Induction of Major Histocompatibility Complex-mismatched Mouse Lung Allograft Acceptance With Combined Donor Bone Marrow: Lung Transplant Using a 12-Hour Nonmyeloablative Conditioning Regimen. Issue 12 (December 2016)

• Record Type: Journal Article
• Authors: Dodd-o, Jeffrey M.; Ganguly, Sudipto; Vulic, Ante; Panoskaltsis-Mortari, Angela; McDyer, John F.; Luznik, Leo
• Is Part Of: Transplantation. Volume 100:Issue 12(2016)
• Publication Date: 2016-12
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000001480
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. Methods: Using the major histocompatibility complex-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low-dose total body irradiation and posttransplant (donor) bone marrow, and splenocyte infusion followed by posttransplantation cyclophosphamide. Results: Our results show that C57BL/6 recipients of BALB/c lung allografts undergoing this complete short-duration nonmyeloablative conditioning regimen had durable lung allograft acceptance. Mice that lacked 1 or more components of this regimen exhibited significant graft loss. Mechanistically, animals with lung allograft acceptance had established higher levels of donor chimerism, lymphocyte responses which were attenuated to donor antigens but maintained to third-party antigens, and clonal deletion of donor-reactive host Vβ T cells. Frequencies of Foxp3 + T regulatory cells were comparable in both surviving and rejected allografts implying that their perturbation was not a dominant cell-regulatory mechanism. Donor chimerism was indispensable for sustained tolerance, as evidenced by acute rejection of allografts in established chimeric recipients of posttransplantation cyclophosphamide after a chimerism-ablating secondary recipient lymphocyte infusion. Conclusions: Together, these data provide proof-of-concept for establishing lung allograft tolerance with tandem donor bone marrow transplantation using a short-duration nonmyeloablative conditioning regimen and posttransplant cyclophosphamide. Abstract : Durable lung allograft acceptance is present in mice recipients of allogeneic lungs with short-duration peri-transplant T cell depletion, low dose total body irradiation, donor bone marrow and splenocyte infusion followed by cyclophosphamide. Tolerance is dependent on the presence of donor chimerism and is associated with deletion of anti- donor-reactive T cells. Supplemental digital content is available in the text.