Rabbit Anti-Thymocyte Globulin (rATG) Induction Therapy Followed by Tacrolimus Conversion to Sirolimus at 3 Months Does Not Expand TREG Cells

Abstract

A variety of therapeutic strategies have been employed to prolong renal transplant survival including creating a more toleragenic immune state and minimizing potential drug toxicity. Since rATG and sirolimus (SLR) may fulfill both requirements, we examined the constituents of peripheral blood leukocytes (PBL) in a prospective trial of rATG induction followed by CNI conversion at 3 mos. from tacrolimus (TAC) to SRL. All 63 renal transplant recipients (RTR) received rATG induction (3-5 mg/kg/total dose), TAC (10-15 ng/ml), EC-MPS (Myfortic) and prednisone for 3 mos. RTR with normal 3 mo. protocol biopsies were then randomized to receive either low-dose TAC (4-6 ng/ml) or SRL (6-10 ng/ml) followed by a protocol biopsy at 12 mos. PBL subsets were enumerated by flow cytometry at 3 and 12 mos. At 3 mo., rATG led to significant depletion in all PBL subsets except CD8 cells. Seven patients had subclinical rejection (SCR) (1 Grade 1A, 6 borderline) on protocol biopsy. Compared to the 56 RTR without SCR, the PBL profile of these 7 RTR showed a higher number of CD4 naïve cells. At 12 mo., both the TAC and SRL groups showed persistent B, NK, NKT and CD4 cell depletion and an increased CD4 memory/naive ratio. Irrespective of TAC or SRL therapy, Treg absolute cell numbers did not recover and the Treg/total or memory CD4 ratios remained normal. Thus, the combination of rATG/TAC/ECMPA/steroids provided adequate short-term immunosuppression with no clinically apparent ACR and approximately 10% SCR. The relatively higher number of CD4 naïve cells in RTR with SCR suggests the need for increased doses of rATG for adequate initial immunosuppression. The lack of Tregs expansion may be due to the initial use of TAC or to an insufficient rATG dose. Thus, the early CNI conversion strategy does not promote a more toleragenic PBL profile.Table: [T cell PBL subset]†p< 0.05 vs. Control, *p< 0.01 vs. Control ¶ p< 0.01 vs. 3 mo. no SCR ¶ p< 0.05 vs. 12 mo TACTable: [PBL Subsets]