Delayed non-myeloablative irradiation to induce long-term allograft acceptance in a large animal lung transplantation model

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Hacker KS, Jansson K, Pichler J, Salman J, Avsar M, Siemeni T, Knöfel AK, Höffler K, Gottlieb J, Frühauf J, Werner M, Poyanmehr R, Jonigk D, Balzer MS, Hewicker-Trautwein M, Haverich A, Sommer W, Warnecke G.Delayed non-myeloablative irradiation to induce long-term allograft acceptance in a large animal lung transplantation model. Transplant immunology. 2021 Apr. 65:101350. doi:10.1016/j.trim.2020.101350. PMID:33127498.

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Abstract

We previously induced long-term allograft acceptance in an allogeneic lung transplantation (LTx) model in miniature swine using perioperative non-myeloablative irradiation (IRR) combined with infusion of donor specific alloantigen. In order to improve clinical applicability, we delayed induction with irradiation in this study. Left sided single LTx was performed in minipigs. Group 1 received non-myeloablative irradiation (7Gy thymus and 1.5Gy whole body IRR) before LTx and a perioperative donor specific splenocyte infusion (SpTx). Group 2 received perioperative SpTx but delayed IRR three days after LTx. Group 3 was exposed to delayed IRR without SpTx. Whereas 4 out of 7 animals from the non-delayed group never rejected their grafts and were electively sacrificed on postoperative day (POD) +500, all animals from group 2 rejected their grafts before POD 108. In group 3, 3 out of 8 animals developed long-term allograft acceptance. In all groups, donor leukocyte chimerism peaked up to 20% in peripheral blood one hour after reperfusion of the lung. Group 1 maintained prolonged chimerism beyond POD 7, whereas chimerism levels in groups 2 and 3 decreased continuously thereafter. Delayed irradiation has the potential to improve long-term graft survival, yet not as efficient as a perioperative conditioning protocol.