*Purpose: We have shown previously that pre-transplantation (Tx) infusion of donor-derived regulatory dendritic cells (DCreg) safely prolongs MHC-mismatched renal allograft survival and regulates donor-reactive T cell responses in nonhuman primates (NHP) treated with co-stimulation blockade (CTLA4Ig) and rapamycin. Here, we evaluated the impact of substituting calcineurin inhibition (CNI; tacrolimus) for rapamycin on allograft survival and DCreg-mediated immune regulation of recipient donor-reactive T cells.

*Methods: Donor monocyte-derived DCreg generated in vitamin D3 and IL-10 were infused systemically, 7 days before renal Tx. Immunosuppression in the form of CTLA4Ig (20mg/kg, with tapering until d180) and tacrolimus (trough levels between 10-15ng/ml, with tapering until day 60) was given to recipients without (n=3) or with (n=3) donor-derived DCreg infusion (2.5-3.5×10⁶/kg). Graft function was determined by serum creatinine level, body weight and urinary protein/creatinine ratio. Donor-reactive memory and regulatory (Treg) T cell phenotypes were assessed by flow cytometry.

*Results: Pre-Tx infusion of donor-derived DCreg prolonged kidney allograft survival significantly (p<0.03) in CTLA4Ig/tacrolimus-treated recipients, with median graft survival times of 42 days in the control group and 90 days in the DCreg group. DCreg-infused monkeys exhibited minimal weight loss and lower urine protein/creatinine ratios compared to control monkeys. No significant differences in memory T cell subsets in peripheral blood were observed between the groups. In all recipients, the incidences of donor-reactive CD4⁺CD25^hiFoxp3^hi Treg were reduced after Tx, compared to before Tx. However, the incidences of CD4⁺CTLA4^hiFoxp3^hi T cells were significantly higher in the DCreg-infused monkeys. Finally, the percentages of donor-reactive CD8⁺PD1⁺CTLA4⁺ and CD8⁺Eomes^loCTLA4^hi T cell populations were increased, compared to before Tx, in the DCreg infused monkeys, but not in the control monkeys.

*Conclusions: Pre-Tx infusion of donor-derived DCreg prolongs kidney allograft survival significantly in rhesus monkeys treated with a clinically applicable immunosuppressive regimen based on CTLA4Ig and CNI. Prolonged graft survival was associated with enhanced CTLA4 expression by donor-reactive T cells after Tx.

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