A novel mechanism for immune regulation after human lung transplantation

Abstract

Objective: Lung transplantation is therapeutic for end-stage lung disease, but survival is limited due to bronchiolitis obliterans syndrome and restrictive chronic lung allograft dysfunction. We sought a common denominator in lung transplant recipients, analyzing risk factors that trigger immune responses that lead to bronchiolitis obliterans syndrome. Methods:We collected blood from patients who underwent lung transplant at our institution. Exosomes were isolated from the sera of recipients with risk factors for chronic rejection and from stable recipients. Exosomes were analyzed with western blot, using antibodies to lung self-antigens K alpha 1 tubulin and collagen-V, costimulatory molecules (costimulatory molecule 80, costimulatory molecule 86), transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells, hypoxia-inducible factor 1a, Class II Major Histocompatibility Complex Transactivator), and 20S proteasome.

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

“…39 These lung-restricted IgG antibodies are capable of fixing complement, they potentially synergize with HLA antibodies, and pathogenicity may be associated with a loss of T-regulatory cells. 40 Vimentin is a type III intermediate filament protein of the cytoskeleton expressed in multiple cell types and represents a major recognized endothelial antigen in sera of heart transplant patients. Anti-vimentin antibodies are independent predictors of cardiac allograft vasculopathy in heart transplant patients.…”

Small Extracellular Vesicles in Transplant Rejection

“…In a study published in 2019, performed for a group of 90 lung transplant recipients with various clinical conditions including: primary graft dysfunction, respiratory viral infection, acute rejection, de novo formation of donor specific antibodies or bronchiolitis obliterans syndrome and recipients with stable lung allograft function, exosomes isolated from all of the aforementioned post-LTx clinical conditions contained important lung SAgs, immunoregulatory molecules and stress markers, which were notably absent in exosomes isolated from stable patients. 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 ].…”

Acute Rejection in the Modern Lung Transplant Era

“…Circulating exosomes isolated from LTx have demonstrated increased levels of mismatched donor HLA molecules and lung-associated tissue-restricted self-antigens (K-α-1 tubulin and collagen type V) during episodes of acute rejection, during CLAD, as well as prior to diagnosis of CLAD, suggesting their potential role as early diagnostic tools for allograft dysfunction. [160][161][162] Exosomelike extracellular vesicles have also been shown to induce autoantibodies involved in allograft rejection. 163 Of note, a transcriptomic analysis of LTx BAL exosomes showed a distinct profile of antigen processing, and both innate and adaptive immune activation during episodes of acute rejection.…”