Carl Atkinson1, Fei Qiao1, Xiaofeng Yang1, Peng Zhu1, Nicholas Reaves1, Liudmila Kulik1, Martin Goddard1, V Michael Holers1, Stephen Tomlinson2. 1. From Department of Microbiology and Immunology, Medical University of South Carolina, Charleston (CA., F.Q., X.Y., P.Z., N.R., S.T.); Department of Medicine and Immunology, University of Colorado Denver, Aurora (L.K., V.M.H.); Department of Pathology, Papworth Hospital, Cambridgeshire, UK (M.G.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (S.T.). 2. From Department of Microbiology and Immunology, Medical University of South Carolina, Charleston (CA., F.Q., X.Y., P.Z., N.R., S.T.); Department of Medicine and Immunology, University of Colorado Denver, Aurora (L.K., V.M.H.); Department of Pathology, Papworth Hospital, Cambridgeshire, UK (M.G.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC (S.T.). tomlinss@musc.edu.
Abstract
BACKGROUND: Natural IgM antibodies represent a class of innate pattern recognition receptors that recognize danger-associated molecular patterns expressed on stressed or dying cells. They play important roles in tissue homeostasis by disposing of prenecrotic cells and suppressing inflammation. However, ischemic insult leads to a pathogenic level of IgM binding and complement activation, resulting in inflammation and injury. We investigate the role of self-reactive IgM in the unique setting of transplantation where the donor organ undergoes both cold and warm ischemia and global ischemic insult. METHODS AND RESULTS: By transplanting hearts from wild-type donor mice into antibody-deficient mice reconstituted with specific self-reactive IgM monoclonal antibodies, we identified neoepitopes expressed after transplantation and demonstrated a key role for IgM recognition of these epitopes in graft injury. With this information, we developed and characterized a therapeutic strategy that exploited the postischemia recognition system of natural antibodies. On the basis of neoepitope identification, we constructed an anti-annexin IV single-chain antibody (scFv) and an scFv linked to Crry, an inhibitor of C3 activation (scFv-Crry). In an allograft transplantation model in which recipients contain a full natural antibody repertoire, both constructs blocked graft IgM binding and complement activation and significantly reduced graft inflammation and injury. Furthermore, scFv-Crry specifically targeted to the transplanted heart and, unlike complement deficiency, did not affect immunity to infection, an important consideration for immunosuppressed transplant recipients. CONCLUSIONS: We identified pathophysiologically important epitopes expressed within the heart after transplantation and described a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches.
BACKGROUND: Natural IgM antibodies represent a class of innate pattern recognition receptors that recognize danger-associated molecular patterns expressed on stressed or dying cells. They play important roles in tissue homeostasis by disposing of prenecrotic cells and suppressing inflammation. However, ischemic insult leads to a pathogenic level of IgM binding and complement activation, resulting in inflammation and injury. We investigate the role of self-reactive IgM in the unique setting of transplantation where the donor organ undergoes both cold and warm ischemia and global ischemic insult. METHODS AND RESULTS: By transplanting hearts from wild-type donormice into antibody-deficientmice reconstituted with specific self-reactive IgM monoclonal antibodies, we identified neoepitopes expressed after transplantation and demonstrated a key role for IgM recognition of these epitopes in graft injury. With this information, we developed and characterized a therapeutic strategy that exploited the postischemia recognition system of natural antibodies. On the basis of neoepitope identification, we constructed an anti-annexin IV single-chain antibody (scFv) and an scFv linked to Crry, an inhibitor of C3 activation (scFv-Crry). In an allograft transplantation model in which recipients contain a full natural antibody repertoire, both constructs blocked graft IgM binding and complement activation and significantly reduced graft inflammation and injury. Furthermore, scFv-Crry specifically targeted to the transplanted heart and, unlike complement deficiency, did not affect immunity to infection, an important consideration for immunosuppressed transplant recipients. CONCLUSIONS: We identified pathophysiologically important epitopes expressed within the heart after transplantation and described a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches.
Authors: Ming Zhang; William G Austen; Isaac Chiu; Elisabeth M Alicot; Rachel Hung; Minghe Ma; Nicola Verna; Min Xu; Herbert B Hechtman; Francis D Moore; Michael C Carroll Journal: Proc Natl Acad Sci U S A Date: 2004-03-03 Impact factor: 11.205
Authors: R J Quigg; Y Kozono; D Berthiaume; A Lim; D J Salant; A Weinfeld; P Griffin; E Kremmer; V M Holers Journal: J Immunol Date: 1998-05-01 Impact factor: 5.422
Authors: N Baumgarth; O C Herman; G C Jager; L Brown; L A Herzenberg; L A Herzenberg Journal: Proc Natl Acad Sci U S A Date: 1999-03-02 Impact factor: 11.205
Authors: Mary C Walsh; Todd Bourcier; Kazue Takahashi; Lei Shi; Marc N Busche; Russell P Rother; Scott D Solomon; R Alan B Ezekowitz; Gregory L Stahl Journal: J Immunol Date: 2005-07-01 Impact factor: 5.422
Authors: Carl Atkinson; Hongbin Song; Bo Lu; Fei Qiao; Tara A Burns; V Michael Holers; George C Tsokos; Stephen Tomlinson Journal: J Clin Invest Date: 2005-08-25 Impact factor: 14.808
Authors: Sherry D Fleming; Ryan P Egan; Chunyan Chai; Guillermina Girardi; V Michael Holers; Jane Salmon; Marc Monestier; George C Tsokos Journal: J Immunol Date: 2004-12-01 Impact factor: 5.422
Authors: Kunal J Patel; Qi Cheng; Sarah Stephenson; D Patterson Allen; Changhai Li; Jane Kilkenny; Ryan Finnegan; Valeria Montalvo-Calero; Scott Esckilsen; Chentha Vasu; Martin Goddard; Satish N Nadig; Carl Atkinson Journal: Am J Respir Cell Mol Biol Date: 2019-06 Impact factor: 6.914
Authors: V Michael Holers; Stephen Tomlinson; Liudmila Kulik; Carl Atkinson; Bärbel Rohrer; Nirmal Banda; Joshua M Thurman Journal: Semin Immunol Date: 2016-06-06 Impact factor: 11.130