IL-2 complex therapy prolongs fully MHC-mismatched murine cardiac allograft survival

Regulatory T cell (Treg)-biased IL-2/anti-IL-2 monoclonal antibody complexes (IL-2c) can preferentially deliver IL-2 to CD25+ Tregs, causing proliferation of Tregs that is potentially advantageous in transplantation. We tested the ability of IL-2c to prolong murine cardiac allograft survival. C57BL/6 (H-2b) mice received fully major histocompatibility complex-mismatched BALB/c (H-2d) or hemi-allogeneic B6 × BALB/c (H-2b/d) F1 allografts. Recipients were treated prior to transplantation with IL-2c or control. Graft survival, anti-donor T cell priming, and donor-specific antibody production were measured. High-dimensional flow cytometry and transcriptomic analyses were used to characterize IL-2c-induced modulation of the alloimmune response. IL-2c treatment prolonged BALB/c allograft survival to 14 d (vs. 7 in control; P < 0.0001), and F1 allograft survival to 22 d (vs. 13 in control; P = 0.0018). Donor-specific T cell priming and antibody production were significantly reduced by IL-2c. Increased frequencies of CD4+CD25+FOXP3+ Tregs expressing high levels of ICOS, GITR, CD73, and CTLA-4 were identified in both the spleen and allograft in IL-2c-treated recipients. Reduced infiltration of F4/80+ cells into allografts and a marked reduction in intragraft myeloid activity were observed in IL-2c-treated recipients. When combined with a transient 21-d course of perioperative tacrolimus therapy, median survival time was extended to 48 d, and some recipients experienced indefinite allograft survival without ongoing immunosuppressive therapy. IL-2c increases Treg populations in priming and effector sites, is associated with downregulation of both the early adaptive immune response and myeloid response to cardiac allografts, and can synergize with tacrolimus to enable long-term graft survival.