A Novel Natural Autoantibody Targeted Complement Inhibitor Protects against Lung Transplant Ischemia Reperfusion Injury
| Autor: | Alexander McQuiston, Carl Atkinson, Qi Cheng, Stephen Tomlinson, Zhenxiao Tu, Kunal Patel, C. Li |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Pulmonary and Respiratory Medicine
Transplantation Lung biology business.industry Autoantibody Ischemia Inflammation medicine.disease_cause medicine.disease Autoimmunity Complement inhibitor medicine.anatomical_structure Immunology medicine biology.protein Surgery Antibody medicine.symptom Cardiology and Cardiovascular Medicine business Reperfusion injury |
| Zdroj: | The Journal of Heart and Lung Transplantation. 40:S55 |
| ISSN: | 1053-2498 |
| DOI: | 10.1016/j.healun.2021.01.1874 |
| Popis: | Purpose Chronic obstructive pulmonary disease is characterized by chronic inflammation and severe lung parenchyma damage that is in part driven by autoimmunity. Lung specific autoreactive antibodies (AAb) are indicative of disease progression and severity. The purpose of this study was to elucidate how pre-existing AAb contribute to ischemia reperfusion injury (IRI) and graft rejection following lung transplant (LTx). We hypothesize that pre-existing AAb bind cryptic antigens exposed during IRI which exacerbates lung graft injury in a complement (C)-dependent pathway. Methods We generated a clinically relevant cigarette smoke (CS)-induced mouse model that exhibits increased serum AAb compared to non-smoke exposed age-matched (NS) controls. We analyzed the impact of a full pre-existing AAb repertoire by creating an orthotopic syngeneic left lung LTx model in which we transplanted the left lungs from age-matched donor mice into NS and CS mice. Furthermore, we developed a novel bifunctional inhibitor that blocks IgM binding and inhibits complement. Results CS exposure significantly increased graft injury and immune infiltration 48 hours after LTx. Syngeneic LTx into Rag−/- mice reconstituted with serum from NS and CS mice demonstrated that AAb present in CS are responsible for the observed graft injury. Immunofluorescent staining showed that IgM/IgG binding was increased in CS recipients and colocalized with C3d deposition. These data suggested that AAb-mediated graft injury may occur via the C pathway. To elucidate the role of C in AAb-mediated graft injury, we treated CS LTx recipients with a novel bifunctional C inhibitor, C2scFv-Crry, that blocks IgM binding and C activation. C2scFv-Crry treatment following LTx dramatically reduced acute graft injury and immune infiltration, and significantly decreased de novo AAb production compared to CS control LTx mice. Conclusion Ultimately, these data reveal that CS induces pre-existing AAb production that exacerbate IRI following LTx in a C-dependent manner. Furthermore, we demonstrate the efficacy of a novel C inhibitor in reducing IRI and acute graft injury. |
| Databáze: | OpenAIRE |
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