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)

We previously demonstrated that, following a 2-day stimulation of T cells by MHC incompatible cells, a ricin A-chain conjugated to a monoclonal anti-IL2 receptor p55 subunit can kill 1.5 log of the activated alloreactive T cells while non specific killing of alloreactive T cells of a third partner does not exceed 0.5 log. This methodology is of potential use for selective alloreactive T cell depletion in MHC incompatible bone marrow transplantation in order to prevent both graft versus host disease and graft rejection. This study shows that this T cell depletion method does not alter T cell reactivity to microorganism antigens encountered in infection following BMT. It was found that T cell proliferation to cytomegalovirus and to candida antigens is not affected as shown in proliferative assays and by limiting dilution analysis for the latter antigen.
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PMID:[Residual lymphocytes after specific depletion. Functional study]. 129 44

Two patients with hematologic relapse of chronic myelogenous leukemia (CML) following allogeneic BMT were treated by abrupt discontinuation of cyclosporine. Both patients rapidly attained complete hematologic and cytogenetic remission and remain free of disease with long follow-up. In the first patient, disappearance of CML was associated with the development of graft-versus-host disease (GVHD). In the second patient GVHD did not develop until after clearing of disease had been documented by cytogenetic analysis. Laboratory studies in the second patient disclosed the presence of lytic activity against both K562 and autologous CML cells that enhanced with IL2. Correlation with serial immunophenotyping data from this patient suggests that the effector for this graft-versus-leukemia (GVL) reaction could have been a T lymphocyte. Abrupt discontinuation of post-transplant immunosuppression with cyclosporine may represent a therapeutic approach to CML which has recurred following BMT. Moreover, investigation of this clinical phenomenon in subsequent cases may permit direct study of the cellular mechanisms involved in the GVL effect.
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PMID:Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. 142 99

A 21-year-old man who had an HLA-identical sibling donor BMT for chronic myeloid leukaemia developed grade IV acute GVHD of the liver that was unresponsive to corticosteroids and anti-IL2 receptor monoclonal antibody. He was treated with an orthotopic liver transplant and is currently well 6 months later with normal liver function and no evidence of GVHD in the transplanted liver.
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PMID:Orthotopic liver transplantation for hepatic GVHD following allogeneic BMT for chronic myeloid leukaemia. 146 11

Recombinant fusion proteins consist of the N-terminal 488 or 513 amino acids of diphtheria toxin joined to human interleukin 2. Initially those fusion proteins were expressed in E. coli under the control of the tox promotor. Western blot analyses showed that E. coli strains bearing the hybrid genes produce 68 kDa or 72 kDa fusion proteins that retain the immunological determinants of both the diphtheria toxin component and the interleukin 2 component. The fusion protein with mol. mass 72 kDa was partially purified by affinity chromatography. The expression of the fusion proteins under the control of the strong promotors was increased (100-fold for tac- promotor) compared to that under the control of the tox promotor. DT-IL2 might be a useful cytotoxic agent in the treatment of diseases involving IL2 receptor-positive cells, such as allograft rejection, graft-versus-host disease, multiple sclerosis et al.
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PMID:[Design and expression of a diphtheria toxin hybrid protein and human interleukin-2 gene in Escherichia coli]. 147 Jan 75

In conclusion, lessons from the animal model of lymphoid leukaemia suggest that in the setting of allogeneic BMT, under certain conditions GVL effects may be separable from GVHD; more specifically, GVL effects may be induced despite development of tolerance of donor cells against allogeneic host alloantigens. The latter phenomenon suggests that either curative GVL effects may be inducible despite subclinical GVHD or alternatively that effector cells of GVL may recognize different tumour-associated targets different from cell surface determinants of 'normal' alloantigens. Alternatively, effector cells of GVL may be distinguished from effector cells of GVHD. It is tempting to suggest that NK and IL2-aspirated NK cells may play a major role as effector cells of GVL in an MHC non-restricted fashion, different from classical CD8+ cytotoxic cells that certainly play a major role in GVHD and GVL. Once proven, the latter hypothesis may help develop new and safer therapeutic approaches since NK cells and products of the NK cell family are unlikely to play a major role, if any, in GVHD. The feasibility of induction of GVL-like effects by MHC non-restricted effector cells, such as that observed by CMI, most likely through cytokine-activated NK cells, seems promising because such effector mechanisms may be utilized clinically through either adoptive transfer of in vitro-activated lymphocytes or activation of lymphocytes in vivo by administration of cytokines such as IL2 and alpha IFN. Similarly, induction of CCI following ABMT may permit establishment of GVL-like effects with no major risk of GVHD. Our animal models suggest that both approaches may be beneficial and perhaps even combined. From a practical standpoint, activation of antitumour effector cells in vivo is much more feasible, in comparison with the cumbersome and expensive technologies for large-scale in vitro manipulation of IL2-activated 'LAK' cells or tumour-infiltrating lymphocytes ('TIL') at dose ranges required for obtaining clinically meaningful responses. No less important is the fact that more potent immunotherapy may be inducible by cytokine combinations (such as IL2 and alpha IFN). We are currently investigating additional cytokine combinations in order to attempt to optimize antitumour effects inducible by allogeneic and syngeneic lymphocytes since it appears logical that amplifying in vivo antitumour responses by multiple cytokine combinations may yield better antitumour effects.
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PMID:Control of relapse due to minimal residual disease (MRD) by cell-mediated cytokine-activated immunotherapy in conjunction with bone marrow transplantation. 195 88

From a bank of 50,000 HLA typed French bone marrow donors, 125 transplants have been performed since 1986, with HLA AB and DR--identical MLC--negative donors. The median age was 25 years and the diagnosis was CGL in 59 cases, ALL in 22 cases, AML in 17 cases, SAA in 7 cases, inborn errors in 7 cases and others in 13 cases. Most of the patients received a standard conditioning regimen according to their diagnosis. The prophylaxis of GVHD was methotrexate and cyclosporine A in 77 cases; in addition to this combination 44 patients received an anti-IL2 receptor monoclonal antibody from day +1 to day +28. There was no difference between the two groups as regards the incidence and severity of GVH or survival. The actuarial survival was 36% with a median follow up of 300 days. Unlike matched sibling grafts, the usual prognostic factors such as stage of disease or age were not found to significantly modify the incidence of GVHD, which was 75%. The results of matched unrelated donor transplants are reasonably good, but must be improved by a better selection of donors and better prevention of GVHD.
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PMID:Matched unrelated bone marrow transplants. Results from the French group (GEGMO). 209 99

Graft-versus-leukemia (GVL) is a major component of the overall beneficial effects of allogeneic bone marrow transplantation (BMT) in the treatment of leukemia. Although several clinical trials have suggested a direct relationship between GVL effects and acute and chronic graft-versus-host disease (GVHD), it is not yet known whether GVL can be separated from GVHD. However, several investigations in murine models of human leukemia indicate that the two may be at least partially separable. Moreover, analysis of clinical data from the International Bone Marrow Transplant Registry suggest that allogeneic BMT may be more advantageous than syngeneic BMT, regardless of the GVHD. Likewise, T lymphocyte depletion is associated with an increased incidence of relapse, independently of GVHD. Recent investigations in murine leukemia suggest that GVL-like effects may be inducible following syngeneic BMT by recombinant cytokines with no overt GVHD. Taken together, current data in experimental animals and man suggest that GVL may be at least partially separable from GVHD. Hence, further understanding of effector and target cells of GVL as well as our ability to induce antitumor effector cells, especially those that are MHC nonrestricted, may lead to new approaches for potentiating anti-tumor effector mechanisms without inducing severe, clinically overt GVHD. Successful attempts in these directions may also lead to improved results following autologous BMT as a result of activation of GVL-like effects by recombinant cytokines that are capable of activating effector cells with anti-leukemic activity in vivo, such as recombinant human IL2, alpha interferon or perhaps a synergistic combination of factors.
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PMID:The graft-versus-leukemia (GVL) phenomenon: is GVL separable from GVHD? 225 54

The pathologic features of the acute graft-vs-host disease occurring in unirradiated (C57Bl/6 X A/J)F1 mice injected intravenously with lymphocytes from the C57Bl/6 parent are similar to those reported for other parental----F1 hybrid combinations. When stimulated in culture with concanavalin A, lipopolysaccharide or alloantigen, spleen cells from B6AF1 mice that had been injected 11 days previously with B6 lymphocytes exhibited proliferative responses that were drastically reduced in comparison to the responses of spleen cells from F1 hosts injected with syngeneic lymphocytes. IL2 production in GVH spleen cell cultures was also diminished. Proliferative responses and IL2 production were partially restored in mice given immunosuppressive therapy with azathioprine, cyclosporin A or Sch 24937 a drug whose inhibitory effects on cellular and humoral immune responses in mice have recently been described. Phenotypic analyses by flow cytometry of the GVH splenocyte population indicated that the most consistent change in the GVH spleen was the appearance of an Lyt2+ L3T4+ T cell subset which in the majority of experiments was accompanied by an increase in cells expressing only the Lyt2 antigen. Both subpopulations were reduced in mice that had recovered immunological responsiveness following immunosuppressive therapy. The results suggest that in this GVH model the development of an immunodeficient state is directly related to the induction of an active T suppressor cell population and that such cells are effectively eliminated from the splenocyte population following treatment with some immunosuppressive drugs.
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PMID:Inhibition of graft-vs-host induced immunodeficiency with immunosuppressive therapy. 297 7

Graft versus host disease is a preventable complication of allogenic bone marrow transplantation. A complex biological manoeuvre has enabled us to achieve this. Unfortunately T-cell depletion of the donor marrow shifts the delicate immunological balance in favour of the recipient immune system. The consequence has been an increased risk of graft rejection and leukaemia relapse. It is necessary to shift this balance back in favour of the donor (derived) immune system. This can be achieved by increasing the immunosuppressive power of the 'conditioning' chemoradiotherapy. Toxicity considerations limit our scope although single fraction fast dose rate radiotherapy appears to diminish the risks inherent with T-cell depletion. Logically an approach with greater promise will be to use specific immunological means of eliminating the recipient T lymphocytes in vivo. Early experience with a monoclonal anti-lymphoid antibody in vivo in an HLA matched unrelated donor programme suggests that this approach has great promise whilst lacking toxicity. We hypothesise that a shift in immunological superiority to the donor derived immune system will not only allow T-cell depletion whilst minimising the risk of graft rejection, but also enhance the anti-leukaemic properties of the graft. Of further interest will be the potential for application of lymphokines (e.g. IL2) without increasing the risk of lethal graft versus host disease.
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PMID:Allogeneic bone marrow transplantation. Recent developments and the potential expansion of the donor pool. 306 Jan 58

Bone marrow mononuclear cell (BMMC) transplant may serve to produce donor specific tolerance for a coincident solid organ graft, but with the risk of graft versus host disease (GVHD). We examined in vitro the immunomodulatory effect of UVB on human BMMCs as potential prophylaxis against GVHD for clinical transplantation. After 10-200 J/m2 UVB-irradiation, BMMCs were examined by proliferative response (in mixed lymphocyte reaction and following phytohemagglutinin stimulation) and by cytokine profile. We also evaluated CFU-GM, CFU-GEMM, and BFU-E progenitor viability by 2-week methyl cellulose cultures following UVB-irradiation. Parallel studies were applied to marrow that was T-cell depleted by soybean agglutination (SBA) or by SBA and sheep erythrocyte rosetting (SBA-E-). We found that (1) UVB produces a dose-dependent inhibition of the proliferative response to stimulators by human BMMCs; (2) increasing doses of UVB-irradiation and increasing levels of T-cell depletion (TCD) are both inversely related to production of lymphokines (IL2, IL3, LIF, IFN-gamma, and GMCSF) and (3) T-cell depletion, but not UVB-irradiation, decreases the production of monokines (IL1, TNF, IL6). Progenitor cell viability was decreased but preserved at 100 J/m2 of UVB. Our findings suggest that UVB compares favorably with TCD as a technique for inhibition of GVHD and therefore that UVB-modulation of bone marrow (BM) inoculum may be useful in the prevention of GVHD in clinical bone marrow transplantation accompanying a solid organ graft.
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PMID:UVB-irradiation of human bone marrow: potential for donor specific tolerance. 876 77


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