Exosomes containing mismatched donor HLA and lung restricted self-antigens (SAgs), Kα1 Tubulin (Kα1T) and Collagen V (Col-V), have demonstrated in sera and bronchoalveolar lavage fluid in adult lung transplant recipients (LTxRs) diagnosed with rejection. The goals of this study are to determine the presence of circulating exosomes in pediatric LTxRs and to define the antigenic and immunoregulatory molecules present in the exosomes from bronchiolitis obliterans syndrome (BOS) and stable pediatric LTxRs. We retrospectively selected 7 patients with BOS and 13 stable pediatric LTxRs and sera collected at 1,6, and 12 months following lung transplant was analyzed. Exosomes were isolated from serum using ultracentrifugation method. Presence of lung SAgs, Kα1T and Col-V, MHC class II molecule and its transcription factors, CIITA, NF-kB, HIF-1α as well as co-stimulatory molecules (CD 40,80,86) and alpha subunit of 20S-proteasome in the exosomes were detected using western blot. Exosomes isolated from sera of LTxRs who developed BOS demonstrated significantly increased levels of lung SAgs (9 fold increase Col-V and 3.1 fold increase Kα1T p=0.002) in comparison to stable LTxRs. Significant increases in expression of MHC class II (37 fold increase p=0.032), CIITA (9.3 fold increase p=0.003), transcription factors (9.8 fold increase in HIF-1α p=0.036, 16.2 fold increase in NF-kB= 0.011), co-stimulatory molecules (20 fold increase in CD 40,80,86 p=0.005), and 20S proteasome (3 fold increase p=0.005) were also detected. Serial analysis of sera suggest that circulating exosomes with lung SAgs can be a potential biomarker since they are present in the sera 6 months prior to clinical diagnosis of BOS. This study demonstrated that circulating exosomes are detectable in the sera from pediatric LTxRs diagnosed with BOS. Preliminary analysis support that it can be a viable biomarker for identifying patients at risk for development of BOS. We also demonstrate that exosomes from BOS pediatric LTxRs differ from stable LTxRs with respect to the presence of lung SAgs, MHC class II and its transcription factor CIITA, costimulatory molecules, transcription factors NF-kB, HIF-1α and 20S proteasomes.

CITATION INFORMATION: Sharma M., Danziger-Isakov L., Heeger P., Sweet S., Mohanakumar T. Circulating Exosomes with Lung Self-Antigens, Kα1Tubulin and Collagen V, and Immunoregulatory Molecules Are Present in Bronchiolitis Obliterans Syndrome Following Pediatric Lung Transplantation Am J Transplant. 2017;17 (suppl 3).

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