Continual treatment of patients with current immunosuppressive drugs has dramatically improved allograft survival rates, with only a minority of patients today suffering from acute rejection. However, the vast majority of transplant patients do develop chronic rejection, which results in impaired graft function or even patient death. To remedy this outcome is to induce a state of permanent acceptance of allografts; namely, transplantation tolerance (TT). As recently shown by other investigators, the selective blockade of B7/CD28 second signals induced TT by increasing activation-induced cell death (AICD) among alloreactive T cells. Rapamycin (RAPA) increased AICD and facilitated induction of TT, while cyclosporine (CsA) prevented both AICD and induction of TT, documenting that active AICD is not necessary for TT.

In our model, TT was induced by modulation of the first TCR signal using donor/recipient class I major histocompatibility complex allochimeric protein. A single portal vein injection or multiple oral gavage with allochimeric protein alone (but not unmodified donor RT1.A^u antigen) induced donor-specific TT. The state of TT is transferable with T cells that display increased expansion of IL-4-producing T helper type 2 (Th2) cells. In contrast to immunogenic RT1.A^u protein, allochimeric protein induces only partial activation (tyrosine phosphorylation of Zap70 kinase) in RT1.A^u-specific T cells. Since CsA facilitated induction of TT by allochimeric protein, we postulate that AICD is not necessary in our model. However, either of two cytokine-receptor signal inhibitors (RAPA or AG490) abolished induction of TT. Therefore, we plan to show that allochimeric protein induces TT without active participation of AICD. Also, we plan to show that incomplete TCR activation requires effective second signal and a continuous activation of the signal transducer and activator of transcription Stat6, to constantly up-regulate Th2 cells. Thus, TT may be induced and maintained without AICD, but with regulation of IL-4-driven Stat6 pathway.