Systematic multicenter clinical evaluation of regulatory cells is being conducted by the EU supported ONE Study trial in which each site is administering a different regulatory population (non- donor specific Tregs, donor specific Tregs (dsTregs), reg-marophages, and tol-DCs) using a common immunosuppressive protocol. We report the first clinical application of dsTregs to kidney recipients as part of the ONE Study.

dsTregs were generated (Guinan et al, STM 2009)by culturing donor and recipient PBL in MLRs with addition of costimulatory blockade (bela). We documented feasibility in vitro with ESRD patient cells finding a similar 2-3X expansion of Tregs after MLR+belatacept. dsTregs isolated post 3 d culture under GMP were purified by sequential negative (CD19, CD8) and positive (CD25) magnetic bead selection for CD4+CD25+ to >95% Foxp3+, and we found these cells had >95% TSDR demethylation. Antigen specificity was verified by suppression of donor but not third party responses and a phase I trial of dsTregs in live donor renal transplants initiated (NCT0209123).

Two patients enrolled were males age 47 (GN) and 53 (IgA) transplanted with LURDs. Frozen donor and recipient PBMCs were processed 1 wk post-op. 3 d later recipients received dsTregs at ~ 2×10(4)/kg. No complications accompanied the infusion. Both successfully discontinued steroids at 15 weeks. At 5 and 8 mo post-tx, both have excellent graft function. Protocol bx at 9 mo will determine eligibility to discontinue MMF leaving only low-dose maintenance tacro. Patient 2 initially experienced mild DGF prior to receiving dsTregs and a slight rise in the creat. on d 12 prompted bx which revealed no rejection. A mild T cell infiltrate was present that was rich in Foxp3+ CD4.

We initiated the first human organ transplant trial of purified dsTregs and demonstrated the feasibility and preliminary safety of dsTreg therapy. While numbers and follow up are limited, there have been no adverse events suggesting safety. In subsequent patients, the dose of Tregs will be escalated. We expect these preliminary studies to lay the foundation for addition of cell based dsTregs to the armamentarium of therapies to prevent rejection and promote transplant tolerance.

CITATION INFORMATION: Markmann J, Guinan E, Geissler E, Cole G, Germana S, Kim J, Sawitzki B. Initial Experience with Donor Specific Tregs in Kidney Transplantation. Am J Transplant. 2016;16 (suppl 3).

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