| T-cells play a central role in cell mediated immune responses to foreign and self antigens that lead to organ transplant rejection as well as autoimmune diseases. Optimal T-cell activation and expansion requires antigen recognition via cognate T-cell receptors (TCRs) along with co-stimulatory and cytokine signals. TCR engagement with specific antigen-MHC complexes regulates T-cell responses against auto- and allo-antigens. In the current study, we have investigated the immune regulatory effects of TCR engagement with its specific mAb, with and without, its cognate antigens. Herein, we found that in vivo administration of an anti-mouse TCRb mAb (H57-597) resulted in a preferential reduction of antigen-reactive T-cells and enrichment of CD4+FoxP3 + Treg cells. In transplantation models, transient H57-597 mAb treatment produced long-term cardiac allograft survivals and significantly prolonged survivals of skin allografts in naive recipients as well as heart allografts in skin-sensitized recipients. While Treg cells were involved in maintaining donor-specific long-term graft survivals, immunity was retained against third party allografts. Strikingly, a single injection of H57-597 mAb completely inhibited the rapid development of type 1 diabetes (T1D) in RIP-OVA hi mice while a transient H57-597 mAb treatment at eight weeks of age prevented the development of T1D in normoglycemic NOD mice. Moreover, a brief course of H57-597 mAb therapy after onset of T1D induced remission in six out of eight NOD mice. In contrast to anti-CD3 mAb, administration of H57-597 mAb induced limited T-cell activation and proliferation signals that correlated with lower levels of inflammatory cytokine production. Thus, transient modulation of the TCRbeta chain by H57-597 mAb exhibits potent and safe therapeutic effects to control auto- and allo-immune responses. |
