Research Group
- Dr. Stanislaw M. Stepkowski, Principal Investigator
- Dr. Min Wang, Co-Investigator
- Dr. Robert A. Kirken, Consultant
- Dr. Lin Tian, Associate
Location
- The University of Texas Health Science Center at Houston, Houston, USA
Title
- Cytokine-Activated Signalling in T Cells is Required for Tolerance Induction by Allochimeric Protein
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.Au
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.Au protein, allochimeric protein induces only partial activation
(tyrosine phosphorylation of Zap70 kinase) in RT1.Au-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 (