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A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury |
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| Authors: | Changhai Li Kunal Patel Zhenxiao Tu Xiaofeng Yang Liudmila Kulik Ali Alawieh Patterson Allen Qi Cheng Caroline Wallace Jane Kilkenny Jennie Kwon Barry Gibney Edward Cantu Ashish Sharma Mauricio Pipkin Tiago Machuca Amir Emtiazjoo Martin Goddard V. Michael Holers Satish Nadig Jason Christie Stephen Tomlinson Carl Atkinson |
| Affiliation: | 1. The Hepatic Surgery Centre at Tongji Hospital, Tongji Medical College, HUST, Wuhan, China Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China Department of Microbiology and Immunology, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA;2. Department of Microbiology and Immunology, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA Department of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA;3. Department of Microbiology and Immunology, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA Department of Surgery, Hepatic and Vascular Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;4. Department of Microbiology and Immunology, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA;5. Department of Medicine and Immunology, University of Colorado Denver, Aurora, Colorado, USA;6. Department of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA;7. The Hepatic Surgery Centre at Tongji Hospital, Tongji Medical College, HUST, Wuhan, China Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China;8. Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA;9. Department of Surgery, University of Florida, Gainesville, Florida, USA;10. Division of Thoracic and Cardiovascular Surgery, University of Florida, Gainesville, Florida, USA;11. Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, USA;12. Pathology Department, Papworth Hospital, NHS Trust, Papworth Everard, Cambridge, UK;13. Department of Medicine and Immunology, University of Colorado Denver, Aurora, Colorado, USA Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA;14. Department of Microbiology and Immunology, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA Department of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, South Carolina, USA South Carolina Investigators in Transplantation, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA;15. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA |
| Abstract: | Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1-/- recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach. |
| Keywords: | basic (laboratory) research / science complement biology immunobiology innate immunity lung (allograft) function / dysfunction lung transplantation / pulmonology |