Introduction: Mitochondria released in the setting of tissue injury and cell death are a source of damage-associated molecular patterns that activate innate immune responses. We sought to determine the impact of extracellular mitochondria on allograft endothelial cell (EC) activation and vascularized allograft rejection in the setting of co-stimulation blockade.

Methods: MHC-mismatched BALB/c to B6 cardiac allograft mean survival time (MST) was determined in the presence or absence of costimulation blockade with CTLA4-Ig along with intravenous treatment with purified murine mitochondria. Following graft rejection, T cells were FACS analyzed for CD28 expression and effector memory (T_EM, CD44+CCR7neg) phenotype. Post-transplant allograft EC CD40 expression was assessed by immunohistochemistry.

Results: In the absence of costimulation blockade, post-transplant intravenous mitochondria treatment (Mito-tx) resulted in similar allograft rejection rates as untreated controls (Mito-tx MST 6.8±0.8 days; n=5, vs control MST 7.6±0.5 days; n=5), but increased CD4+T_EM frequency (Mito-tx 51±8% vs control 34±14%, p=0.034), and CD8+T_EM frequency (Mito-tx 87±1.4% vs control 66±13%, p=0.005). Costimulation blockade with CTLA4-Ig dramatically increased allograft survival (>65 days, n=5) and reduced T_EM frequencies (CD4⁺ 14±18%, CD8⁺ 20±4%). However, co-treatment with CTLA4-Ig and mitochondria resulted in rapid rates of allograft rejection (MST 14.9±2.6 days, n=6) and correspondingly increased T_EM frequencies (CD4⁺ 30±7%, CD8⁺ 35±5%). Mito-tx had no effect on T_EM cell expression of CD28, but induced CD40 expression on allograft vascular ECs compared to untreated mice.

Summary: Extracellular mitochondria cause costimulation resistant allograft rejection in mice by activating graft EC and increasing CD4+ and CD8+ T_EM responses. Tissue injury resulting in mitochondrial release may predispose allografts to rejection mediated by effector memory T cells.

CITATION INFORMATION: Brennan T, Lin L, Song M, Feng F, Li Q.-J, Kirk A, Xu H. Extracellular Mitochondria Cause B7 Costimulation Blockade Resistant Allograft Rejection in Mice. Am J Transplant. 2017;17 (suppl 3).

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