Date: Sunday, June 12, 2016
Session Time: 4:30pm-6:00pm
Presentation Time: 5:06pm-5:18pm
Location: Room 309
Antibodies (Abs) to donor MHC and lung self-antigens (SAgs) administered following induction of lung allograft tolerance by co-stimulation blockade can result in breaking of tolerance and augmentation of immune responses to donor MHC and SAgs. In addition, loss of BATF can result in significant reduction in anti-MHC induced obliterative airway disease (OAD). The aim of this study is to determine the impact of anti-MHC or anti-SAgs in breaking established lung allograft tolerance in BATF deficient recipients. Orthotopic vascularized left lung transplant (LTx) was performed (BALB/c to C57BL/6 or Batf-/-, n=3/group). Tolerance was established by costimulation blockade using anti-CD154 and anti-CD40 with MR1 and CTLA4Ig. Abs to donor MHC (anti-H-2Kd), Kα 1 Tubulin (Kα1T) or Collagen V (Col-V) were administered intraperitoneally (i.p.) 30 days after LTx in the tolerant recipients. Histopathological analysis of transplanted lungs from tolerant C57/BL6 animals following administration of anti-MHC or anti-SAgs 30 days after tolerance was established demonstrated marked cellular infiltration (~9 folds), epithelial metaplasia (~9 folds), and fibrosis (~10 folds) indicating that anti-MHC or anti-SAgs can break established tolerance. In contrast, Batf-/- recipients demonstrated significant reduction in cellular infiltration (~7 fold, p<0.05), epithelial metaplasia (~10 fold, p<0.05), and fibrosis (~12 fold, p<0.05) around bronchioles by days 30 following Abs administration. Anti-H2Kd administration induced cellular (Th17) and humoral (Ab) immune responses to both anti-donor MHC and SAgs. Similarly, anti-SAgs lead to immune responses, not only to Sags, but also to donor MHC, demonstrating spreading of the immune responses that culminate in OAD. Significant reduction in Th9 cells (p<0.01) and Th17 cells (p<0.01) specific to SAgs were also noted in Batf-/- recipients compared to WT B6 recipients. Significant dysregulation of a substantial proportion of immunoregulatory miRNAs, including miR-155 (~5 down regulation, p<0.05), and miR-126a-5p (~4 up regulation, p<0.05) were also seen in Batf-/- recipients. Together, lack of intrinsic BATF signaling in tolerant lung allograft recipients leads to resistance to anti-MHC and anti-SAgs mediated abrogation of established lung allograft tolerance and OAD development.
CITATION INFORMATION: Xu Z, Lin X, Gunasekaran M, Sharma M, Gelman A, Mohanakumar T. BATF Deficiency in Tolerant Lung Allograft Recipients Are Resistant to Anti-MHC and Anti-Self-Antigen Mediated Pathogenesis of Obliterative Airway Disease. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Xu Z, Lin X, Gunasekaran M, Sharma M, Gelman A, Mohanakumar T. BATF Deficiency in Tolerant Lung Allograft Recipients Are Resistant to Anti-MHC and Anti-Self-Antigen Mediated Pathogenesis of Obliterative Airway Disease. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/batf-deficiency-in-tolerant-lung-allograft-recipients-are-resistant-to-anti-mhc-and-anti-self-antigen-mediated-pathogenesis-of-obliterative-airway-disease/. Accessed August 5, 2020.
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