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)

An anti-CD5 monoclonal antibody (mAb) was linked to the plant toxin momordin, a type-1 ribosome-inactivating protein purified from Momordica charantia. The in vitro cytotoxicity of the immunotoxin was evaluated as the inhibition of protein and/or DNA synthesis on isolated peripheral blood mononuclear cells (PBMC) and on human T cell leukemia Jurkat. The potency of the immunotoxin on PBMC was very high (IC50 = 1 - 10 pM) and was not affected by blood components. The conjugate was also very efficient in the inhibition of the proliferative response in a mixed lymphocyte reaction (IC50 = 10 pM). Moreover, the in vitro performance of the immunotoxin compared favorably with those reported for other anti-CD5-based immunoconjugates containing ricin A chain. The in vivo activity of the immunotoxin was assessed in the model of nu/nu mice bearing Jurkat leukemia. A significant inhibition of the tumour development (80%, P < 0.01) in the animals treated with immunotoxin was observed. Taken together, the in vitro and in vivo results suggest that the anti-CD5-momordin conjugate may be useful for graft-versus-host disease therapy and potentially in the treatment of CD5-positive leukemias and lymphomas.
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PMID:In vitro and in vivo properties of an anti-CD5-momordin immunotoxin on normal and neoplastic T lymphocytes. 768 94

Donor lymphocyte responses to minor histocompatibility antigen (mHA) differences are involved in allo-responses between HLA matched pairs causing GVHD and graft-versus-leukaemia (GVL). Since some mHA are tissue-restricted, GVHD and GVL responses may be separable. We studied donor lymphocyte responses to patients with CML in a series of 10 HLA-matched sibling and 10 unrelated donor-recipient pairs comparing proliferation to recipient PHA blasts and CML cells and attempting to selectively deplete responses to PHA blasts in vitro. Responses in counts per min (c.p.m) to CML cells and PHA blasts were, respectively, 2809 +/- 2205 (SD) and 7376 +/- 1877 in related and 12,107 +/- 7191 and 26,136 +/- 22,479 in unrelated pairs. Autologous responses to PHA blasts were significantly lower (mean 779 +/- 735) (p < 0.001). Results correlated with clinical outcome: higher responses to recipient cells correlated with transplant-related death (p = 0.02 for CML and p = 0.06 for PHA blasts). Higher responses to CML correlated with GVHD grade > or = II (p = 0.025). Donor lymphocytes exposed to recipient PHA blasts for 5 days and treated with a ricin-conjugated anti-CD25 antibody retained over 75% of their response to CML but < 10% to PHA blasts. Similarly, depletion of response to CML but not to PHA blasts occurred when CML was the primary challenge. These results indicate that distinct populations of donor T cells respond to recipient leukaemic and non-leukaemic cells, and provide the basis for a clinically applicable technique to selectively deplete donor GVHD reacting cells while conserving GVL.
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PMID:Distinct T cell populations distinguish chronic myeloid leukaemia cells from lymphocytes in the same individual: a model for separating GVHD from GVL reactions. 785 26

In this study we describe immunotoxins prepared with different CD2 monoclonal antibodies (mAbs) and a ribosome-inactivating protein, saporin. The CD2 immunotoxins were tested on different models. Anti-CD2-saporin conjugates inhibited protein synthesis by a neoplastic CD2+ cell line (SKW-3) and by an interleukin 2 dependent polyclonal CD2+ lymphoid cell culture (T lymphoblasts), with IC50s ranging from 10(-13) M to 10(-11) M (as saporin). Similar results were obtained with proliferation inhibition tests (3H-thymidine incorporation) on phytohaemagglutinin (PHA) driven lymphoid cultures and on mixed lymphocyte culture activated lymphocytes. Moreover a CD2-ricin A chain conjugate was less effective than an analogous immunotoxin containing the same CD2 mAb and saporin in inhibiting lymphocyte proliferation induced by PHA (IC50 approximately 10(-9) M as ricin A chain versus 10(-12) M as saporin). The conjugates were not toxic on bone marrow stem cells. These results suggest that CD2-saporin immunotoxins could represent an effective tool for CD2+ lymphomas or leukaemias, and for T-dependent immune disorders, such as transplanted organ rejection and graft-versus-host disease.
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PMID:Immunotoxins containing saporin linked to different CD2 monoclonal antibodies: in vitro evaluation. 791 1

Thirty adults with hematologic malignancies at high-risk for relapse were treated on a phase I-II study of high-dose thiotepa, busulfan (BU) and cyclophosphamide (CY) as the preparative regimen for allogeneic marrow transplantation. Cyclosporine and methylprednisolone or anti-CD5 ricin A chain immunoconjugate were used as graft-versus-host disease prophylaxis. Filgrastim was given from day 1 to enhance engraftment. Median follow-up time is 16 months (range 9-29 months). Grades III-IV regimen-related toxicity occurred in 5 (26%) of 19 patients treated with thiotepa 250 mg/m2 x 3, BU 1 mg/kg x 12 and CY 60 mg/kg x 2 and this was considered the maximal tolerated dose-schedule. Stomatitis and hepatoxicity were dose-limiting. All patients engrafted and had complete donor chimerism. The actuarial rate of acute graft-versus-host disease was 71% (95% CI 62-80%). The relapse rate at 1 year was 38% (95% CI 25-50%) and the actuarial survival at 1 year was 30% (95% CI 22-38%). The combination of thiotepa, BU and CY is tolerable as a preparative regimen for allogeneic marrow transplantation.
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PMID:A phase I-II study of high-dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic marrow transplantation. 799 71

We report the development of a potent anti-pan T-cell immunotoxin capable of killing cells in an antigen dependent manner. The immunotoxin is composed of a high affinity anti-CD6 antibody (IgG2a, Kd = 1.3 x 10(-11) M) conjugated to blocked ricin that is a chemically modified ricin molecule wherein the lectin binding sites of the B-chain have been blocked by covalent attachment of affinity ligands. Conjugation of blocked ricin to the antibody has minimal effect on the apparent affinity of the antibody and no effect on the ribosome-inactivating activity of the ricin A-chain moiety. Anti-CD6-blocked ricin is a specific and highly toxic immunoconjugate killing the antigen-positive Molt-4 cell line with an IC37 of 4 x 10(-12) M after a 24 h exposure of cells to the immunotoxin. Nonspecific cytotoxicity of anti-CD6-blocked ricin for the antigen-negative Namalwa cell line was more than 750-fold lower with an IC37 > 3 x 10(-9) M. The cytotoxicity of anti-CD6-blocked ricin is dependent on the length of the incubation of cells with the conjugate ranging from an IC37 of 1.5 x 10(-11) M leaving a surviving fraction of Molt-4 cells of 0.03 after a 2.5 h exposure to an IC37 of 5 x 10(-13) M and leaving a surviving fraction of 3 x 10(-6) after a continuous (3 weeks) exposure. Anti-CD6-blocked ricin is also capable of killing CD6 positive cells in human peripheral blood lymphocyte populations. Systemic toxicity of anti-CD6-blocked ricin in mice is similar to the toxicity of other immunotoxins containing blocked ricin that were found to be tolerated well by patients. An application of this immunoconjugate for the prevention and treatment of graft versus host disease or tissue graft rejection is suggested.
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PMID:Anti-CD6-blocked ricin: an anti-pan T-cell immunotoxin. 815 May 54

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

This study reviews results of a radiation-free preparative regimen consisting of busulfan and cyclophosphamide in 65 unrelated allogeneic bone marrow transplant recipients. Thirty-eight patients had chronic myelogenous leukemia (17 patients chronic phase, 13 patients accelerated phase, eight patients blast phase), 19 patients had acute leukemia (second complete remission or relapse) and eight patients had myelodysplasia. The patients were transplanted at four different medical centers from July 1988 to November 1992. Ages ranged 4-48 years (median 32). Fifty-seven patients received busulfan 16 mg/kg and cyclophosphamide 120 mg/kg, and eight received busulfan at doses between 15 and 17 mg/kg and cyclophosphamide at doses 100-200 mg/kg as preparative regimens. All patients received cyclosporine for graft-versus-host disease prophylaxis; in addition 46 patients received corticosteroid, 38 methotrexate, six anti-CD5 ricin A-immunotoxin, and four T cell-depleted bone marrow. Median follow-up of survivors was 53 months (range 15-68 months). Four year actuarial survival was 24 +/- 12%. Four-year survival based on disease was 29 +/- 27% for chronic myelogenous leukemia (CML) in chronic phase, 20 +/- 9% for chronic myelogenous leukemia in accelerated phase, 0% for chronic myelogenous leukemia in blast phase, 32 +/- 40% for acute leukemia, and 38 +/- 34% for myelodysplasia. Actuarial survival was 66 +/- 40% in patients age < 20 years, vs 23 +/- 13% for patients ages 20 to 40, and 10 +/- 14% for patients age > 40 years. Fifty patients (88%) engrafted. Graft failure occurred in eight patients. Acute graft-versus-host disease grade II-IV occurred in 36 (72%). Two patients relapsed after engraftment with the donor cells and died of leukemia within a month of relapse. The most common causes of death were graft-versus-host disease (37%), and transplant-related toxicity (59%); relapse (4%) was a rare cause of death. Busulfan/cyclophosphamide is an effective preparative regimen in unrelated bone marrow transplantation permitting adequate engraftment and a low relapse rate. Best results are observed in patients less than 20 years old.
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PMID:Unrelated allogeneic bone marrow transplantation using high-dose busulfan and cyclophosphamide (BU-CY) for the preparative regimen. 873 82

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.
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PMID:Prevention of graft-versus-host disease with anti-CD5 ricin A chain immunotoxin after CD3-depleted HLA-nonidentical marrow transplantation in pediatric leukemia patients. 875 Feb 62

Immunotoxins (ITs) are potent cytotoxic agents used in the treatment of cancer, autoimmune disease, and graft-versus-host disease. Results from clinical trials demonstrate that many IT-treated patients, especially those with an intact immune system, develop anti-IT antibodies that may prohibit repeated IT dosing. We, therefore, evaluated a panel of novel immunosuppressive (IS) agents for their ability to inhibit the antitoxin immune response in mice receiving multiple courses of a ricin A chain (RTA)-containing IT and also assessed whether this suppression would result in an increase in IT-mediated antitumor activity. The results indicate that a 3-day pretreatment, plus one additional boost 2 weeks later, of a combination of hCTLA4Ig + anti-CD40L, virtually eliminated the anti-RTA response in normal mice receiving six weekly injections of an IT. When tested in BCL1 tumor-bearing mice, the concomitant use of a combination of hCTLA4Ig + anti-CD40L and six doses of the IT resulted in a 1.5-fold increase in tumor cell killing, as compared with treatment with IT alone. We conclude that a combination of IS + IT therapy should facilitate the administration of multiple courses of IT, as well as enhance its antitumor activity.
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PMID:Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice. 960 90

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


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