Distinct molecular and immunological properties of circulating exosomes isolated from pediatric lung transplant recipients with bronchiolitis obliterans syndrome ‐ a retrospective study

Abstract

Long-term success following human lung transplantation is poor due to chronic rejection. We demonstrated circulating exosomes of lung origin during acute and chronic lung allograft rejection. We analyzed plasma from pediatric lung transplant recipients (LTxRs) enrolled in the CTOT-C-03 to determine whether circulating exosomes are released into circulation during bronchiolitis obliterans syndrome (BOS). Plasma exosomes were isolated, and human leukocyte antigens (HLA) were detected. Exosomes were analyzed for lung self-antigens (SAgs), co-stimulatory molecules transcription factors, major histocompatibility complex class II (MHC-II), adhesion molecules, and 20S proteasome. Mice were immunized with exosomes from BOS or stable to determine their immunogenicity. Circulating exosomes from BOS LTxRs contained increased levels of SAgs, donor HLA class I, MHC-II, transcription factors, co-stimulatory molecules, and 20S proteasome compared with stable. Serial analysis of exosomes containing SAgs demonstrated that exosomes are detectable in the circulation before BOS. Mice immunized with exosomes from BOS, or stable, demonstrated that exosomes from BOS are distinct in inducing both humoral and cellular immune responses to SAgs. Circulating exosomes from BOS LTxRs elicit distinct humoral and cellular response. In addition, detection of SAgs on circulatory exosomes 12 months before diagnosis of BOS suggest that exosomes could serve as biomarker.

Community-Acquired Respiratory Viruses Post–Lung Transplant

“…141 Injection of exosomes from pediatric LTRs with CLAD into mice stimulated the development of antibodies to SAgs and led to airway fibrosis. 142 A recent study provided evidence for a mechanistic link between viral infection, exosomes, and antibodies to SAgs. Gunasekaran et al immunized mice with exosomes isolated from LTRs infected with symptomatic respiratory viral infections compared with stable controls.…”

Small Extracellular Vesicles in Transplant Rejection

“…Moreover, exosomes isolated from patients with symptomatic RVI did not include costimulatory molecules CD80 and CD86 in their cargo, contrary to other aforementioned pathologies [152]. These results were consistent when validated in external populations of lung transplant recipients [150] or pediatric patients [155]. Later, Gunasekaran et al showed that in lung transplant recipients with respiratory viral infections exosomes contained also viral antigens and elicited immune response that resulted in the development of chronic lung allograft dysfunction in immunized mice [156].…”

The emerging field of non–human leukocyte antigen antibodies in transplant medicine and beyond

“…34,35 Mohanakumar et al have identified exosomes containing collagen V and Ka1 tubulin as potential vectors to provide antigenic signaling after lung transplantation. 36 Anti-collagen V antibodies are also associated with ABMR and cardiac allograft vasculopathy in heart transplantation, 37 whereas anti-collagen IV is correlated with development of transplant glomerulopathy in kidney transplant recipients. 38 More important, increased collagen-specific T-helper cell 17 cells could promote the generation of anti-collagen antibodies, and experimental transfer of such antibodies could recapitulate allograft injury in models of lung transplantation.…”