Donor HLA−DR Drives the Development of De Novo Autoimmunity Following Lung and Heart Transplantation. Issue 10 (October 2020)

• Record Type: Journal Article
• Authors: Jankowska−Gan, Ewa; Agashe, Vrushali V.; Lema, Diego A.; Zhou, Ying; Gonzalez Bosc, Laura; Sullivan, Jeremy A.; Greenspan, Daniel S.; Burlingham, William J.
• Is Part Of: Transplantation direct. Volume 6:Issue 10(2020)
• Publication Date: 2020-10
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation -- Periodicals; 362.19795
• DOI: 10.1097/TXD.0000000000001062
• Languages: English
• ISSNs: 2373-8731

Abstract

Abstract : Background: Individuals harbor preexisting HLA−DR/DQ−restricted responses to collagen type V (ColV) mediated by Th17 cells under Treg control, both specific to peptides that bind to inherited HLA class II antigens. Yet after transplant, the donor−DR type somehow influences graft outcome. We hypothesized that, long after a lung or heart allograft, the particular HLA−DR type of the mismatched transplant donor transforms the specificity of the "anti−self" response. This could explain why, over long term, certain donor DRs could be more immunogenic than others. Methods: We analyzed 7 HLA−DR15 neg patients who had received a lung allograft from a DR15 + donor. To determine the mechanism of acquired specificity in self−reactivity, we analyzed the kinetics of DR1 (host) and DR15 (donor) peptide restriction in a heart transplant model using DR−transgenic mice. Results: Beyond 1.5 years post-lung transplant, all patients tested had acquired DR15−restricted immune responses to ColV peptides. These responses were either unrestrained Th17 type (n = 4) or Th17 controlled by Treg arising early (<5 y) or late (>7 y) after transplant (n = 4). Treg suppression via conventional (transforming growth factor−β [TGF−β]) and extracellular vesicle−associated (IL−35) cytokines correlated with superior outcomes. Naïve DR1 and DR15 transgenic mice had preexisting DR−restricted responses, exclusively to ColV fragments containing DR1− or DR15−binding peptides. When HLA−DR1 transgenic recipients of a HLA−DR15 heart developed ColV reactivity post-transplant, mice that acutely rejected (20–25 d) responded only to the DR1−restricted ColV peptide epitope. In animals whose grafts survived long term, we could detect acquisition of DR from the transplant donor onto the surface of recipient dendritic cells, and immune responses against a donor DR15–restricted ColV peptide. Conclusions: These results might explain how certain donor HLA−DR types redirect host immune responses to novel peptides of critical self−antigens. Unless regulated, such responses may predispose the allograft to chronic rejection.