLC in two cases with severe lethal transplantation-related complications (graft failure and grade III acute GVHD). These findings suggest that increased cytokine mRNA expression and cytokine products in this assay may be predictive of the development of transplantation-related complications.
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PMID:Cytokine gene expression in the mixed lymphocyte culture in allogenic bone marrow transplants as a predictive method for transplantation-related complications. 794 91

Severe combined immunodeficient (SCID) mice defective in stem cells for T and B cells appear to be an ideal host for construction of chimeric mice. When bone marrow cells are used as a source of stem cells, however, host SCID mice do not always show sufficient reconstitution. In this study, fetal liver cells from AKR embryos were transplanted into SCID mice without prior irradiation. This treatment induced full reconstitution of lymphopoiesis as evaluated by flow cytometry analysis and serum Ig production 2 months after transplantation. Thus, fetal liver cells seem to be a better source for reconstitution of SCID mice than bone marrow cells. Lymph node (LN) cells of these mice (FLT mice) had no proliferative or cytotoxic activities against either host-type (C.B-17) or donor-type (AKR) spleen cells. However, spleen cells from FLT mice exhibited marked proliferative and cytotoxic activities against C.B-17 cells, with no activities against AKR cells. Split tolerance against C.B-17 cells in spleen and LN cells was not a transient phenomenon, since similar results were obtained from a cytotoxic T lymphocyte assay 4 months later. In spite of the strong host reactivity in vitro, aberration of clonal deletion or development of a graft-versus-host disease was not seen in FLT mice. As IL-2 induced the host reactivity of LN cells in a mixed lymphocyte reaction, potentially host-reactive T cells were present in LN but were rendered anergic. Tolerance in FLT mice seems to be regulated by a peripheral mechanism. We supposed that the split tolerance in FLT mice was induced by the different antigenicity between the spleen and LN.
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PMID:Split tolerance between spleen and lymph node cells in severe combined immunodeficiency mice grafted with AKR fetal liver cells. 798 Nov 49

Interleukin-6 (IL-6) induced increased, leukocyte and platelet counts on around day 20 when it was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 1 to day 12. Increased leukocyte counts and hemoglobin (Hb) levels were also observed at around day 60 and from day 41 to 80, respectively. On the other hand, hematopoietic recovery in [C3H/He-->C3H/He] bone marrow chimeras injected with IL-6 was different from that in [BALB/c-->C3H/He] bone marrow chimeras, showing no delayed and long-lasting increase in Hb levels but showing an early and transient increase in Hb levels and platelet counts. Sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 showed predominant productions of IL-3 and/or IL-4. Reverse transcriptase polymerase chain reaction (RT-PCR) showed that stem cell factor (SCF) mRNA expression was increased in bone marrow or spleen cells from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 on day 36. Furthermore, we analyzed influence of IL-6 on graft-versus-host disease (GVHD) in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6. Decreased survival days and body weights were not observed when compared with the control. Histopathological changes of the liver due to GVHD were also not obvious. However, alloreactive mixed lymphocyte reactions (MLRs) were readily detected although cytotoxic T cells were not generated. Since H-2 typing showed that donor-type chimerism was predominantly observed, it was suggested that split tolerance might be induced by IL-6 administration. Increased IL-2 levels were not detected in sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 whereas IL-4 was detected in the same sera, indicating that type 2 helper T (TH2) cells appeared to be predominantly generated. These results suggest that IL-3/IL-4 and SCF appeared to synergistically support delayed effects on hematopoiesis in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 although early effects appeared to be mediated mainly by IL-6 directly or indirectly. Furthermore, IL-6 could induce split tolerance in [BALB/c-->C3H/He] bone marrow chimeras via a preferable activation of TH2 type cells without inducing severe GVHD.
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PMID:In vivo administration of interleukin-6 in murine allogeneic bone marrow chimeras: early and delayed enhancement of hematopoiesis accompanied with split tolerance but not with graft-versus-host disease. 798 20

Donor/recipient histocompatibility antigen differences initiate acute graft-versus-host disease (GVHD) after bone marrow transplantation. Frequency analysis, using limiting dilution techniques, of functionally defined (helper or cytotoxic) antirecipient T lymphocyte precursors in the peripheral blood of the donor has been shown to be an accurate predictor for the development of moderate-to-severe acute GVHD. Here, we describe a sensitive assay for measuring alloreactive helper (IL-2-producing) T lymphocyte precursor (HTLp) frequencies, and compare the ability of this assay and the cytotoxic T lymphocyte precursor (CTLp) assay to detect HLA- class II and class I differences and to predict clinical outcome in a cohort of unrelated donor/recipient BMT pairs. Twenty-two pairs underwent unrelated donor BMT. Patients with high (> 1:100 x 10(3)) HTLp or CTLp frequencies had a higher incidence of moderate-to-severe (grades II-IV) acute GVHD (80% and 100%, respectively) than pairs with low (< 1:100 x 10(3)) frequencies (40% and 57%, respectively). Ten (45%) patients have died, but all patients with both a low HTLp and low CTLp frequency remain alive. The HTLp and CTLp assays provided similar predictive information for outcome. Given that the HTLp assay is more rapid and less labor intensive, it offers an additional or alternative functional method for donor selection in unrelated donor BMT.
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PMID:Comparison of helper and cytotoxic antirecipient T cell frequencies in unrelated bone marrow transplantation. 799 63

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

To determine the degree of graft versus host disease (GVHD) prophylaxis that might be necessary if cord blood (CB) transplantation is more widely applied, we compared human cord blood mononuclear cell (CBMC) and adult peripheral blood mononuclear cell (PBMC) proliferative responses and stimulatory capabilities; to examine the utility of UVB irradiation for GVHD prophylaxis, we compared proliferative responses, antigen-presenting cell (APC) stimulatory functions, and cytokine production by untreated and UVB-irradiated CBMCs. The two cell types, CBMC and PBMC, proliferated equally both in response to phytohemagglutinin (PHA) and alloantigen in mixed lymphocyte culture (MLC). Cord blood stimulatory function in MLC was significantly (P < 0.05) reduced to 60% of PBMC stimulatory capability. Ultraviolet-B irradiation at a dose of 100 J/m2 of CBMCs significantly (P < 0.01) inhibited PHA stimulation by 79.4%, reduced responder activity in MLC by 75.8%, and inhibited stimulatory activity in MLC by 55.6% as compared with the activity shown by untreated CBMCs. The same dose of UVB preserved 59.9% of CFU-GM and 65.9% of BFU-E colony growth as compared with untreated CBMCs. Production of lymphokines (IL-2, GM-CSF, LIF, and gamma-IFN) by PHA-stimulated CBMCs was decreased, but monokine (IL-1 beta and IL-6) production was unchanged. We conclude that UVB irradiation at a dose of 100 J/m2 inhibits CB lymphocyte activation and preserves the cellular growth potential of CB hematopoietic progenitor cells.
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PMID:The effect of UVB irradiation on proliferative activity and cell growth potential of cord blood. 807 20

Prior work using the parent-into-F1 model of graft-versus-host disease (GVHD) has shown that production of IL-2 by donor CD4+ T cells is an early, initiating event in either acute or stimulatory forms of GVHD. The aim of the present study was to determine whether acute GVHD could be prevented by blocking the effects of IL-2 in vivo during the first 2 weeks of disease. Acute GVHD was induced in B6D2F1 mice by the injection of C57BL/6 spleen cells i.v. Mice were untreated or received either anti-IL-2 mAb (S4B6) or control mAb at the time of GVHD induction and 1 week later. At 2 weeks, untreated or control mAb treated GVHD mice exhibited findings typical of acute GVHD, i.e. (i) in vitro donor anti-host cytotoxic T lymphocyte (CTL) activity, (ii) significant reductions in both numbers and function of splenic lymphocytes, and (iii) in vitro suppressor cell activity which profoundly blocked IL-2 production by normal syngeneic spleen cells. All of these findings were reversed or significantly inhibited in acute GVHD mice receiving anti-IL-2 treatment. Additionally, anti-IL-2 treated GVHD mice exhibited features previously observed in stimulatory GVHD such as: (i) B cell hyperactivity, (ii) a mild defect in CD4+ T cell production of IL-2 in vitro, and (iii) the ability to induce in co-culture a similar CD4+ cell defect in normal, syngeneic F1 spleen cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Critical role of interleukin-2 in the development of acute graft-versus-host disease. 810 48

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


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