Transient TCR engagement with an anti-TCRβ monoclonal antibody induces tolerogenic effects to allografts as well as prevents the development and reverses the onset of type 1 diabetes (169.1)

Abstract

Abstract In the current study, we investigated the immune regulatory effects of TCR engagement simultaneously by an anti-TCRβ chain mAb (H57-597) without or with antigens. We found that administration of anti-mouse TCRβ mAb resulted in a preferential reduction of antigen-reactive T cells with simultaneous enrichment (~3-fold increase) of CD4+Foxp3+ Treg cells. Moreover, administration of H57-597 mAb did not produce high levels of TNF-α, IFN-γ, IL-2 and IL-6 cytokines in serum in contrast to anti-CD3 mAb (145-2C11). Strikingly, a single injection of H57-597 mAb into RIP-OVAhi mice completely inhibited the development of type 1 diabetes (T1D) that was induced by adoptively transferred OVA-specific T cells. In NOD mice, a short course treatment with H57-597, not only prevented development of T1D (90% disease free treated at 8-weeks), but also induced remission in 7 of 7 mice treated at onset. In a transplantation model, transient H57-597 mAb treatment alone produced long-term Balb/c cardiac allograft survivals (>100 days; n=9) in C57BL/6 mice. Adoptive transfer of splenocytes from the heart allograft-accepting recipients to Rag1-/- recipients (B6 background, heart grafted) showed significantly extended survival of donor-specific (Balb/c) but not third-party (C3H) heart allografts. Thus, transient modulation of TCRβ chain during an ongoing immune response exhibits potent tolerogenic effects applicable for the therapy of T cell-mediated diseases and transplant rejection.