Calcineurin Inhibition and Development: Insights from Research Models

Abstract

Because of its role in the T cell response, pharmacological inhibition of calcineurin is clinically useful to suppress the immune system following organ transplantation. Introduction of calcineurin inhibitors (CIs) in the early 1980s resulted in a profound improvement in graft survival. For this reason, calcineurin inhibitors have become a cornerstone for post-transplant management. CIs are also used to treat an increasingly wide array of immune-related disorders. However, inhibition of calcineurin is known to affect tissues other than the immune system and long-term use of CIs often produces therapeutically-limiting side-effects; the most common of which is nephrotoxicity. An additional complex issue arises with the use of CI during pregnancy as the role of calcineurin in development is still incompletely understood. Survey of the literature reveals a growing number of studies demonstrating direct links between calcineurin action and development, particularly of the immune system and kidney structures. Data thus far point to important roles for calcineurin in regulation of transcription, cell hypertrophy, extracellular matrix accumulation, and apoptosis effectively linking observed therapeutic side-effects with direct actions of calcineurin in immune and renal cells. Thus, it seems prudent to review what is known about calcineurin inhibition in animal models with an emphasis on developmental affects and to then compare with the albeit limited data available from human subjects. Just as laboratory research is demonstrating mechanistic explanations for some features of calcineurin inhibitor nephrotoxicity, so to may laboratory results yield important information about the contribution of calcineurin to development. Keywords: Cyclosporin A, development, calcineurin knockout