IMMUNE REGULATION AND TOLERANCE I

P. Riquelme¹, J.A. Hutchinson², E.K. Geissler^1
1General And Experimental Surgery, University Hospital Regensburg, Regensburg/GERMANY, ²Allgemeine Chirurgie, Universitätsklinikum Regensburg, Regensburg/GERMANY

Body: Regulating immune responses in the early post-operative period is critical for the induction of transplantation tolerance because tissue injury and inflammation in the early postoperative period dictate the shape of subsequent immunological responses to the graft. In principle, there are two alternative approaches to this problem, namely, profound immunosuppressive therapy aimed at preventing all immunological responses in the immediate postoperative period and perioperative conditioning strategies aimed at biasing the recipient’s immune system towards a more tolerogenic state. In this report, we present evidence that a single intravenous administration of 5x10⁶ donor-strain regulatory macrophages (M reg) prior to transplantation substantially prolonged heterotopic heart allograft survival in unconditioned, non-immunosuppressed recipients, using both the stringent C3H-to-BALB/c (31.4 vs. 8.7 days; p<0.001) and B6-to-BALB/c (21.9 vs. 10.0 days; p=0.001) strain combinations. We demonstrate that the beneficial effect of M regs is a particular to living donor-derived M regs, since recipient- and third party- derived M regs, and donor-derived monocytes were not effective. Administration of M regs in conjunction with a 10-day course of 1 mg/kg/day rapamycin further enhanced the graft-protective effect of M reg infusion, such that 25% of recipients accepted their grafts indefinitely. As M regs are potent suppressors of T cell proliferation through the action of IDO, we conclude that pre-operative treatment with M regs affects the balance of effector and regulatory cell populations in the recipient, causing a state of specific hyporesponsiveness to alloantigen.

Disclosure: All authors have declared no conflicts of interest.