Thioredoxin priming prolongs lung allograft survival by promoting immune tolerance

• Published in: PloS one 2015-05, Vol.10 (5), p.e0124705-e0124705
• Main Authors: Hu, Hanbo, Zhu, Xiaoyan, Joshi, Sunil, Lu, Li, Xia, Chang-Qing, Patel, Jawaharlal M
• Format: Article
• Language: English
• Subjects: Allografts - immunology; Animals; Antibodies; Antibodies - immunology; Antigens; CD4 antigen; Cell survival; Cytology; Dendritic cells; Forkhead Transcription Factors - metabolism; Foxp3 protein; Graft rejection; Graft Rejection - immunology; Graft Survival - immunology; Grafting; Grafts; Immune response (humoral); Immune Tolerance - immunology; Immunity, Humoral; Immunological tolerance; Immunology; Immunoregulation; Immunosuppression; Immunotherapy; Injury prevention; Interleukin 10; Interleukin-10 - biosynthesis; Isoantigens - immunology; Laboratory animals; Lung morphology; Lung Transplantation; Lungs; Lymphocytes; Lymphocytes T; Male; Medicine; Pathology; Priming; Pulmonary arteries; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Rats, Wistar; Rejection; Rodents; Spleen; Spleen - cytology; Survival; T cells; T-Lymphocytes, Regulatory - immunology; Thioredoxin; Thioredoxins; Thioredoxins - metabolism; Transplantation; Transplantation, Homologous; Transplants & implants; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124705

Tolerance to allograft antigen is the major challenge and final goal of transplant medicine. Our previous study demonstrated that thioredoxin-1 (Trx) priming of donor lung significantly protected allogeneic lung graft. To determine whether Trx priming of donor lung inhibits allograft rejection, extends allograft survival and induces immune tolerance, orthotopic left lung transplantation was performed from Lewis to Sprague-Dawley rats without immunosuppression. Donor lungs were primed with Trx at 4°C for 4 hr prior to transplantation. After up to 37 days post-transplantation, allograft lung morphology, recipient T cell and humoral alloantigen-specific immune responses were examined. We found that Trx-primed lungs exhibited much reduced acute rejection and associated lung injuries resulting in loss of graft functional area at 5-37 days post-transplant in contrast to the control groups. CD4+ T cells from the recipients with Trx-primed grafts responded to the stimulation of dendritic cells (DCs) of donor origin, in contrast to DCs from the third party, with significantly reduced proliferation. Consistent with above findings, we observed that CD4+Foxp3+ regulatory T cells in spleen cells from the recipients with Trx-primed grafts were significantly increased compared to controls, and CD4+ T cells from the recipients with Trx-primed grafts produced much higher levels of immunosuppressive cytokine, IL-10 when stimulated with allogeneic donor DCs. In addition, humoral immune tolerance was also induced as there was no significant increase levels of serum antibodies against donor antigens in Trx-lung recipients when re-challenged with allogeneic donor antigens. Our results demonstrate that one-time Trx-priming of donor lung grafts prior to transplantation significantly prolongs the survival of the grafts through inducing or promoting cellular and humoral alloantigen-specific immune tolerance, which might be associated with the induction of immunosuppressive regulatory T cells.