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

Karolin S Hacker; Katharina Jansson; Jeanette Pichler; Jawad Salman; Murat Avsar; Thierry Siemeni; Ann-Kathrin Knöfel; Klaus Höffler; Jens Gottlieb; Jörg Frühauf; Martin Werner; Reza Poyanmehr; Danny Jonigk; Michael S Balzer; Marion Hewicker-Trautwein; Axel Haverich; Wiebke Sommer; Gregor Warnecke

doi:10.1016/j.trim.2020.101350

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

Transpl Immunol. 2021 Apr:65:101350. doi: 10.1016/j.trim.2020.101350. Epub 2020 Oct 27.

Authors

Karolin S Hacker¹, Katharina Jansson¹, Jeanette Pichler¹, Jawad Salman², Murat Avsar², Thierry Siemeni², Ann-Kathrin Knöfel¹, Klaus Höffler², Jens Gottlieb³, Jörg Frühauf⁴, Martin Werner⁴, Reza Poyanmehr², Danny Jonigk⁵, Michael S Balzer⁶, Marion Hewicker-Trautwein⁷, Axel Haverich¹, Wiebke Sommer¹, Gregor Warnecke⁸

Affiliations

¹ Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Centre for Lung Research, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
² Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
³ German Centre for Lung Research, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Department of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
⁴ Department of Radiation Therapy and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
⁵ Institute for Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
⁶ Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
⁷ Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany.
⁸ Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Centre for Lung Research, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: [email protected].

PMID: 33127498
DOI: 10.1016/j.trim.2020.101350

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.

Keywords: Irradiation; Lung transplantation; Porcine; Preconditioning regime; Tolerance; Transplantation tolerance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Graft Survival
Hematopoietic Stem Cell Transplantation*
Immune Tolerance
Lung Transplantation*
Swine
Swine, Miniature
Transplantation Chimera
Transplantation Conditioning