Taming inflammation by targeting cytokine signaling: new perspectives in the induction of transplantation tolerance

Transplantation tolerance remains an elusive goal, partly due to limitations in our understanding of the interplay between inflammatory mediators and their role in the activation and regulation of T lymphocytes. Although multiple mechanisms acting both centrally and peripherally are responsible for tolerance induction, the signaling pathways leading to activation or regulation of adaptive immunity are often complex, branched, redundant and modulated by the microenvironment's inflammatory milieu. Accumulating evidence clearly indicates that inflammatory cytokines limit the tolerogenic potential of immunomodulatory protocols by supporting priming of the immune system and counteracting regulatory mechanisms, ultimately promoting rejection. In this review, we summarize recent progress in the development of novel therapeutics to manipulate this inflammatory environment and achievements in targeted inhibition of inflammatory cytokine signaling. Ultimately, robust transplant tolerance induction will probably require a multifaceted, holistic approach that integrates the various mechanisms of tolerance induction, incorporates the dynamic alterations in costimulatory requirements of alloreactive T cells, while maintaining endogenous mechanisms of immune regulation.