Introduction: A2AR agonist is known to potently attenuate lung ischemia-reperfusion injury. However, the long-term effects of A2AR agonist on lung allograft survival remain unclear especially in large animal. The aim of this study is to investigate whether A2AR agonist (CGS21680) has beneficial effects on pulmonary allograft survival using MHC-defined CLAWN miniature swine.

Methods: Twelve swine received fully MHC-mismatched lungs with 12 days of FK506 (35-45 ng/ml). In Group 1 (G1), six recipients received FK506 alone. In Group 2 (G2), in order to examine whether brain death (BD) affects the graft survival, three recipients were transplanted with lungs from BD donors induced by subdural balloon inflation for 6 hours (h) before procurement. In Group 3 (G3), three recipients were transplanted with BD lungs treated with A2AR agonist (5 [micro]g/kg/min) starting 3h after BD induction. In addition, all recipients in G3 received the same dose of A2AR agonist for 3h after reperfusion. Graft function was assessed by blood gases from the graft pulmonary vein (PV) and serial lung biopsies. The expression of mRNA of proinflammatory cytokines (IL-1β and IL-6) of the grafts were quantified by real-time RT-PCR.

Results: All grafts in G1 was rejected by day 63 (d63) with diffuse mononuclear infiltrates associated with intra-alveolar hemorrhage and capillary congestion. All three animals in G2 completely rejected the grafts by d35, indicating rejection of grafts was accelerated by donor BD. In G3, A2AR agonist was effective on early graft function. PO2 of graft PV in G3 was higher than G2 (552 ± 22 vs. 414 ± 106 at 2h; 553 ± 19 vs. 349 ± 28 mmHg at d2) associated with fewer inflammatory cell infiltrates at 2h and d2 biopsies. Up-regulation of proinflammatory cytokines in G3 was markedly reduced at the time of organ procurement as well as at 2h and d2 compared with G2. Although we lost one animal due to pneumonia at d21, other two animals accepted the grafts over 120 days (>d120, >d150 currently) even after cessation of 12 days of FK506.

Conclusions: Not only short-term effects, treatment of A2AR agonist with 12 days of FK506 facilitates induction of tolerance to fully allogeneic lung. This is the first evidence of successful induction of tolerance with short course of FK506 with A2AR agonist in a clinically relevant large animal model.

CITATION INFORMATION: Sahara H, Sekijima M, Murokawa T, Ariyoshi Y, Iwanaga T, Ichinari Y, Shimizu A, Yamada K. Successful Induction of Tolerance of Fully Allogeneic Lung Graft with Adenosine A_2A Receptor (A2AR) Agonist in MHC-Defined CLAWN Miniature Swine. Am J Transplant. 2017;17 (suppl 3).

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