T cell proliferation is a key step in amplification of immune responses to alloantigens and thus is a prime target of immunosuppressive therapy in solid organ transplantation. Interleukin-2 (IL-2), a soluble cytokine released by activated T cells, plays a major role in this amplification by autocrine and paracrine mechanisms after binding to IL-2 receptors (IL-2R). The IL-2R structure is dependent on the activation state of T cells; two chains (β/g) are expressed on the surface of resting T cells and three (a, β, g) on activated T cells.

Recently, antibodies have been developed that specifically target activated T cells by binding to the inducible IL-2Ra chain. Anti-IL-2Ra antibodies reduce the incidence and severity of acute rejection, but in clinical practice require concomitant use of agents that decrease IL-2 expression (i.e. calcineurin inhibitors). We have found marked differences in the Jak/STAT signaling pathway of T cells activated in the presence or absence of the anti-IL-2Ra antibody daclizumab. The Jak/STAT pathway is one of three inter-related pathways involved in IL-2R-mediated signaling (Jak/STAT, Ras/MAPK, and c-myc/bcl-2). Blockade of IL-2R-mediated signaling has the potential to effect multiple pathways in the T cell, resulting in modification of a wide number of functions from proliferation to apoptosis.

Using biochemical and molecular technologies we will examine the impact of daclizumab on the Ras/MAPK and c-myc/bcl-2 signaling pathways. In addition, daclizumab causes internalization of IL-2Ra chains, leaving residual cell surface IL-2R β/g chains. We will also examine signals generated through residual IL-2R β/g chains. Information obtained from these studies will expand our understanding of IL-2-induced cell signaling and the interplay of the intracellular signaling pathways. We believe that defining molecular targets of IL-2Ra blockade will elucidate new strategies for the use of anti-IL-2Ra antibodies and may lead to the development of novel immunosuppressive agents.