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)

We studied a severe combined immunodeficiency (SCID) patient who received transplantations with completely HLA-mismatched fetal liver and thymus from two different donors. The patient is now 14 years old, healthy and shows normal immunoresponses to recall antigens. His T cells are of donor origin, whereas the monocytes, B cells, and natural killer (NK) cells are of the recipient. The successful immunological reconstitution raised questions as to how T and B cells could collaborate across an HLA barrier and how tolerance was achieved. We have shown that tetanus toxin-specific T cell clones isolated from this patient recognized this antigen in the context of host and not of donor HLA-DR, indicating that those cells were educated in the host environment, presumably the thymus. Despite this, an unexpectedly high frequency of host-reactive clones was found that could recognize MHC antigens of the host. It was particularly striking that CD8+ CTL clones were obtained that recognized class I MHC antigens on the host cells. Nevertheless, the patient did not show any sign of acute or chronic graft-versus-host disease (GVHD). These data indicated that no or only incomplete clonal deletion had taken place in this patient and suggest the presence of a peripheral suppressor mechanism. Thus far, we have no indication for the existence of suppressor T cells. Inasmuch as it was found that host-reactive T cells fail to produce IL-4, which is exceptional for CD4+ T cells, we are exploring the possibility that abnormal cytokine production patterns of host-reactive T cells are associated with suppression of these cells in vivo.
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PMID:A SCID patient reconstituted with HLA-incompatible fetal stem cells as a model for studying transplantation tolerance. 168 May 8

We have shown that acute (GVH) reactions produced in the parental-F1 hybrid combination, A/J----(C57BL/6 x A/J)F1 result in the activation of two cytotoxic cell populations: a host-derived Thy-1+/- natural killer (NK) cell with a lytic spectrum confined to YAC-1 targets, and a donor-derived Thy-1+ NK-like cell that has the ability to lyse target cells that are normally insensitive to lysis by NK cells. Cold-target inhibition (CTI) experiments have shown that the greater range of target cell killing seen in the NK-like population is mediated by a single effector cell with a broadened lytic repertoire. Percoll density fractionation studies have revealed that NK and NK-like cells co-fractionate, suggesting that both are large granular lymphocytes. We we have also shown that NK-like cells do not express either Lyt-2 or L3T4 markers. We have also observed that there is a close temporal relationship between elevated levels of interleukin-2 (IL-2) secretion by spleen cell cultures from mice with GVH disease and the subsequent emergence of splenic NK activity in both acute [A/J----(C57BL/6 x A/J)F1] and chronic (A/J----CBA x A/J)F1 GVH reactions. We have also noted that, despite high levels of IL-2 secretion, mice with chronic GVH reactions do not generate NK-like activity. Interferon (IFN) measurements have shown that, although increased IFN activity can be detected in both acute and chronic models, a preponderance of IFN-alpha/beta and some IFN-gamma is produced in the acute reaction, whereas only IFN-gamma can be detected in the chronic model. These results suggest that, although IL-2 may participate in augmenting conventional NK activity, IL-2 by itself does not generate NK-like activity. We suggest that IFN-alpha/beta may be the cytokine that, either alone or in concert with IL-2, triggers the NK-like cell response. The NK-like cell described in our study resembles a phenotypically identical, donor-derived large granular lymphocyte, identified by others, in close proximity to dead or dying epithelial cells in mice with GVH disease [14]. It has been suggested that these cells may mediate tissue injury. If in fact these graft-derived NK-like cells are involved in the pathogenesis of acute GVH disease, our present findings suggest that they must first be activated by an appropriate complement of cytokines that includes IFN-alpha/beta.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Natural killer (NK) cell activity in mice with acute graft-versus-host reactions: characterization of a Thy-1+ NK-like cell with a broadened spectrum of lytic activity in the spleen and lymph nodes. 170 18

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.
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PMID:Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. 174 91

Follow-up studies on the release of tumor necrosis factor-alpha (TNF-alpha) in 114 patients confirm that this cytokine is released early in the course of endothelial complications, acute graft-versus-host disease, and interstitial pneumonitis following allogeneic bone marrow transplantation. Possible sources of systemic TNF-alpha activity are, in particular, tissue macrophages of the recipient type that are stimulated by pretransplant conditioning and endotoxin and subsequently further activated by interferon gamma released by donor lymphocytes. Consideration of these interactions permits the early recognition of high-risk patients, and suggests new strategies for prophylaxis and treatment of complications.
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PMID:[TNF-alpha in allogeneic bone marrow transplantation. Significance for immunologic reconstitution, acute graft versus host disease and risk of complications after bone marrow transplantation]. 185 57

The role of cytokines in the development of acute graft-vs-host disease (GVHD) was investigated in B6AF1 mice that were injected with parental A/J lymphocytes. Splenocytes from GVH mice exhibited an increased capacity to produce interleukin (IL)-1, IL-6, and TNF-a when stimulated in culture with lipopolysaccharide (LPS). This enhanced capacity was diminished following in vivo treatment with immunosuppressive drugs. Concanavalin A-stimulated GVH spleen cells produced significantly lower levels of IL-2 but higher levels of interferon-gamma (IFN-gamma) than did syngeneic spleen cells. Immunosuppressive therapy in vivo increased the capacity of GVH spleen cells to produce IL-2. However, immunosuppressants differed in their effects on IFN-gamma production. Sch 24937 (6-bromo-5-chloro-2-[1-(methylsulfonyl)acetyl] 3-(2-pyridyl)indole) enhanced or had no effect while cyclosporin A consistently decreased the capacity of splenocytes to produce this lymphokine. These results indicate that the capacity of GVH splenocytes for cytokine production can be differentially affected by the actions of some pharmacological agents. The data also indicate that there may be differential regulation of the production of IL-2 and IFN-gamma by the Th1 subset in the GVH spleen.
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PMID:A study of cytokine production in acute graft-vs-host disease. 190 99

Monoclonal antibodies are increasingly used for treatment of acute graft-versus-host disease (aGVHD) in bone marrow transplantation. We treated seven patients with steroid resistant aGVHD with the monoclonal anti-T cell antibody OKT3. Though five patients showed improvement of aGVHD, only two became long-term survivors. OKT3 treatment was accompanied by deterioration of microangiopathy and prolonged increase of tumor-necrosis-factor alpha serum levels indicating activation of monocytes/macrophages in vivo, as this was not observed in a control group of patients receiving anti-T cell globulin. These findings may be related to immunostimulatory activity reported for OKT3 in vitro. Strategies interfering with cytokine release should improve clinical results of OKT3 treatment.
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PMID:Treatment of aGVHD with OKT3: clinical outcome and side-effects associated with release of TNF alpha. 193 64

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

Current graft-versus-host disease (GVHD) prophylaxis is not uniformly successful. Since the development of GVHD has a profound impact on transplant success, treatment is required. The mainstay of therapy has been glucocorticoids (steroids), along with anti-thymocyte globulin, cyclosporine, monoclonal antibodies, and aggressive supportive care, resulting in response rates of 30-50%, dependent upon severity of the disease, type of transplant, underlying diagnosis, prophylaxis given and other factors. Dose intensification or combinations of agents may increase response rates (60-80%), however, without necessarily improving survival, due to intervening complications. Nevertheless, patients with complete responses have a higher probability of survival, and a subgroup of patients will not develop chronic GVHD. As our understanding of cell recruitment, cell interactions and cytokine networks improves, new strategies are likely to be developed. The sequential use of antibodies directed at different cell populations or cytokines, along with anti-inflammatory measures, may be helpful. Prevention of GVHD has to remain our objective; however, efforts at therapy must continue until that goal is achieved.
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PMID:Management of acute graft-versus-host disease. 220 60

Tumor necrosis factor is one of the recently cloned cytokines with pleiotropic effects on normal and malignant cells. Our knowledge about the scope of cells producing or responding to this cytokine has enormously expanded. In critically ill patients with acute hepatic failure, acute graft-versus-host disease, or septic shock, circulating tumor necrosis factor can be measured and useful prognostic correlations do exist. Despite promising in vitro results, early clinical trials with tumor necrosis factor for the treatment of cancer have failed thus far to reveal major antineoplastic activity in cancer patients. However, more clinical trials are necessary, since different routes of administration and combinations with other cytokines may lead to favorable results.
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PMID:Tumor necrosis factor: an update on basic research and clinical applications. 221 7

Tumor necrosis factor (TNF) is a cytokine produced mainly by activated monocytes/macrophages. We review here data obtained in four experimental models analyzed in our laboratory: cerebral malaria, graft-versus-host disease, BCG infection, and bleomycin-induced pulmonary fibrosis. We have shown that the triggering of these pathological conditions requires activation of T lymphocytes and overproduction of TNF, since these syndromes are associated with increased production of TNF mRNA and can be prevented either by T-cell depletion or by in vivo administration of neutralizing anti-TNF antibodies. These observations suggest that TNF is a central mediator in various immunopathological conditions and thus widen the field of T-cell mediated pathology.
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PMID:[Tumor necrosis factor (TNF) and pathology; its relationships with other cytokines]. 248 41


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