Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.1.1.69 (BMT)
 2,655 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

This article has outlined the special problems associated with evaluation of bone marrow before and after BMT. Marrow grafting has become a major form of therapy in oncology and hematology whose potential is only beginning to be fully realized. The transplantation of healthy hematopoietic and lymphoid cells has made possible the use of otherwise superlethal doses of radiation and chemotherapy in preparing the patient for engraftment. In the case of tumors, this allows massive doses of tumorocidal therapy prior to rescue with a BMT. In the case of aplastic anemia, it allows massive immunosuppression and ablation of the residual host marrow in preparation for replacement by the healthy donor marrow. The complications of this procedure include the toxicity of chemotherapy and irradiation upon the liver, lung, and gut as well as less serious toxicity to skin and other organs. The double barrier associated with marrow transplantation consists of rejection and GVHD. Marrow graft failure occurs by two distinct mechanisms, graft resistance and graft rejection. The former is marked by a total failure of any evidence of engraftment and the latter by engraftment followed by disappearance of the graft. GVHD is the immunologic attack upon host tissues by donor lymphoid cells (predominantly mature T cells). In the acute phase, it attacks liver, skin, and gut, with the latter producing the most life-threatening syndrome. Chronic GVHD resembles scleroderma. Treatment of GVHD includes the use of prednisone, cyclosporin A, ATG, and monoclonal antilymphoid antibodies. Prevention includes the attempt to remove T cells from the donor marrow with monoclonal antibodies using complement-mediated cytolysis and other approaches such as conjugation of antibodies to ricin and other toxins. GVHD also produces severe immunosuppression in and of itself added to that produced by chemoirradiation therapy. As a result, the marrow transplant recipient is extremely susceptible to infections. During the early period, the patient is granulocytopenic and susceptible to bacterial and fungal infections, which are dealt with by antibiotics and isolation procedures. Later, viral infections become very important, particularly CMV and other herpes viruses. The relative success in dealing with bacterial and, to some extent, viral infections has brought fungal infections to the fore as major causes of death, especially in higher risk categories of patients. Hemorrhage is a frequent complication owing to delayed megakaryocyte engraftment and thrombocytopenia during the early period and is a serious problem in patients with GVHD of the gut.
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PMID:Pathology of bone marrow in transplant recipients. 306 26

Clinical trials in autologous BMT to date have indicated that significant salvage and potential cures can be obtained in patients with high grade non-Hodgkin's lymphoma (NHL) who have failed primary therapy and are treated with high dose chemoradiotherapy and autologous marrow rescue. The major need in NHL is to better define those patients who might benefit by autologous BMT and to reduce the relapse rate by improved pre- or post-transplant therapy. Similar results to those in NHL could be obtained in acute leukemia if occult tumor cells could be eliminated from autologous marrow. Animal model experiments have shown that it is feasible to eliminate low level contamination with tumor cells by in vitro immunologic or pharmacologic treatment. While it is too early to accurately assess the efficacy of ongoing clinical trials using those marrow purging techniques, a few patients have exhibited encouraging durations of CCR. Should these approaches prove to be effective in only a fraction of cases, combination in vitro treatment or the use of more efficient effector mechanisms for cell killing (e.g., ricin conjugated antibody) may very well clear occult tumor from the marrow of most patients. The encouraging results with autologous BMT in leukemia and lymphoma stand in sharp contrast to the disappointing results so far achieved with the non-hematologic solid tumors. It is, however, possible that those cancers have not been subjected to the most rigorous test for successful autologous BMT and that the search for newer agents which can produce operationally irreversible aplasia may provide a fairer test of this approach. It is to be hoped that future research will settle this point.
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PMID:Autologous bone marrow transplantation (ABMT) in the treatment of cancer. 632 87

Three murine anti-human monoclonal antibodies broadly reactive with human T cells were conjugated to intact ricin toxin. The purgative effects of these immunotoxins (IT) on alloreactive T cells after in vitro pretreatment was tested in an in vitro assay measuring the generation of cytotoxic T cells (CTL). Pretreatment was performed in the presence of lactose to block the native binding of ricin, thus rendering IT antibody specific. Blocking studies with free antibody showed that selective toxicity was determined by the antibody moiety of the antibody-toxin conjugate. Our assay system permitted the measurement of significant CTL levels in the bone marrow. Thus, we were able to determine the differential selectivity of IT for T cells as compared with stem cells in the same donor preparation. Our studies show that antibody-intact ricin conjugates have great potential as T cell purgative reagents for GVHD prophylaxis in human BMT.
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PMID:Anti-T cell monoclonal antibodies conjugated to ricin as potential reagents for human GVHD prophylaxis: effect on the generation of cytotoxic T cells in both peripheral blood and bone marrow. 660 76

Despite the use of conventional chemoprophylaxis regimens, patients receiving unrelated-donor BMT are at high risk of developing severe acute GVHD. We evaluated a prophylactic regimen combining CsA, MTX and anti-CD5-ricin A chain immunotoxin (H65-RTA) in 31 patients; pentoxifylline was also given to reduce the anticipated nephrotoxicity of CsA. In most cases, planned doses of CsA, MTX and H65-RTA were given (i.e. to 77%, 77% and 93% of patients, respectively). Although fluid retention requiring diuretic therapy was frequent, only 1 patient had a > 10% unexplained increase in body weight during the first 21 days post-BMT. Also, while significant increase of the baseline serum creatinine was noted in 7 patients, none required dialysis. One patient suffered a reversible allergic reaction to the immunotoxin; no other side effects attributable to this regimen were observed. All but 2 patients engrafted (1 died of fungemia on d + 19 and the other had persistent leukemia) and no late graft failures were observed. Seventeen patients developed acute GVHD grade > or = II (probability, 58% [95% CI 41-76%]); 7 had grade > or = III (probability, 24% [95% CI 12-43%]). In the 27 patients who achieved stable engraftment and have survived beyond d + 100, the 3-year probability of developing chronic GVHD was 66% (95% CI 48-84%). As of the last follow-up prior to 01 May 1994, 13 patients are alive in CR and one in relapse; 9 of these patients are off all immunosuppressives and well. Four other patients relapsed and died, and 13 died of other transplant-related causes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prophylaxis for acute graft-versus-host disease following unrelated donor bone marrow transplantation. 753 67

Six patients (five children < or = 12 years old and one young adult) underwent allogeneic BMT (not T lymphocyte-depleted) from sex-matched HLA-identical siblings. GVHD prophylaxis consisted of methylprednisolone (30 mg/m2) and anti-pan T lymphocyte ricin A chain immunotoxin (H65-RTA) (0.1 mg/kg) administered daily for 12 consecutive doses. H65-RTA was initiated at day +5 (n = 4) or day +2 (n = 2). All patients engrafted. Despite receiving the planned GVHD prophylaxis, all patients developed moderate to severe acute GVHD; five patients developed Grade III/IV GVHD. Four patients died 34 to 78 days post-transplant; GVHD was a contributory cause of death in each case. H65-RTA as used in this study was ineffective for the prophylaxis of acute GVHD.
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PMID:Anti-pan T lymphocyte ricin A chain immunotoxin (H65-RTA) and methylprednisolone for acute GVHD prophylaxis following allogeneic BMT from HLA-identical sibling donors. 843 9

Between June 1988 and May 1996, 428 patients underwent allogeneic BMT (288 related donor (RD) and 140 unrelated donor (UD)) at the Vancouver General Hospital. Eight patients (UD six and RD two) developed a post-transplant lymphoproliferative disorder (PTLD). Median age at BMT was 38 years (range 22-51). Five of the six UD allografts were T cell depleted. Cyclosporine+/-methotrexate was used for GVHD prophylaxis. All eight patients developed GVHD; in six this was refractory to treatment with corticosteroids. Rabbit antithymocyte globulin (ATG) or an anti-CD5-ricin A chain immunotoxin (Xomazyme) was used as second-line therapy for GVHD. Presentation with PTLD occurred at median day 90.5 (range 34-282) post BMT. Five of the eight patients had a rapidly progressive course characterized by fever, lymphadenopathy, lung and liver involvement and died within 3-8 days. PTLD was an incidental finding at post mortem examination in two patients. The remaining patient had localized disease and recovered. Pathological analysis revealed two morphological patterns; diffuse large B cell lymphoma (DLBC lymphoma, five patients) and polymorphous B cell hyperplasia (PBCH, three patients). EBV expression was positive in all eight cases and monoclonality was demonstrated in seven cases. In multivariate analysis, T cell depletion of the allograft (P=0.0001, relative risk (RR)=30.5), anti-T cell therapy for GVHD (P=0.006, RR=12.7) and acute GVHD grades 3-4 (P=0.04, RR=7.7) were the significant factors for development of PTLD. In conclusion, we have identified two forms of PTLD after BMT: one is characterized by disseminated disease with a rapidly progressive and often fulminant course and the other by localized, relatively indolent disease. Morphology, EBV positivity and clonality do not appear to correlate with the clinical course. The major risk factors for development of PTLD after BMT are ex vivo T cell depletion of the allograft and in vivo anti-T cell therapy for GVHD.
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PMID:Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience. 984 95