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.

Regulation of cutaneous immunity by the environment: An important role for UV irradiation and vitamin D

“…These data demonstrate that the activation of LC via CD40/CD40L signaling can be the initial event, which triggers a cascade of immune responses resulting in the final breakdown of tolerance against self [12,13]. Besides initiating cutaneous immunity LC can also inhibit cutaneous immune responses and induce tolerance since K14-driven overexpression of RANKL led to immunosuppression, functional alterations of epidermal LC, and a systemic increase of CD4 + CD25 + regulatory T cells [14].…”

The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas

“…For in vivo inhibition of NFAT signaling, FK506 was used to inhibit the activating interaction between calcineurin and NFAT, at a dose of 10 mg/kg (administered i.p. every 3 days) (50). The Stat6 inhibitor, AS1517499, was purchased from Axon Medchem, and was used at a concentration of 50 nM for in vitro use, and dosed at 10 mg/kg for in vivo use (administered i.p.…”

Tacrolimus in the Treatment of Ocular Diseases

“…[130,131] Qian and Dana [132] demonstrated in a BALB c mice model that local ocular administration of anti-CD154 is effective in the prevention of corneal allograft rejection in normal-risk recipients, and in delaying the incidence of rejection in high-risk recipients. Another study [133] showed the beneficial therapeutic effects of tacrolimus for the treatment of CD40L-induced autoimmunity. Taken together, the findings listed above indicate that the anti-inflammatory and antirejection effects of tacrolimus may be partly due to blockade of CD40-CD154 interaction.…”