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

SUBMITTER: Uehara M

PROVIDER: S-EPMC5802749 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Uehara Mayuko M Solhjou Zhabiz Z Banouni Naima N Kasinath Vivek V Xiaqun Ye Y Dai Li L Yilmam Osman O Yilmaz Mine M Ichimura Takaharu T Fiorina Paolo P Martins Paulo N PN Ohori Shunsuke S Guleria Indira I Maarouf Omar H OH Tullius Stefan G SG McGrath Martina M MM Abdi Reza R

Scientific reports 20180206 1

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 ...[more]

PMID: 29410442

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Project description:Age impacts alloimmunity. Effects of aging on T-cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4+ and CD8+ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4+ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age-independent source of mitochondria for activated CD4+ T cells, old but not young CD4+ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4+ T cells with 6-diazo-5-oxo-l-norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN-γ production and compromised proliferative capacities specifically of old CD4+ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1- and Th17-driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4+ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2-deoxy-d-glucose, 2-DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4+ T cells as adoptively transferred young CD4+ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8+ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age-specific metabolic reprogramming of CD4+ T cells. Targeting those pathways offers novel and age-specific approaches for immunosuppression.

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

Publications

Ischemia augments alloimmune injury through IL-6-driven CD4<sup>+</sup> alloreactivity.

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

Publications

Ischemia augments alloimmune injury through IL-6-driven CD4&lt;sup&gt;+&lt;/sup&gt; alloreactivity.

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OmicsDI is part of the ELIXIR infrastructure

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

Ischemia augments alloimmune injury through IL-6-driven CD4<sup>+</sup> alloreactivity.