Frontiers in Immunosuppression

Because of the pleiotropic toxicities of available immunosuppressants, new approaches have employed agents that seek to mitigate nephrotoxicity. Phase III trials of belatacept, a conjugate of cytotoxic lymphocyte antigen-4 (CTLA-4) and immunoglobulin that seeks to block T-cell activation signal 2, displayed significantly improved renal allograft function among standard (but much less so, among extended) criteria donor kidneys. However, there was no evident protection against chronic processes. Indeed, the study arm experienced an increased incidence of acute rejection episodes and posttransplant lymphoproliferative diseases. A Phase II trial of sotrastaurin, a nonselective protein kinase C (PKC) inhibitor that may exert effects on signals 1 and 2, showed little benefit on renal graft function with an excess of acute rejection episodes, tachycardia, and serious infections when used as base therapy in combination with mycophenolate sodium and steroids after withdrawal of tacrolimus (TRL) treatment at 3 months. Phase II trials of tasocitimib, a putative blocker of Janus kinase (Jak)3-mediated transduction of signal 3, produced improved renal allograft function compared with TRL-based therapy. However, treated patients showed prominent inhibition of Jak 2, a widely distributed mediator of growth and differentiation signals in a variety of tissues, thereby engendering increased rates of infections and serious diseases. Major advances in this enterprise might be achieved with the discovery of agents that more specifically target intermediates selective for lymphoid cells: For example, lymphocyte cell kinase (lck; signal 1), CTLA-4 itself (signal 2), or Jak 3 (signal 3). Preliminary work in animal models supports these avenues for future drug development.