Introduction: The mammalian Target of Rapamycin (mTOR) is the active catalytic subunit of two mTOR-containing complexes – mTOR complex (mTORC) 1 and mTORC2. mTORC1 is targeted by the immunosuppressant pro-drug rapamycin (RAPA) and its analogues to impede allograft rejection, and its inhibition has tolerance-sparing properties. Recently described inhibitors of mTOR compete with adenosine triphosphate (ATP) at the catalytic site of mTOR and thus inhibit both mTORC1 and mTORC2. Although ATP-competitive mTOR inhibitors are being tested as anti-neoplastic agents, their immunomodulatory properties and the effect of mTORC2 inhibition in transplantation have not been investigated. It is unknown whether ATP-competitive mTOR inhibitors are viable immunosuppressive agents that can be harnessed in transplantation.

Methods: C57BL/6 (B6; H2^b) mice received fully MHC-mismatched BALB/c (H2^d) heterotopic heart allografts. Recipients were treated with a 10 d course of RAPA (2 mg/kg loading dose and 1 mg/kg/d i.p. maintenance dose) or the ATP-competitive mTOR inhibitor AZD8055 (10 mg/kg twice daily i.p.). Recipients were monitored for allograft survival by abdominal palpation, or euthanized at d 10 for immune monitoring and graft histology.

Results and Conclusions: A short 10 d course of AZD8055 prolonged allograft survival significantly [median survival time (MST): 28 d] compared to untreated recipients (MST: 9 d; p<0.005). Survival was comparably prolonged in recipients treated with 1 mg/kg/d RAPA for 10 d (MST: 35 d). Graft histology revealed similar CD3⁺ T cell infiltration at d 10 in RAPA- and AZD8055-treated recipients. While untreated recipients demonstrated no Foxp3⁺ regulatory T cells (Treg) in the allograft at d 10, RAPA- and AZD8055-treated recipients demonstrated significant Treg in the graft. RAPA and AZD8055 treatment reduced CD4⁺ and CD8⁺ IFNΓ-producing splenic T cells. AZD8055 specifically reduced CD11b⁺Gr1^hi neutrophil and CD11b⁺CD11c⁺ dendritic cell frequencies in the spleen compared to untreated and RAPA-treated recipients. Together, these data demonstrate for the first time, the ability of novel ATP-competitive mTOR inhibitors to prolong organ allograft survival. AZD8055 shares similar tolerance-sparing properties to RAPA, but uniquely reduces splenic myeloid cell populations, suggesting that these mTOR-inhibiting agents may have novel immunomodulatory properties.

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