Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia

• Published in: American journal of transplantation Vol. 18; no. 5; pp. 1238 - 1246
• Main Authors: Ayasoufi, Katayoun, Kohei, Naoki, Nicosia, Michael, Fan, Ran, Farr, George W., McGuirk, Paul R., Pelletier, Marc F., Fairchild, Robert L., Valujskikh, Anna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.05.2018
• Subjects: Abatacept - pharmacology; Allografts; animal models: murine; Animals; Apoptosis; Aquaporin 4; Aquaporin 4 - antagonists & inhibitors; basic (laboratory) research/science; Cell proliferation; cellular biology; Cold Ischemia - adverse effects; CTLA-4 Antigen - antagonists & inhibitors; Cytotoxicity; Female; Heart diseases; Heart Transplantation - mortality; Homeostasis; immune regulation; immunobiology; Immunoglobulins; Immunosuppression; Immunosuppression Therapy; immunosuppression/immune modulation; Immunosuppressive Agents - pharmacology; Ischemia; Lymphocytes T; Major histocompatibility complex; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Primary Graft Dysfunction - etiology; Primary Graft Dysfunction - mortality; Primary Graft Dysfunction - prevention & control; Reperfusion; Reperfusion Injury - etiology; Reperfusion Injury - mortality; Reperfusion Injury - prevention & control; Survival Rate; T cell biology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Transplantation; Transplants & implants; animal models: murine; immunosuppression/immune modulation; T cell biology; cellular biology; immunobiology; immune regulation; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.14624

Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia–reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC‐mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short‐time posttransplantation improves the viability of donor graft cells, diminishes donor‐reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte–associated antigen 4–Ig in prolonging survival of 8‐hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor‐reactive T cells. These results identify AQPs as a promising target for diminishing donor‐specific alloreactivity and improving the survival of high‐risk organ transplants. Using a robust mouse model of heart allograft rejection, this study provides the first evidence that aquaporin water channels regulate adaptive alloimmunity and can be targeted to improve transplant outcome.