Vascularized Composite Allotransplantation (VCA) is a procedure to restore limb function or facial appearance. Rapamycin is used in efforts to preserve host Treg function and number, while suppressing Teff cells. We established a mouse forelimb orthotopic Tx model to test the effects of rapamycin (RPM, 3 mg/kg, 28 days). RPM prolonged VCA survival for ~5 days compared to untreated controls (P<0.005). No differences in Treg function were observed in vitro, using Tregs isolated from spleens of mice in each group. However, in vivo studies indicated that RPM treated Tregs+WT Teff, which were injected into Rag1-/- mice and received transplantation then, decreased allograft survival significantly comparing to the control group Tregs+WT Teff (P<0.05). By IHC analysis, fewer CXCR3+ Foxp3+ Tregs (p<0.05) were found in allografts of RPM-treated vs. control mice treated allografts, suggesting that RPM might impair Treg migration. An in vivo Treg assay using WT Teff combined with cd4^cre-tbx21^fl/fl or WT Tregs showed that Tregs with decreased CXCR3 expression had impaired migration ability, which was controlled by T-bet (P<0.05) and could be rescued by WT Tregs (P<0.05). While host CD8 T cells were suppressed effectively, the numbers of CD4⁺Foxp3^–CD44⁺CD62L^– T cells were higher in the RPM-treated group (P<0.05), again consistent with impaired Treg migration. Thus, we conclude that in VCA, though high-dosage RPM can prolong allograft survival for several days, it downregulates CXCR3 on Tregs and impairs their migration ability significantly. Maintenance of CXCR3 expression by recipient Foxp3+ Treg cells may be important to further efforts to enhance VCA survival.

CITATION INFORMATION: Xu H., Chen Z., Hancock W., Levin S., Zhang Y. Rapamycin Therapy Impairs Treg Expression of CXCR3 and Limits Treg-Dependent Survival of Vascularized Composite Allotransplants Am J Transplant. 2017;17 (suppl 3).

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