Sanglifehrin A Blocks Key Dendritic Cell Functions In Vivo and Promotes Long-Term Allograft Survival Together with Low-Dose CsA

Abstract

Sanglifehrin A (SFA) is a novel compound with unsurpassed cyclophilin-binding affinity, but relatively low direct antilymphocytic activity. Here, we report the capacity of SFA to selectively inhibit key dendritic cell (DC) functions in vivo and to suppress acute and chronic heart allograft rejection. We show that in vivo, SFA profoundly decreases DC receptor-mediated endocytosis and macropinocytosis and DC-T-cell allostimulatory activity. Furthermore, SFA abrogates >90% of IL-12p70 production in vivo while having no significant effect on IL-10 and TNF-a production. In a rat vascularized heart transplant model, SFA alone did not prevent graft rejection and rejection occurred within 23 days after low-dose CsA, whereas addition of SFA to low-dose CsA promoted long-term graft survival (median survival time >100 days; p = 0.0007). With respect to chronic rejection, SFA + CsA almost completely prevented graft arteriosclerosis compared to animals treated with CsA alone and controls. We propose that SFA represents a novel class of immunophilin-binding immunosuppressants with high activity against DCs and the development of graft vasculopathy in CsAtreated recipients.

Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1

“…DCs are professional APCs that have been shown to be involved in the initiation of the allogenic humoral reaction directed against allografts. [15][16][17] Our study provides further evidence that DCs play a crucial role in transplant arteriosclerosis, as adoptive transfer of alloantigen-primed BMDCs accelerated the disease progression in the mouse aortic allograft model. The data further suggest that HO1 is a key regulator in BMDC function during the alloimmune response in transplantation arteriosclerosis.…”

Insights into peptidyl-prolyl cis–trans isomerase structure and function in immunocytes

“…In a comprehensive study, SfA was found to suppress antigen uptake and to reduce IL-12 and IL-18 production of DCs in vitro and in vivo without inhibiting the differentiation and surface costimulatory molecule expression of DCs [125][126][127][128]. Immecke et al recently claimed that SfA-mediated suppression of chemokine and CD38 receptor expression in monocyte-derived dendritic cells (moDC) is unique and independent of CyPA [129].…”

The Cyclophilin-Binding Agent Sanglifehrin A Is a Dendritic Cell Chemokine and Migration Inhibitor

“…In an experimental transplant model, SFA monotherapy did not suppress acute organ allograft rejection supporting the hypothesis that it does not represent a primary T cell inhibitor [11]. Interestingly, in combination with CsA, SFA efficiently promoted long-term allograft survival [11].…”