Nicholas Chun1,2, Julian Horwitz1,3, Peter S Heeger1,2,3. 1. Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai. 2. Division of Nephrology in the Department of Medicine, Icahn School of Medicine at Mount Sinai. 3. The Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai.
Abstract
PURPOSE: Novel paradigms have broadened our understanding of mechanisms through which complement mediates allograft inflammation/injury. Herein we review advances in the field and highlight therapeutic implications. RECENT FINDINGS: Pre-clinical and translational human trials have elucidated complement-dependent mechanisms of post-transplant ischemia-reperfusion (I/R) injury. Immune cell-derived, and intracellular, complement activation are newly linked to proinflammatory T cell immunity relevant to allograft rejection. Complement-induced immune regulation, including C5a ligation of C5a receptor 2 on T cells, C5a/C5a receptor 1 interactions on regulatory myeloid cells, and C1q binding to CD8+ T cells can inhibit proinflammatory T cells and/or prolong murine allograft survival. Pilot trials of complement inhibition to treat/prevent human I/R- or antibody-initiated allograft injury show promise. SUMMARY: The complement system participates in allograft injury through multiple context- dependent mechanisms involving various components and receptors. These new insights along with development and implementation of individualized complement inhibitory strategies have potential to improve transplant outcomes.
PURPOSE: Novel paradigms have broadened our understanding of mechanisms through which complement mediates allograft inflammation/injury. Herein we review advances in the field and highlight therapeutic implications. RECENT FINDINGS: Pre-clinical and translational human trials have elucidated complement-dependent mechanisms of post-transplant ischemia-reperfusion (I/R) injury. Immune cell-derived, and intracellular, complement activation are newly linked to proinflammatory T cell immunity relevant to allograft rejection. Complement-induced immune regulation, including C5a ligation of C5a receptor 2 on T cells, C5a/C5a receptor 1 interactions on regulatory myeloid cells, and C1q binding to CD8+ T cells can inhibit proinflammatory T cells and/or prolong murine allograft survival. Pilot trials of complement inhibition to treat/prevent human I/R- or antibody-initiated allograft injury show promise. SUMMARY: The complement system participates in allograft injury through multiple context- dependent mechanisms involving various components and receptors. These new insights along with development and implementation of individualized complement inhibitory strategies have potential to improve transplant outcomes.
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