CLINICAL EVALUATION OF INDUCTION IMMUNOSUPPRESSION WITH A MURINE IgG2b MONOCLONAL ANTIBODY (BMA 031) DIRECTED TOWARD THE HUMAN α/β-T CELL RECEPTOR

Knight, Richard J.; Kurrle, R.; McClain, J. Bruce; Racenberg, J.; Baghdahsarian, Vano; Kerman, Ronald H.; Lewis, Richard; Buren, Charles T. Van; Kahan, Barry D.

doi:10.1097/00007890-199457110-00008

Cited by 27 publications

(3 citation statements)

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“…Previous clinical trials with T10B9 and BMA031 show the effectiveness of targeting the TCR using anti‐TCR mAbs for treating renal and heart transplantations (15,17,18). Our results further indicate the potency of anti‐TCR mAb in preventing allograft rejection, and show that a transient treatment of anti‐TCR mAb induces long‐term cardiac allograft survival.…”

Section: Discussionmentioning

confidence: 99%

“…In 1994, we applied a mouse anti‐human TCR mAb (BMA 031) as an induction therapy for kidney transplant patients. Transient administration of BMA 031 mAb improved kidney allograft survival, and none of the treated patients showed even moderately adverse effects as seen in OKT3 mAb‐treated patients (15). Other groups also showed that a different anti‐human TCR mAb (T10B9) provided prevention and treatment for allograft rejection as effective as that of OKT3 mAb with fewer untoward effects, namely less cytokine release and fewer serious infections (16–18).…”

Section: Introductionmentioning

confidence: 98%

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Anti-TCRβ mAb Induces Long-Term Allograft Survival by Reducing Antigen-Reactive T Cells and Sparing Regulatory T Cells

Miyahara

Khattar

Schroder

et al. 2012

American Journal of Transplantation

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TCR specific antibodies may modulate the TCR engagement with antigen–MHC complexes, and in turn regulate in vivo T cell responses to alloantigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57–597), TCRα or CD3 promptly reduced the number of CD4+ and CD8+ T cells in normal mice, but H57–597 mAb most potently increased the frequency of CD4+Foxp3+ Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57–597 mAb, the expansion of SEB‐reactive Vβ8+ T cells was completely abrogated while SEB‐nonreactive Vβ2+ T cells remained unaffected. More importantly, transient H57–597 mAb treatment exerted long‐lasting effect in preventing T cell responses to alloantigens, and produced long‐term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor‐specific long‐term graft survival, T cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57–597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin‐sensitized recipients. Thus, transient modulation of the TCRβ chain by H57–597 mAb exhibits potent, long‐lasting therapeutic effects to control alloimmune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Anti-TCRβ mAb Induces Long-Term Allograft Survival by Reducing Antigen-Reactive T Cells and Sparing Regulatory T Cells

Miyahara

Khattar

Schroder

et al. 2012

American Journal of Transplantation

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“…Both anti-TCRβ mAb and anti-LFA1 mAb therapies have shown effectiveness as part of immunosuppressive regimens in the clinic [40]–[43]. In addition, both were used as successful induction therapies in transplant patients [14], [44].…”

Section: Discussionmentioning

confidence: 99%

Transient Combination Therapy Targeting the Immune Synapse Abrogates T Cell Responses and Prolongs Allograft Survival in Mice

et al. 2013

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T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen−1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.

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Immunopharmacologic Therapy in Renal Transplantation

Shoker

1996

Pharmacotherapy

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The long‐term kidney allograft survival rate is still far from optimum. Conventional immunosuppressive drugs used to prevent allograft rejection are associated with significant side effects. Moreover, withdrawal of these agents is often associated with graft loss due to rejection. No treatment is available for chronic rejection. Graft tolerance is difficult to achieve in humans, and therefore a continued goal in organ transplantation is to develop immunosuppressive regimens that are associated with fewer side effects and decreased rates of rejection, and that promote graft tolerance. The advent of newer pharmacologic agents and bioreagents is expected to improve patient and graft survival rates.

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CLINICAL EVALUATION OF INDUCTION IMMUNOSUPPRESSION WITH A MURINE IgG2b MONOCLONAL ANTIBODY (BMA 031) DIRECTED TOWARD THE HUMAN α/β-T CELL RECEPTOR

Cited by 27 publications

References 0 publications

Anti-TCRβ mAb Induces Long-Term Allograft Survival by Reducing Antigen-Reactive T Cells and Sparing Regulatory T Cells

Anti-TCRβ mAb Induces Long-Term Allograft Survival by Reducing Antigen-Reactive T Cells and Sparing Regulatory T Cells

Transient Combination Therapy Targeting the Immune Synapse Abrogates T Cell Responses and Prolongs Allograft Survival in Mice

Immunopharmacologic Therapy in Renal Transplantation

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