Department of Surgery
Immunity | Other Immunology and Infectious Disease | Pathological Conditions, Signs and Symptoms | Surgery | Surgical Procedures, Operative
Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4(+) and CD8(+) T cell graft infiltration, with a predominantly CD8(+) IFNgamma(+) infiltrate. This process is dependent on the presence of alloreactive CD4(+) T cells, where depletion prevented infiltration of ischemic grafts by CD8(+) IFNgamma(+) T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8(+) IFNgamma(+) allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.
Immunology, Transplant immunology
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DOI of Published Version
Sci Rep. 2018 Feb 6;8(1):2461. doi: 10.1038/s41598-018-20858-4. Link to article on publisher's site
Uehara M, Solhjou Z, Banouni N, Kasinath V, Xiaqun Y, Dai L, Yilmam O, Yilmaz M, Ichimura T, Fiorina P, Martins PN, Ohori S, Guleria I, Maarouf OH, Tullius SG, McGrath MM, Abdi R. (2018). Ischemia augments alloimmune injury through IL-6-driven CD4(+) alloreactivity. Open Access Articles. https://doi.org/10.1038/s41598-018-20858-4. Retrieved from https://escholarship.umassmed.edu/oapubs/3400
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.