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)

This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10(-8 )mol/L (about 1.8 microg/mL). Because most natural killer (NK) cells are CD7(+), NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have been treated with 3 to 4 infusions of 2 or 4 mg/m(2) IT combination, administered intravenously at 48-hour intervals. The T(1/2) was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL. Drug-associated side effects were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells. (Blood. 2000;95:3693-3701)
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PMID:A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease. 1084 99

This report describes the preparation of an immunotoxin-combination, consisting of an anti-CD3 and anti-CD7 monoclonal antibody (MoAb) both conjugated to the A-chain of plant toxin ricin, for the experimental treatment of graft-versus-host disease. MoAbs and toxin were conjugated by conventional biochemical and chromatographic techniques. Raw materials, intermediate and final products were evaluated in accordance with the relevant 'points to consider' of the FDA. Yields, purity and sterility of the two final products were all satisfactory. Preservation of MoAb-affinity and toxin-activity were confirmed in biological assays. The LD50, 25-45 mg immunotoxin-combination/kg mouse, equalled that of similar immunotoxins already in clinical use. Because in vitro cross-reactivity screening revealed an unexpected binding of the CD3-MoAb to the esophagus epithelium, human doses of immunotoxin-combination were administered to two cynomolgus monkeys. Clinically relevant serum concentrations were obtained without irreversible toxicities occurring. The T(1/2) varied between approximately 6 and 9 h and the C(max) ranged from 1.8 to 3.9 microg/ml. The main side effect was a transient rise of serum creatine kinase. Importantly, neither damage nor binding of the CD3-immunotoxin to the monkey esophagus epithelium could be demonstrated. It was concluded that sufficient material of proper quality and with an acceptable toxicity profile was produced, warranting the evaluation in a clinical pilot-study.
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PMID:Production of anti-CD3 and anti-CD7 ricin A-immunotoxins for a clinical pilot study. 1139 79

This study was aimed to investigate the clinical outcome of ricin-immunotoxin mediated T cell partially depleted HLA/MLC mismatched allogeneic hematopoietic stem cell transplantation. 13 patients with hematological malignancies were treated by ricin-immunotoxin mediated T cell partially depleted allogeneic hematopoietic stem cell transplantations from HLA/MLC mismatched donors, including 6 cases of CML in CP(1), 1 case of ALL in CR(1), 1 case of ALL in CR(2), 1 case of ALL in relapse, 2 cases of AML in CR(1), 1 case of AML in CR(2), 1 case of MDS-RAEBT-AML (M(4)) in CR(1). The results showed that 8 cases were engrafted successfully, 2 cases of them developed grade II acute GVHD and 2 cases developed grade III-IV acute GVHD. Within following-up of 8 - 90 months, 2 patients who experienced grade III-IV acute GVHD died early after transplantation; 1 patient died of late onset of infection; the other 5 patients survived free from diseases. After failure at first infusion, 4 patients were given reinfusion of peripheral blood hematopoietic stem cells from the same donor. 3 out of 4 cases failed to engraft and only one patient got engraftment but died of related complications of transplantation. One patient was performed a second transplantation from a syngeneic donor and survive free of disease until now. In conclusion, T cell partially depleted HLA/MLC mismatched allogeneic hematopoietic stem cell transplantation by ricin-immunotoxin decreases the occurrence of severe acute GVHD but with high risk of rejection, which clinical outcome still needs further evaluation.
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PMID:[Application of ricin-immunotoxin mediated T cell depletion to allogeneic hematopoietic stem cell transplantation]. 1522 48

Donor T cells activated by recipient alloantigens cause graft-versus-host disease (GVHD) after hematopoietic cell transplantation. Activated T cells express CD25, among other components of the interleukin-2 receptor. We conducted a phase I/II study to determine whether administration of CD25-specific antibody conjugated to ricin toxin A could reduce the risk of grade III or IV GVHD after marrow transplantation from HLA-matched unrelated donors. All patients received methotrexate and cyclosporine after the transplantation. The immunotoxin was given to 36 patients for 4 consecutive days beginning approximately 36 hours after the marrow infusion was completed. Fourteen (40%) of the 35 patients who could be evaluated developed grade III or IV GVHD. In a contemporaneous population of 121 patients who received marrow from HLA-matched unrelated donors and were given methotrexate and cyclosporine without the immunotoxin, the incidence of grades III and IV GVHD was 24%. Cyclosporine blocked the induction of CD25 expression on alloactivated T cells in vitro but had no detectable effect on CD25 expression by T-regulatory cells. Taken together, these results are consistent with the hypothesis that cyclosporine protected alloactivated donor T cells from the effects of the immunotoxin, whereas the CD25+ T-regulatory cells remained susceptible, causing an unexpected exacerbation of acute GVHD.
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PMID:Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation. 1528 33


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