Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

Abstract

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+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ 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.

Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes

“…Though IL-17 levels in posttransplant MLR cultures were suppressed in Cohort C but not in Cohort B, we did not see a significant difference between the Cohorts in the frequency of IFN-γ-secreting T cells in response to irradiated donor PBLs in ELISPOT assays. Several studies have demonstrated that donor-specific alloimmune responses can be mediated through the production of cytokines other than IFN-γ including IL-6 40,41 and IL-17 42–44 and that CD4 + T cells with indirect specificity can mediate skin graft rejection in the absence of IFN-γ 19,45 . These findings suggest that our ADL infusions and one DRB matching did play important roles in tolerance induction and maintenance.…”

Anti-IL-6 eluting immunomodulatory biomaterials prolong skin allograft survival

“…A growing body of evidence highlights the importance of novel strategies that can reduce intra-graft inflammatory responses effectively 13,14 . Intra-graft inflammatory responses have increasingly received attention as an instigator of the alloimmune response 15–19 .…”

Reduction of Transplant Vasculopathy by Intraoperative Nucleic Acid-based Therapy in a Mouse Aortic Allograft Model

“…However, it has been demonstrated that ischemia promotes alloimmune activation, leading to more severe histological features of rejection and increased leukocyte graft infiltration. 41 Despite the effectiveness of the single graft pre-treatment with AP-1 dODN in our study, the restricted dODN stability is a further limiting factor. As it is possible to generate intracellularly any single-stranded DNA, 42 a dODN expression system generating therapeutic nucleic acids in bioactive form may provide an improved therapeutic approach for continuous generation of the dODN in cells of the graft vessel wall, which may have an even more pronounced effect on neointima formation.…”