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)

Recent studies performed in Seattle, USA have suggested that pretransplant assignment of high or low donor alloreactivity may predict acute graft-versus-host disease (aGvHD) after allogeneic HLA identical marrow transplantation for acute leukaemia. The effect of such pretransplant assignment was studied in a Scandinavian population of 114 consecutive transplantations for acute and chronic leukaemias in 1st remission (n = 74) or chronic phase (n = 40) performed between 1975 and 1989. The selected cut-off value for discriminating between donors of high and low responding capacity (DRC) was based on distribution plots of results from the pretransplant mixed lymphocyte culture (MLC) and chosen as the median value (80% normalized response). Then 57 donors were assigned with high DRC and 57 donors assigned with low DRC. Kaplan-Meier estimates of the probability of patients to develop Grade II or higher aGvHD in receipt of high or low responder donor transplants were compared by univariant analysis. The patients in first remission or chronic phase transplanted with bone marrow from donors assigned as high or low responders had a 36.1% and 10.6% risk for aGvHD, respectively, a difference found to be significant by log rank test (chi-squared = 10.1, d.f. = 1, P = 0.0015). Subsequent studies of the cellular and humoral requirements for this predictive response of donor cells, by blocking with cytokine specific antibodies, addition of excess of recombinant human cytokines and scanning of lymphocyte subsets during the response, showed that the response against pool cells mostly depended upon IL-2 responding cells with the phenotype CD3+, CD4+, CD8-, CD25+, CD16-. It is concluded that prospective studies of alloreactivity as a risk factor should be performed to confirm the above findings.
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PMID:A study of donor alloreactivity, which may predict acute graft-versus-host disease in HLA identical bone marrow transplantations for early leukaemia. 153 90

The observation that malignant cells express antigens that may be recognized by immunocytes and that immune effector mechanisms have the capability of destroying tumor cells has increased our appreciation of the biology of cancer and its relationship to immune function as well as offered new options for therapeutic intervention. Clinical trials are in progress to evaluate several different approaches to modifying the host's immune response against tumor. One approach is to administer agents that have direct activity against the malignancy. For example, antibody conjugates bring cytotoxic molecules of chemotherapy, radioisotopes, or toxins directly to the tumor. A second approach is to administer agents that modulate the host's own antitumor response such as IFN-alpha and IFN-gamma. Adoptive cellular immunotherapy aimed at isolating and expanding the host's own tumor-specific lymphocytes and inducing activation and proliferation with lymphokines such as IL-2 has shown encouraging results. Even though clinical data are still quite premature, it is reasonable to assume that in the future immunomodulation including the stimulation of immune effector mechanisms to eradicate tumor, the reconstitution of immune deficiency in diseases such as AIDS, the suppression of immune function to avoid graft rejection and GVHD, and the isolation and insertion of genes encoding tumor antigens into recombinant vectors to immunize the host to the tumor antigen will be commonly and successfully employed.
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PMID:The role of the immune system in the pathogenesis of cancer. 154 19

Only in the last decade have autologous grafts begun to be studied extensively. Their most attractive feature is the avoidance of GVHD. However, GVHD has antitumoral effect on residual leukemic cells called "graft versus leukemia" effect and better understanding of this phenomenon explains the higher relapse rate after autologous bone marrow transplantation. New approaches such as cyclosporin--induced GVHD and IL-2 administration after autograft bring great expectations in this field. Colony stimulating factors and harvesting of peripheral stem cells help to reduce the duration of neutropenia. Finally, various techniques for marrow purging and hematopoietic cell isolation should make it possible to eliminate minimal residual disease. Recent results of autologous bone marrow transplantation in various malignancies are discussed.
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PMID:[Bone marrow autograft in malignant hemopathies. The Team of the Sterile Unit]. 160 91

Four to six weeks after total lymphoid irradiation (TLI), there is a selective deficit in the CD4+ T cells which secrete IL-2, proliferate in the MLR, and induce GVHD (Th1-like functions). A similar deficit in CD4+ T cells which secrete IL-4 and help antibody responses (Th2-like functions) is not observed. In the present study, shielding of the thymus with lead during TLI increased the Th1-like functions of CD4+ cells. Mice without thymus shields showed a marked selective reduction in the medullary stromal cells identified with the monoclonal antibody, MD1, and the severe reduction was prevented with thymus shields. Thus, shielding the thymus prevents the depletion of thymic medullary stromal cells and allows for a rapid recovery of Th1-like functions in the mouse spleen after TLI. Th2-like functions recover rapidly after TLI whether or not the thymus is irradiated.
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PMID:Thymic irradiation inhibits the rapid recovery of TH1 but not TH2-like functions of CD4+ T cells after total lymphoid irradiation. 168 27

Twenty-nine patients with advanced leukemias (median age 34 years) received histocompatible sibling marrow that had been depleted of T cells by ex vivo incubation with anti-CD5 monoclonal antibody-ricin immunotoxin (T101-R) for the purpose of graft-versus-host disease prophylaxis. Donor cell engraftment was documented in 28/29 patients by DNA restriction fragment length polymorphisms. In this pilot study the dose of T101-R incubated with donor marrow was increased in a stepwise manner from 300 ng (10 patients) to 600 ng (5 patients) to 1000 ng immunotoxin (IT)/10(7) bone marrow mononuclear cells (14 patients) in an attempt to achieve more effective GvHD prophylaxis. A statistically significant reduction in acute GvHD was achieved for patients receiving marrow pretreated with 1000 ng of immunotoxin (34%) compared to recipients of BM treated with 300 ng immunotoxin (100%, P = 0.0004). T-depleted marrow samples were evaluated for residual T cell activity using several in vitro assays including proliferation to the purified mitogen PHA (HA-17) and in mixed lymphocyte culture (MLC), T cell cytotoxicity, a limiting dilution assay for detecting precursors of proliferating T cells (LDApPTL), and phenotypic analysis of viable T cells expanded in 16-day culture with interleukin 2. The extent of T cell depletion determined by LDA assay varied widely at each immunotoxin concentration used. Thus, there was no correlation between the dose of T cells infused and subsequent GvHD. Phenotyping of lymphocytes recovered from immunotoxin-treated marrow demonstrated that residual T cells were CD5 negative in all cases tested. The only in vitro parameter that predicted subsequent acute or chronic GvHD was the demonstration of viable CD5 negative lymphocytes with T cell phenotype (CD2, CD3, and/or CD7 positive) after 16-day culture with IL-2 of the T-depleted bone marrow. We observed that such CD5 negative cells expressing other T cell markers have cytotoxic function and speculate that these cells may be capable of mediating GvHD in allogeneic transplantation.
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PMID:T cell depletion with anti-CD5 immunotoxin in histocompatible bone marrow transplantation. The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease. 169 19

The pteridine neopterin is a marker of immunological activation and has been shown to be a useful marker of graft-versus-host disease (GVHD) in bone marrow transplant patients. High levels of both neopterin and interferon-gamma (IFN-gamma) were produced in vitro during mixed lymphocyte responses, which may be considered to be a model of the primary events leading to GVHD. Neopterin was shown to be produced by monocytes in response to stimulation with IFN-gamma, but not other cytokines. However, the interleukins IL-1 alpha, IL-1 beta, IL-2, and tumour necrosis factor (TNF) alpha and beta, but not IL-6, stimulated neopterin production by unfractionated peripheral blood mononuclear cells (PBMC), and culture supernatants from PBMC stimulated with IL-1 alpha, IL-1 beta, IL-2 and IL-6, but not TNF-alpha or TNF-beta induced neopterin production following transfer to fresh monocyte cultures. It therefore appears that cytokines may generate neopterin by induction of IFN-gamma, by synergy with low levels of induced IFN-gamma, or by non-IFN-gamma-dependent mechanisms.
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PMID:Cytokine induction of neopterin production. 182 41

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

Serial determination of soluble CD8 (sCD8), soluble IL-2 receptors (sIL-2R), and tumor necrosis factor-alpha serum levels were performed in bone marrow transplant patients upon initiation, day 0 (D0) and at D10 of an anti-IL-2 receptor (alpha chain) monoclonal antibody (B-B10) in vivo treatment for steroid-resistant grade greater than or equal to 2 acute graft-versus-host disease (aGVHD). D0 and D10 sCD8 serum levels correlated strongly with response to B-B10 treatment (p = .003 and .001, respectively); 76% of the patients with D0 sCD8 levels less than 500 U/ml responded favorably to B-B10 treatment, versus only a 30% response if the sCD8 levels were greater than 500 U/ml (p = .02). Likewise, D0 tumor necrosis factor-alpha levels significantly correlated with subsequent response to B-B10 treatment (p = .03). D0 sIL-2R levels were not significantly different in B-B10-responsive and nonresponsive aGVHD patients. These results suggest that the serial determination of sCD8 and TNF serum levels could provide valuable predictive information as to steroid-resistant aGVHD responsiveness to anti-IL-2R treatment.
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PMID:Soluble CD8, IL-2 receptor, and tumor necrosis factor-alpha levels in steroid-resistant acute graft-versus-host disease. Relation with subsequent response to anti-IL-2 receptor monoclonal antibody treatment. 191 Feb 17

Cyclosporine (CS) is a potent immunosuppressive agent which under some circumstances paradoxically augments DTH responses, aggravates some autoimmune diseases, and induces specific forms of autoimmunity. The enhancement of DTH and other immune responses is closely related to the timing of CS administration relative to immunization. CS inhibits IL-2 production (and several other lymphokines) at a pretranscriptional level, but does not usually prevent the antigen-specific priming of T cells, such that T cells may be poised to respond as soon as CS is withdrawn. Thus, accelerated GVHD and allograft rejection may occur after withdrawal of CS. CS has been shown to aggravate and/or induce relapse in several autoimmune diseases including collagen-induced arthritis, EAE, autoimmune thyroiditis, uveitis in SDA chickens, and an autoimmune form of myocarditis in mice. CS may enhance immune responses by inactivating suppressor cells, by altering Th1/Th2 antagonism (e.g., CS promotes a protective Th1-type response in BALB/c mice infected with Leishmania major), or by promoting T cell activation through a CS-resistant IL-2-independent T cell activation/differentiation pathway. At least three forms of CS-induced autoimmunity have been described: Syngeneic or autologous GVHD which occurs in CS-treated syngeneic or autologous bone marrow transplant recipients after CS is withdrawn in rats, mice, and humans; a systemic autoimmune disease with polyarthritis and glomerulonephritis which occurs in irradiated CBA/N mice treated with CS; and organ-specific autoimmune diseases which occur in mice treated with CS during the neonatal period. The precise mechanisms by which CS induces these autoimmune diseases are not clear, however, CS affects immune tolerance at three levels. CS induces thymic medullary involution with loss of medullary Ia+ cells, and appears to at least partially block the transition from double positive (CD4+CD8+) to single positive (mature type) thymocytes. In syngeneic bone marrow chimeras, CS appears to inhibit the intrathymic deletion of clones with relatively low affinity, but not those with high affinity, to self antigens. CS appears to inhibit the action of suppressor T cells which normally maintain an innate form of resistance to autoimmunity. Finally, CS has been shown to prevent the development of T cell clonal anergy. There is redundancy in immune tolerance mechanisms, i.e., clonal deletion, clonal anergy, and suppressor cells can each maintain tolerance to similar antigens, such that it is likely that CS must cripple more than one tolerance mechanism for autoimmunity to occur.
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PMID:Cyclosporine-induced autoimmunity and immune hyperreactivity. 195 15

Depletion of donor CD6+ cells in HLA-identical allogeneic bone marrow transplantation has been reported to reduce graft-versus-host disease without interfering with engraftment. We have established an immunomagnetic cell separation technique capable of producing a 2-3 log depletion of CD6+ cells. Median recovery of CD6- cells and hematopoietic progenitor cells was 65-70%, and cell viability was unaffected. Significant numbers of CD2+, CD3+ cells responsive to phytohemagglutinin (PHA), OKT3, recombinant interleukin-2 (rIL-2), and allogeneic cells remained after depletion, and the number of cells able to respond to stimulation with PHA and IL-2 in vitro was reduced by only 1-2 log. These observations are not easily reconciled with the ability of CD6 depletion to prevent GVHD, but raise the question whether the depletion causes a sufficient reduction of the T cell load or removes a critical T cell subset.
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PMID:Immunomagnetic depletion of CD6+ cells from bone marrow and peripheral blood. 197 Apr 90


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