FK506 controls CD40L-induced systemic autoimmunity in mice

Abstract

Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8 + T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses. © 2006 The Society for Investigative Dermatology.