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)

Interleukin-2 (IL-2) therapy generates killer cells with major histocompatibility complex (MHC)-unrestricted cytotoxicity against most tumors but not normal tissues. Cyclosporine A (CsA) has been reported to break tolerance to self and to induce killer cells with specificity against class II MHC (Ia) antigens both on the host and the tumor cells, resulting in a mild graft-versus-host disease (GVHD) in an autologous bone marrow transplantation (BMT) setting in the rat. We used these two agents in a syngeneic BMT model in a strain of mice that does not develop GVHD with CsA. Therapy with either agent alone was ineffective, whereas a combination of CsA plus IL-2 after BMT induced a potent graft-versus-tumor (GVT) effect against a melanoma and an acute myeloid leukemia. The antitumor effect could be adoptively transferred by infusing spleen cells harvested from mice treated with CsA plus IL-2 into secondary recipients that received chemoradiotherapy. The cytotoxicity of these cells was not influenced by treatment of tumor cells with gamma-interferon or Ia antibody. The cytotoxic effect was mediated by Thy 1+ and asialo GM 1+ cells. There was no GVHD either in the primary recipients of CsA and IL-2 or in those receiving the adoptively transferred spleen cells. Our findings show that combination therapy with CsA and IL-2 after syngeneic BMT induces a potent GVT effect in a non-MHC-restricted manner, and point to the existence of differences between the mechanisms of GVT and GVHD.
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PMID:Synergism of interleukin-2 and cyclosporine A in induction of a graft-versus-tumor effect without graft-versus-host disease after syngeneic bone marrow transplantation. 161 Oct 84

Immunotoxins constructed by conjugating monoclonal antibodies to plant and bacterial toxin molecules are being evaluated clinically for the treatment of cancer and as immunosuppressive agents in treating autoimmune diseases. Immunoconjugates constructed with ricin A-chain and in certain indications, whole ricin have been most extensively investigated. The experience with these immunotoxins has highlighted issues to be dealt with in order to improve therapeutic efficacy. Immunotoxins containing ricin A-chain conjugated to monoclonal antibody reacting with the CD5 molecule on T lymphocytes has proved most efficacious in treating acute graft versus host disease (aGvHD) in patients receiving bone marrow transplants as part of a regimen of high dose chemotherapy in leukaemias and lymphomas. This involved immunotoxin used after the onset of a GvHD or prophylactically to reduce the development of the condition. Immunotoxin treatment of leukaemias and lymphomas is also showing promise with clinical responses being observed. In comparison, treatment of solid cancers such as colorectal cancer and malignant melanoma has not yet proved effective. Factors to be resolved in order to improve treatment include better pharmacokinetic properties of immunotoxins, improved tumour penetration and the use of antibody cocktails to accommodate antigenic heterogeneity of tumours.
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PMID:Rationale for clinical use of immunotoxins in cancer and autoimmune disease. 195 44

Fifty-six long-term survivors of bone marrow allografts were followed for a minimum of 40 months after bone marrow transplantation (BMT) to determine the frequency of secondary malignancies. The 56 patients included ten with severe aplastic anemia (SAA), 16 with acute myeloblastic leukemia (AML), 11 with acute lymphoblastic leukemia (ALL), and 19 with chronic myelogenous leukemia (CML). All patients received a preparative regimen combining high-dose chemotherapy with total body irradiation (TBI). Three patients developed a malignancy of the skin or oral mucosa. Two were diagnosed as squamous cell carcinoma and one as a malignant melanoma. All three patients had chronic graft versus host disease (GvHD) and were treated for prolonged periods with immunosuppressive medications. The lesions of all patients developed in areas involved by chronic GvHD.
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PMID:Cutaneous and mucosal neoplasms in bone marrow transplant recipients. 229 38

To determine the incidence of secondary cancers after bone marrow transplantation, we reviewed the records of all patients at our center who received allogeneic, syngeneic, or autologous transplants for leukemia (n = 1926) or aplastic anemia (n = 320). Thirty-five patients were given a diagnosis of secondary cancer between 1.5 months and 13.9 years (median, 1.0 year) after transplantation. Sixteen patients had non-Hodgkin's lymphomas, 6 had leukemias, and 13 had solid tumors (including 3 each with glioblastoma, melanoma, and squamous-cell carcinoma). There were 1.2 secondary cancers per 100 exposure-years during the first year after transplantation (95 percent confidence interval, 0.7 to 2.0). The rate declined to 0.4 (95 percent confidence interval, 0.2 to 0.7) after one year. The age-adjusted incidence of secondary cancer was 6.69 times higher than that of primary cancer in the general population. In a multivariate model, the predictors (and relative risks) of any type of secondary cancer were acute graft-versus-host disease treated with either antithymocyte globulin (relative risk, 4.2) or an anti-CD3 monoclonal antibody (13.6) and total-body irradiation (3.9). Two additional factors were associated with secondary non-Hodgkin's lymphomas: T-lymphocyte depletion of donor marrow (12.4) and HLA mismatch (3.8). We conclude that recipients of bone marrow transplantation have a low but significant risk of a secondary cancer, particularly non-Hodgkin's lymphoma.
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PMID:Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. 230 21

We investigated whether the adoptive transfer of H-2-incompatible lymphokine-activated killer (LAK) cells would efficiently demonstrate antitumor activity without damaging the normal host cells. Allogeneic LAK cells (5 X 10(7] did not cause graft-versus-host disease (GVHD) in irradiated recipients, whereas more than half of the mice transferred with the same dose of fresh allogeneic spleen cells developed GVHD. Repeated transfer (three times at 4-day intervals, 1.2 X 10(8) cells/mouse) did not result in GVHD. Graft-versus-host reaction (GVHR), which is detectable by spleen enlargement of recipients transferred with allogeneic lymphoid cells was also absent in LAK cell-transferred mice of all strain combinations tested. Host immune responses were not affected in these mice. Therefore, it is feasible to transfer allogeneic LAK cells. With the antitumor efficacy of allogeneic LAK cells, they preferentially lysed allogeneic tumor targets. Adoptive transfer of the allogeneic LAK cells led to a significant decrease in the lung-colonizing foci of intravenously inoculated B16 melanoma cells. Allogeneic LAK cells and syngeneic ones were equally active, in vivo. The use of allogeneic LAK cells may prove to be a valuable method for effective clinical antitumor immunotherapy.
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PMID:Adoptive transfer of H-2-incompatible lymphokine-activated killer (LAK) cells: an approach for successful cancer immunotherapy free from graft-versus-host disease (GVHD) using murine models. 340 29

Haemopoietic radiation chimeras across the H-2 barrier (BALB/c----C57Bl/6; H-2d----H-2b chimeras and vice versa) have been studied for their capacity to suppress the growth, or to reject, transplantable B16 melanotic melanoma and radiation leukaemia virus-induced, transplantable leukaemia. Also, radiation leukaemia virus (RadLV) obtained from the thymus of leukaemic C57Bl/6 mice was injected i.p. into established chimeras (H-2d----H-2b). As expected, long lived, graft versus host disease free allogeneic chimeras constructed with intact bone marrow were unable to reject the tumours both when recipients were BALB/c----C57Bl/6 or C57Bl/6----BALB/c chimeras. However, also inoculation of a large number of immunocompetent cells from normal BALB/c mice into BALB/c----C57Bl/6 chimeras, failed to promote a rejection of the tumours. On the contrary, the same amount of syngeneic (BALB/c) immunocompetent cells prevented growth of melanoma when transferred into athymic nude BALB/c mice, while the tumour grew unimpaired in untreated athymic nude BALB/c mice. The same type of H-2d----H-2b chimeras displayed complete resistance to inculation of leukaemogenic H-2b restricted RadLV while all H-2b----H-2b, syngeneically reconstituted mice developed disseminated leukaemia. These findings demonstrate that: (a) a powerful suppressive principle operates in the chimeras which does not allow effector function and anti-tumour activity of passively transferred normal, mature T cells from resistant BALB/c mice. Thus, no H-2 restriction of donor T cells can be advocated for suppression of anti-tumour effector functions in the chimeras. (b) New donor (BALB/c, H-2d) marrow character in the H-2d----H-2b chimeras prevents expression of the H-2b restricted viral activity and leukaemogenic transformation and/or proliferation.
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PMID:Growth of transplantable melanoma and leukaemia and prevention of virus-induced leukaemia in long lived radiation chimeras constructed with unmanipulated bone marrow. 388 84

Many examples of oligoclonal T-cell expansion in infiltrated diseased tissues have been reported. However, it remains to be established whether such observations can be generalized and to what extent oligoclonal patterns obtained after in vitro culture of T-cell infiltrates reflect in vivo situations. Using new high resolution analysis which requires no in vitro cellular expansion, we detected such oligoclonal T-cell expansions in 7/7 melanoma tumour biopsies, 3/3 biopsies of inflammatory skin during acute graft versus host disease (aGVHD) after allogeneic bone marrow transplantation (alloBMT) and 7/7 synovial membranes from patients with rheumatoid arthritis. Thus, oligoclonal T-cell expansions are readily observed when a sufficiently sensitive detection method is used, suggesting that similar expansions are the rule among T-cell infiltrates in different diseases. This observation and the monitoring of the in vivo evolution of such expansion during the course of the disease and during in vitro culture should have important clinical implications.
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PMID:T-cell repertoires in healthy and diseased human tissues analysed by T-cell receptor beta-chain CDR3 size determination: evidence for oligoclonal expansions in tumours and inflammatory diseases. 748 Oct 75

In the last decade, immunomodulation has emerged as a mode of therapy capable of mediating the regression of cancer in some patients. This article reviews our experience with immunomodulation following transplant and non-transplant chemotherapy. We used interferon and cyclosporine A following conventional chemotherapy in a non-transplant setting for a B16 melanoma in a murine model. This combination generated cells with MHC-unrestricted cytotoxicity. We have also used immunotherapy in the transplant setting with IL-2 activated PBSC in patients with breast cancer. Of the 28 patients treated, 20 developed GVHD and the average time to reconstitution was 12 days (comparable to a control group). This article also raises the possibility of extending immunomodulation to breast cancer patients in the nontransplant setting to induce an antitumor immune response following cytoreductive chemotherapy.
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PMID:Immunomodulation following chemotherapy. 882 21

Death receptors are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Expression and signaling by death receptors and their respective ligands is a tightly regulated process essential for key physiologic functions in a variety of organs, including the skin. Several death receptors and ligands, Fas and Fas ligand being the most important to date, are expressed in the skin and have proven to be essential in contributing to its functional integrity. Recent evidence has shown that Fas-induced keratinocyte apoptosis in response to ultraviolet light, prevents the accumulation of pro-carcinogenic p53 mutations by deleting ultraviolet-mutated keratinocytes. Further- more, there is strong evidence that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of toxic epidermal necrolysis, acute cutaneous graft versus host disease, contact hypersensitivity and melanoma metastasis. With these new developments, strategies for modulating the function of death receptor signaling pathways have emerged and provided novel therapeutic possibilities. Specific blockade of Fas, for example with intravenous immunoglobulin preparations that contain specific anti-Fas antibodies, has shown great promise in the treatment of toxic epidermal necrolysis and may also be useful in the treatment acute graft versus host disease. Likewise, induction of death signaling by ultraviolet light can lead to hapten-specific tolerance, and gene transfer of Fas ligand to dendritic cells can be used to induce antigen specific tolerance by deleting antigen-specific T cells. Further developments in this field may have important clinical implications in cutaneous disease.
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PMID:Death receptors in cutaneous biology and disease. 1095 Dec 28

Recent studies have demonstrated that granzymes A and B make an important contribution to the clearance of the orthopoxvirus ectromelia, and in graft versus host disease. To test whether granzymes are generally necessary for lymphocyte-mediated cytotoxicity in vivo, we assessed the cytotoxic capacity of granzyme A and/or B-deficient lymphocytes in several perforin-dependent settings. Splenocytes and allogeneic CTL of granzyme A and/or B-deficient mice were defective for induction of DNA fragmentation, but induced significant membrane damage and target cell death. These results correlated well with the behavior of granzyme A/B-deficient CTL and NK cells in three different perforin-dependent tumor models. In a classical assay of NK cell-mediated rejection, granzyme A and/or B-deficient mice inoculated with RMA-S cells were as susceptible to tumor as wild-type mice. Perforin-deficient mice were also considerably more susceptible to tumor initiation by methylcholanthrene than granzyme A and/or B-deficient mice. Furthermore, rejection of the K1735-melanoma expressing MHC class I and II molecules was mediated by adoptively transferred H-2b anti-k CTL from immunized granzyme A and/or B-deficient mice. In summary, these data suggest that granzymes A and B are not critical for most anti-tumor effector functions of NK cells and CTL that are perforin mediated.
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PMID:Granzyme A and B-deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti-tumor capacity. 1116 36


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