Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In allogeneic marrow transplantation, donor T cells that recognize recipient alloantigens prevent rejection but also cause graft-versus-host disease (GVHD). To evaluate whether the ability to prevent marrow graft rejection could be dissociated from the ability to cause GVHD, we generated a panel of four different CD8 cytotoxic T-lymphocyte clones specific for H2(d) alloantigens. Three of the clones caused no overt toxicity when as many as 20 x 10(6) cells were infused intravenously into irradiated H2(d)-positive recipients, and one clone caused acute lethal toxicity within 1 to 3 days after transferring 10 x 10(6) cells into H2(d)-positive recipients. One clone that did not cause toxicity was able to prevent rejection of (C57BL/6J x C3H/HeJ)F1 marrow in 800 cGy-irradiated (BALB/cJ x C57BL/6J)F1 recipients without causing GVHD. Large numbers of cells and exogenously administered interleukin-2 were required to prevent rejection. These results with different CD8 clones suggest that GVHD and prevention of rejection could be separable effects mediated by distinct populations of donor T cells that recognize recipient alloantigens.
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PMID:Prevention of marrow graft rejection without induction of graft-versus-host disease by a cytotoxic T-cell clone that recognizes recipient alloantigens. 959 47

Irradiated (800 rads) AKR mice received intravenous (i.v.) reconstitution with a mixture of B10.BR T-depleted bone marrow cells and spleen cells. Only in groups of mice treated additionally with i.v. cyclophosphamide (Cy; 150 mg/kg), 24 hr before transplantation, was long-term (> 60% at 50 days) survival seen. In mice receiving only irradiation all animals died by 30 days post-transplantation. Histological changes consistent with graft-versus-host disease (GVHD) were seen in the liver of reconstituted mice at 30 days, along with an organ-specific increase in V beta 3 T-cell receptor-positive (TCR+) cells. No such increase in V beta 3 TCR+ cells was seen in the spleen from the same mice. These data are consistent with a tissue antigen-driven expansion of V beta 3 TCR+ cells associated with GVHD in the liver in this model. When we analysed cytokine production in vitro from CD3+ cells restimulated with 'host' (AKR) antigen-presenting cells (APC), we found a transition in cytokine production from preferential synthesis of type-1 cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] at early times (day 15) post-reconstitution to increased production of type-2 cytokines [IL-4, transforming growth factor-beta (TGF-beta) and IL-10] at later times (day 30) post-reconstitution in Cy-treated recipients. Animals not receiving Cy did not show this 'switch' in cytokine production at later time points. We have observed a similar polarization in cytokine production, along with increased graft survival, in recipients of vascularized and non-vascularized allografts after portal venous (p.v.), but not i.v., pretransplant donor-specific immunization. We next studied AKR mice receiving 800 rads and subsequently reconstituted with B10.BR stem cells via the p.v. route. Again these mice showed prolonged survival (> 50% at 50 days), with polarization to IL-4, IL-10 and TGF-beta on restimulation of CD3+ cells in vitro at 30 days post-transplant and increased V beta 3 TCR+ cells in the liver. Infusion of anti-IL-12 monoclonal antibodies into irradiated mice receiving i.v. cell reconstitution produced a similar pattern of changes to those seen after p.v. reconstitution, while a combination of anti-IL-10 and anti-TGF-beta monoclonal antibodies reversed the changes seen after p.v. reconstitution. These data are consistent with an important role for differential cytokine production in the regulation of GVHD following allogeneic bone marrow transplantation.
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PMID:Analysis of cytokine production and V beta T-cell receptor subsets in irradiated recipients receiving portal or peripheral venous reconstitution with allogeneic bone marrow cells, with or without additional anti-cytokine monoclonal antibodies. 961 72

Natural killer (NK) cells can kill target cells by either necrotic or apoptotic mechanisms. Using the 51Cr-release assay to measure necrotic death of target cells, neonatal NK cells had low NK activity (K562 targets) and high lymphokine-activated killer (LAK) activity (Daudi targets) compared with adult cells, as has been previously reported. Using a 125I-deoxyuridine (125I-UdR) release assay, cord cells were shown to also have higher apoptotic LAK activity against YAC-1 target cells. Interleukin-4 (IL-4) inhibited interleukin-2 (IL-2)-induced necrotic killing of target cells by adult effectors but had no such inhibitory effect on cord cells. In contrast, IL-4 inhibited both adult and cord LAK cytotoxicity of YAC-1 target cells by apoptotic mechanisms with higher suppression observed in cord cell preparations. Using a colorimetric substrate conversion assay, IL-2 induced higher, and IL-4 had a more significant suppressive effect on, cord cell granzyme B enzyme activity compared with adult cells, paralleling apoptosis cytotoxicity data. Co-culture of either adult or cord LAK cells with IL-4 had a similar inhibitory effect on granzyme B protein expression, as detected by Western blotting. In contrast, IL-4 did not inhibit perforin expression, thereby defining IL-4 as a cytokine that can differentially regulate the NK cell-mediated cytotoxicity processes of apoptosis and necrosis. The differential sensitivity of cord cells to cytokine regulation of cytotoxicity may also have implications for cord blood transplantations, as NK cells are known to function as an effector cell in both graft-versus-host disease and in the graft-versus-leukaemia phenomena.
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PMID:Differential cytokine regulation of natural killer cell-mediated necrotic and apoptotic cytotoxicity. 965 23

Detection of natural killer (NK) cells in the mixed lymphocyte reaction (MLR) was investigated by flow cytometry and cytotoxicity toward the K562 cell line. Peripheral blood mononuclear cells (PBMCs) from normal individuals were stimulated with either lymphoblastoid cell lines (LCLs) or PBMCs. This approach allowed the following observations: 1) after stimulation by LCLs, the percentage of NK cells increased concomitantly with the level of cytotoxicity, in contrast to when PBMCs were used as stimulators; 2) anti-interleukin-2 monoclonal antibody strongly inhibited NK proliferation in the MLR, but antibody to interferon gamma did not; and 3) purified NK cells were unable to proliferate against LCLs. All these data suggest that NK cells induced by LCL stimulators depend on T cells to proliferate in the MLR. Flow cytometric detection of NK cells in the MLR was also used on cryopreserved PBMCs from 31 bone marrow donors, because it has been reported that an enhanced donor NK cell activity was correlated with the development of graft-versus-host disease after HLA-identical sibling bone marrow transplantation. NK cell proliferation under LCL stimulation was intense and varied greatly among the donors tested. However, no statistical correlation was observed between LCL-induced donor NK cell proliferation in the MLR and the occurrence of graft-versus-host disease after bone marrow grafting.
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PMID:Flow cytometric characterization of proliferating natural killer lymphocytes from bone marrow donors in the mixed lymphocyte reaction. 972 60

In the context of allogeneic bone marrow transplantation, an accurate estimate of the risk of developing graft-versus-host disease (GVHD) is of major interest. The pre-transplant frequency of donor's helper T-lymphocyte precursors (HTLp) directed against host's antigens may be helpful in predicting this risk. This technique relies on an indirect measurement of interleukin-2 (IL-2) secreted by the HTLp, as assessed by the proliferation of an IL-2 dependent cell line. Many authors use the murine CTLL-2 cell line in this assay, but these cells do not respond to the presence of minute amounts of IL-2 in the culture medium, and thus do not discriminate between the absence or the presence of very low levels of IL-2. We therefore decided to compare CTLL-2 with another IL-2 dependent cell line, the murine A9.12 cell line. A comparison was made using serial dilutions of recombinant human IL-2, limiting dilutions of baby hamster kidney (BHK) cells transfected with human IL-2 gene and in the context of clinical tests performed for the detection of pre-transplant HTLp. Both the sensitivity and reliability of the tests were better using A9.12. We conclude that the A9.12 cell line might be a more suitable tool for pre-transplant HTLp determinations before allogeneic bone marrow transplantation or whenever low IL-2 levels are to be measured.
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PMID:Improved IL-2 detection for determination of helper T lymphocyte precursor frequency in limiting dilution assay. 974 50

Because CD28-mediated T-cell costimulation has a pivotal role in the initiation and maintenance of T-cell responses, we tested the hypothesis that CD28 is critical for the development of graft-versus-host disease (GVHD). We compared the in vivo effects of CD28(-/-) T cells transplanted from B6 donor with the CD28 gene deleted by homologous recombination with those of CD28(+/+) T cells transplanted from wild-type C57BL/6 (B6) donor. Fifty million CD28(-/-) or CD28(+/+) splenocytes from B6 mice were transplanted into unirradiated (B6 x DBA/2)F1 (BDF1) recipients. Unlike CD28(+/+), CD28(-/-) T cells from B6 mice had lower levels of proliferation and interleukin-2 production, had a limited ability to generate cytotoxic T lymphocytes against the recipient, and did not induce immune deficiency, despite survival in the recipient for at least 28 days. The ability to prevent rejection was reduced by the absence of CD28, because as many as 1.0 x 10(7) CD28(-/-) CD8(+) cells were needed to prevent rejection of major histocompatibility complex (MHC) class-I incompatible marrow in sublethally irradiated (550 cGy) bm1 recipients, whereas 8.0 x 10(5) CD28(+/+) CD8(+) T cells were sufficient to produce a similar effect, indicating that CD28 on donor CD8(+) cells helps to eliminate host immunity. Two million CD4(+) CD28(-/-) or CD28(+/+) T cells were transplanted into sublethally irradiated (750 cGy), MHC class-II incompatible (B6 x bm12)F1 recipients. With CD28(-/-) cells, 44% of the recipients died at a median of 20 days compared with 94% at a median of 15 days with CD28(+/+) cells (P < .001). Two million CD8(+) CD28(-/-) or CD28(+/+) T cells were transplanted into sublethally irradiated (750 cGy), MHC class-I incompatible (B6 x bm1) F1 recipients. With CD28(-/-) cells, 25% of the recipients died at a median of 41 days compared with 100% at a median of 15 days with CD28(+/+) cells (P < . 001). (B6 x bm12)F1 and (B6 x bm1)F1 mice surviving after transplantation of CD28(-/-) cells recovered thymocytes, T cells, and B cells in numbers and function comparable with that of irradiation-control F1 mice. We conclude that CD28 contributes to the pathogenesis and the severity of GVHD. Our results suggest that the severity of GVHD could be decreased by the administration of agents that block CD28 function in T lymphocytes.
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PMID:Role of CD28 in acute graft-versus-host disease. 976 84

This study demonstrates that systemic interleukin 2 (IL-2) can decrease the homing of syngeneic immune T cells to the target organ of metastases and accelerate unwanted side effects of allogeneic immune T cells. As a tumor system, we used the well-characterized highly aggressive DBA/2 mouse leukemia ESb and its less aggressive adhesion variant, ESb-MP. Systemic IL-2 treatment was performed with recombinant human interleukin-2 (Proleukin), which was slowly released via an implanted osmotic pump or was modified with polyethylene glycol (PEG-IL-2) to achieve constant plasma levels. Allogeneic B10.D2 antitumor immune spleen cells (ISPL cells) exerted strong graft-versus-leukemia (GvL) reactivity after adoptive transfer into late-stage ESb-MP tumor-bearing DBA/2 mice. Mls(a) superantigen-reactive vbeta6 donor T cells were not eliminated or tolerized by in vivo priming with the tumor cells and were present in active proliferation in liver infiltrates. When exogenous PEG-IL-2 or Proleukin was applied in addition to ISPL cells in such mice, the strong GvL-mediated protective immunity was converted into a fatal graft-versus-host disease. IL-2 treatment alone had no toxic effect and caused a moderate protection effect in the absence of an effect on local tumor growth. Potentiation of GvH reactivity of B10.D2 ISPL by PEG-IL-2 was proven in non-tumor-bearing DBA/2 mice, in which graft-versus-host disease was characterized by: (a) heavy hepatic lymphocytic infiltration, (b) irreversible increase of serum glutamate-oxalacetate-transaminase and glutamate-pyruvate-transaminase levels, (c) weight loss, and (d) death. Antagonistic effects of systemic IL-2 on GvL were observed with syngeneic DBA/2 anti-ESb immune peritoneal effector cells (PECs). There was a detrimental effect of systemic IL-2 on liver target organ infiltration by immune T cells causing, at day 6 after transfer, a drop from 20-30 CD4 or CD8 T cells per liver lobule in the PEC group to <5 in the PEC plus IL-2 group. The results emphasize the importance of a better understanding of IL-2 function in vivo and of its interaction with immune cell function to improve protocols for optimal application in the clinic to achieve maximal GvL effects.
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PMID:Antagonistic effects of systemic interleukin 2 on immune Tcell-mediated graft-versus-leukemia reactivity. 982 26

T cell activation is assumed to play a crucial role in many viral infections. An important marker for the activation of T cells is the interleukin-2 receptor (IL-2R); resting T lymphocytes do not bear detectable amounts of IL-2R. AMT13, a rat monoclonal antibody against mouse IL-2R, inhibits interleukin-2-dependent cell growth both in vitro and in vivo. Therefore, to clarify the effects of anti-IL-2R antibody treatment upon coxsackievirus B3 (CB3)-infected C3H/He mice, AMT13, 1 microg/mouse per day, was administered, subcutaneously, starting on day 0 (group 2) in experiment I or on day 7 (group 4) in Experiment II for 7 days, respectively. Groups 1 and 3 were examined as infected controls. In both experiments, there was no significant difference in mortality or in the severity of myocarditis between the treated and the untreated groups. Also, myocardial CB3 titers on day 7 did not differ significantly between groups 1 and 2. In addition, the distribution of activated T cell subsets in the inflamed myocardium was not changed by the treatment, and the paucity of myocardial IL-2R-positive cells was confirmed in all groups. Effects of the antibody treatment were confirmed by a decrease in delayed type hypersensitivity. Although some reports have shown that anti-IL-2R antibody has been successfully applied to ameliorate acute renal graft-versus-host disease, to enhance survival of skin allografts, and to suppress diabetic insulitis, it did not exert a beneficial effect on acute CB3 myocarditis in mice.
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PMID:Failure of treatment with interleukin-2 receptor-specific monoclonal antibody in acute coxsackievirus B3 myocarditis in mice. 984 7

Long-term outcome of 23 acute myeloid (AML, n=16) or lymphoblastic (ALL, n=7) leukemia patients who had received immunotherapy for treatment of persistent or recurrent disease 1.5-26 (median 4) months after allogeneic transplantation was studied to determine eventual survival. Immune manipulation comprised donor leukocyte infusion (n=18), interferon-alpha2b and/or interleukin-2 (n=15), and cyclosporine withdrawal (n=11) in various combinations. Graft-versus-host disease (GVHD) developed in 12 patients. Thirteen of 20 evaluable patients responded; 6 relapsing again. Eight patients died of toxicity, and 10 of progressive disease at 3-206 weeks (median 11). Five patients (3 AML, 2 ALL) are alive in remission with GVHD 2-46 months (median 23) after immunotherapy with Karnofsky scores of 70-100% (median 80). The overall survival of the whole group is 1-206 weeks (median 12), with an actuarial survival of 22% at 2 years. The development of GVHD was associated with superior survival in multivariate analysis (P=.007). Seven patients received immunosuppression because of the severity of GVHD (grade III/IV acute or extensive chronic): 3 died of GVHD, 3 improved but relapsed concomitantly, and 1 is alive in remission with extensive chronic GVHD. Four episodes of extramedullary relapse (granulocytic sarcomas) were seen in 3 patients with AML whose marrow remained in remission. We conclude that GVHD appears to be inseparable from graft-versus-leukemia in relapsed acute leukemia patients undergoing immunotherapy with a high proportion of patients dying due to toxicity or progressive disease, and isolated extramedullary relapse seems to be unusually common.
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PMID:Long-term follow-up of relapsed acute leukemia treated with immunotherapy after allogeneic transplantation: the inseparability of graft-versus-host disease and graft-versus-leukemia, and the problem of extramedullary relapse. 1004 23

Intercellular adhesion molecule-1 (ICAM-1) is expressed abnormally on the bile duct epithelium during the course of primary biliary cirrhosis (PBC), but the importance of ICAM-1 and its lymphocyte function-associated antigen-1 (LFA-1) receptor during the course of nonsuppurative destructive cholangitis (NSDC) has not been defined. To address this question, we defined the relationship between ICAM-1 on the intrahepatic bile duct epithelium and the evolution of NSDC lesions in a mouse graft-versus-host disease (GVHD) model. We also determined the effects of anti-ICAM-1 and anti-LFA-1 treatments on NSDC, intrahepatic lymphokine production, and the homing of lymphocytes to the livers of GVHD mice. ICAM-1 was initially detected on the bile duct epithelium and portal vein endothelium on day 7 of GVHD. There was a significant positive correlation between the intensity of ICAM-1 staining and histological bile duct damage (r =.58, P <.05) between day 3 and 28. Treatment with anti-ICAM-1 (but not anti-LFA-1) decreased both the mean grades of portal inflammation (P =.003) and NSDC (P =.002) lesions compared with control immunoglobulin G (IgG) treatments. Combined treatment with anti-ICAM-1 and anti-LFA-1 caused a further decrease in the amount of portal inflammation and bile duct damage compared with anti-ICAM-1, alone (P =.02). Anti-ICAM-1 treatment also decreased both the percentage of T cells and the production of interleukin-2 (IL-2) and IL-12 in the liver (P <.01), but had no effect on IL-4, IL-10, and interferon gamma. Neither anti-ICAM-1 nor anti-LFA-1 prevented lymphocytes from homing to the liver. These results indicate that both ICAM-1 and LFA-1 are important to the pathogenesis of NSDC.
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PMID:Role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 during nonsuppurative destructive cholangitis in a mouse graft-versus-host disease model. 1005 78


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