Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: The aim of the study is to determine the role for circulating exosomes with cardiac self-antigens (SAgs) (Myosin, Vimentin) in the development of immune responses leading to rejection following heterotopic cardiac transplantation (HTx) immunosuppressed with mTOR inhibitor and low dose of IL-2. It has been proposed that IL-2 may selectively induce proliferation of T regulatory cells leading to graft acceptance.
*Methods: Allogenic (BALB/c to C57BL/6) HTx was performed heterotopically in the abdominal cavity. Immunosuppression was given with mTOR inhibitor, Rapamycin (RAPA) 1mg/kg/day (d), i.p. days 0 – +8 or small dose of IL-2 (30000 IU) i.p., or Rapamycin 1mg/kg i.p days 0 – +8 and IL2 (30,000IU). Sera were analyzed for antibody (Ab) development and characterization of exosomes by western blot was done using specific Abs.
*Results: HTx without any immunosuppression rejected on days 6-8 mean survival time. IL-2 (30000 IU) alone did not significantly prolong graft survival as compared to no treatment (mean survival time) (9.5 vs 6 days (d)). IL2 demonstrated induction of circulating exosomes containing SAgs; Myosin (>3.2fold (f)) and Vimentin (>3.5f) at the time of rejection and interestingly had higher levels PDL1 (>1.8 f), CD73 (>2.2 f), markers associated with allograft tolerance. RAPA treatment significantly prolonged allograft survival (16d p=0.0177) and RAPA +IL2 further prolonged cardiac allograft survival significantly (28d p=0.002). Increased levels of Abs to Vimentin occurred on day 28 when rejection was observed in the RAPA+IL-2 group (124.5±12.6 ng/ml vs 49.2±23.7 ng/ml control; p<0.05). IL2+RAPA group also demonstrated induction of circulating exosomes containing SAgs; Myosin (>3f) and Vimentin (>2.5f), respectively on day 28. Masson staining revealed myocyte damage and fibrosis in RAPA+IL-2 group suggesting antibody mediated damage.
*Conclusions: RAPA and IL2 therapy significantly promoted graft survival following HTx. Low dose IL-2 therapy led to circulating exosomes containing not only cardiac SAgs but also markers associated with tolerance (PDL1 and CD73). However, exosomes with cardiac SAgs could override the influence of PDL1 and CD73 resulting in Ab development to cardiac SAgs leading to rejection of allografts.
To cite this abstract in AMA style:Itabashi Y, Ravichandran R, Bansal S, Fleming T, Mohanakumar T. Circulating Exosomes with Cardiac Self-Antigens, Myosin and Vimentin, Induced Immune Responses Leading to Rejection Following Heterotopic Cardiac Transplantation Immunosuppressed with mTOR Inhibitor and Low Dose of IL-2 Therapy [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/circulating-exosomes-with-cardiac-self-antigens-myosin-and-vimentin-induced-immune-responses-leading-to-rejection-following-heterotopic-cardiac-transplantation-immunosuppressed-with-mtor-inhibitor-a/. Accessed March 1, 2021.
« Back to 2020 American Transplant Congress