IMMUNOSUPPRESSION - PRE-CLINICAL AGENTS

A.K. Khanna
Medicine (cardiology), University of Maryland, Baltimore/MD/UNITED STATES OF AMERICA

Body: Uncontrolled proliferation of T-cells is considered a barrier to the induction of transplantation tolerance by T regulatory cells. This particularly is due to the increased proliferative response of CD4+CD25- T cells compared to CD4+CD25+ T cells. Similar proliferative discrepancies are observed in T cells with cyclin kinase inhibitor p21 deficiency. Therefore, it was e hypothesized that CD4+CD25- T regulatory cells and p21-deficient T cells share similar proliferating properties and in contrast CD4+CD25+ T regulatory cells and p21 expressing T cells possess identical characteristics relevant to the induction of immune tolerance. We observed that the difference in proliferation among CD4+CD25+ and CD4+CD25- T-cells were proportionately similar to the difference in proliferation of lymphocytes from wild type and p21^-/- mice. Similar to CD4+CD25- T cells, CD4+ T cells from p21^-/- mice lacked FoxP3 gene expression. The analysis indicated that the number of T regulatory cells in p21^-/-mice were significantly lower than wild type mice T cells from wild type mice inhibited the proliferation of T cells from p21^-/- mice in a one way MLR assay similar to the effect of CD4⁺CD25⁺ T cells on the proliferation of CD4⁺CD25^- cells. The proliferation of CD4+CD25- T cells and p21^-/- lymphocytes was resistant to the inhibition by CsA. Gene expression of FoxP3, ILT3 and GITR supported these findings. Expression of the cyclin kinase inhibitor p21 creates a milieu consistent with an antiproliferative and immunosuppressive effect of CD4⁺CD25⁺T-reg cells. These results were confirmed by targeted overexpression of p21 in heart tissue that resulted in increased p21 and FoxP3 mRNA expression, suggesting a temporal relationship between two entities. These findings support the notion that p21 could be used clinically in controlling allo-immune activation in an effort to prolong graft survival.

Disclosure: All authors have declared no conflicts of interest.