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At least 613 records · Page 34Linked to original sources
PubMed1994

A non-activating "humanized" anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo.

OKT3, a mouse anti-human CD3 mAb, is a potent immunosuppressive agent used in clinical transplantation to prevent or treat allograft rejection. Associated with this therapy is the systemic release of several cytokines that result in a series of adverse side effects. This release of cytokines is dependent on the cross-linking mediated by OKT3 between T cells and the Fc gamma R-bearing cells. To generate an anti-human CD3 mAb with reduced activating properties as compared with OKT3, we have transferred the complementary determining regions of OKT3 onto human IgG frameworks and then performed point mutations that reduce the affinity of the "humanized" anti-CD3 mAbs for Fc gamma Rs. Initial, in vitro, studies showed that whereas OKT3 and the parental humanized anti-CD3 mAbs activated T cells similarly, a humanized Fc variant failed to do so. Both the Fc variant and the activating anti-CD3 mAbs induced comparable modulation of the TCR and suppression of cytolytic T cell activity, in vitro. In the current study, we exploited an experimental model in which human splenocytes from cadaveric organ donors were inoculated into severe combined immunodeficient mice (hu-SPL-SCID mice) to test the activating and immunosuppressive properties of these anti-human CD3 mAbs in vivo. Unlike injection of OKT3 or of the parental humanized mAb, administration of the Fc variant did not result in T cell activation in vivo, as evidenced by the lack of induction of surface markers of activation, and of systemic human cytokines, including IL-2. Importantly, similar prolongation of human allograft survival was achieved with all anti-CD3 mAbs, indicating that the nonactivating anti-CD3 mAbs retained significant immunosuppressive properties in vivo. Thus, the use of an Fc variant in clinical transplantation should result in fewer side effects than observed with OKT3, while maintaining its clinical efficacy.

Animals↗
PubMed1994

Prevention of the humoral response induced by an anti-CD3 monoclonal antibody by deoxyspergualin in a murine model.

Multiple treatments with the potent immunosuppressant murine antihuman CD3 mAb OKT3 is sometimes precluded by the onset of a neutralizing humoral response mostly consisting of anti-idiotypic antibodies. A hamster antimurine CD3 monoclonal Ab, 145-2C11, shares many properties with OKT3, in particular the ability to induce a strong Ab response in mice. Deoxyspergulain (DSG), a metabolite of the antibiotic spergualin, has been shown to reduce Ab production triggered by pathogens in a variety of infectious models and against common antigens. In this study, we examined the ability of DSG to inhibit the humoral response induced by 145-2C11. DSG prevented the Ab production triggered by the anti-CD3 mAb in an Ag-specific manner and significantly reduced the Ab production in mice previously primed with 145-2C11. We showed that DSG had a long-term effect on B cells and a transient effect on T cells. In effect, DSG was found to induce a prolonged Ag-specific unresponsiveness of B lymphocytes, and to transiently reduce the capacity of T lymphocytes to deliver help to B cells, in part by reducing IL-4 production. DSG did not reduce the immunosuppressive properties of the anti-CD3 mAb. In fact, the combination of DSG with 145-2C11 prolonged the survival of allogeneic skin grafts when compared with the administration of 145-2C11 or DSG alone. Thus, the coadministration of DSG with OKT3 may be of clinical interest to reduce the humoral response triggered by the mAb.

Animals↗
PubMed1993

[Orthoclone OKT3 in the treatment of intractable acute renal allograft rejection].

Fifteen patients receiving cadaveric renal allograft had intractable acute rejection during the application cyclosporin-A (Cs-A), from 1991 to 1992. After treating with orthoclone (OKT3, switzerland), 13 patients recovered and 2 died of cerebro-vascular diseases. The main side-effects of OKT3 were sensitization, over-immunosuppression and cytokine release syndrome. The symptoms included chills, fever, dyspnea, diarrhea, pulmonary edema, etc. We consider that when the acute rejection of renal allograft is resistant to Cs-A or steroids, OKT3 is a good therapy with high reverse rate.

Adolescent↗
PubMedDate not supplied

How successful is OKT3 rescue therapy for steroid-resistant acute rejection episodes after heart transplantation?

OKT3 is recommended as rescue therapy for cases of steroid-resistant, clinically persistant acute rejection episodes after heart transplantation. In this study we determined the efficacy of such treatment. One hundred thirty-two patients were included in this study. The postoperative immunosuppressive regimen consisted of triple-drug therapy and perioperative antithymocyte globulin. During a follow-up of 10 to 108 weeks (mean, 51 +/- 20 weeks) 281 treatment-requiring acute rejection episodes (International Society for Heart and Lung Transplantation > or = II) were observed. In 29 cases (10.3%) the grade of the acute rejection episodes was either unchanged after two series of intravenous steroid pulse therapy, was worsened after the first steroid course, or the patient experienced clinical deterioration as a result of the acute rejection episodes. These patients were considered to have steroid-resistant acute rejection episodes and received a 10-day rescue therapy with OKT3, followed by control endomyocardial biopsy. In 17 cases, control endomyocardial biopsy revealed normal myocardium (group I). In 10 cases acute rejection episodes remained unchanged (group II); twice a deterioration was found (group III). However, 12 of the 17 patients from group I experienced a rebound of the acute rejection episodes (International Society for Heart and Lung Transplantation > or = II) 1 to 3 weeks later. Side effects of OKT3 treatment were fever, chills, intestinal complications, hemodynamic response, convulsions, and viral infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗