Background: Rapamycin (RAPA), an immunosuppressive agent, inhibits the mechanistic target of Rapamycin (mTOR), the kinase subunit of two mTOR- containing complexes (mTORC1 and mTORC2). While RAPA targets mTORC1 and consequently, growth responses of activated T cells, its inhibitory effect on mTORC2 is less consistent. By contrast, novel mTORC kinase inhibitors (TORKinibs) suppress the catalytic function of both complexes. Although mTORC2 has been reported to play an important role in B cell homeostasis and vasculopathy, little is known about the immunosuppressive potential of TORKinibs or their ability to affect allograft survival.

Methods: A 9 -day course of the dual mTORC inhibitor AZD2014 (10 mg/kg twice daily ip) was administered to recipients of MHC-mismatched vascularized heterotopic heart allografts (BALB/c to B6). Graft survival was assessed by daily abdominal palpation and rejection confirmed histologically. Immune cell subsets in spleen, intra-graft T cells and cytokine production by host lymphocytes were analyzed by flow cytometry pre- and post transplant.

Results: AZD2014 markedly prolonged fully MHC-mismatched heart graft survival (median graft survival time > 90 days vs 10 days; p<0.001). This effect was associated with reduced heart graft mononuclear cell infiltration and reduced numbers of splenic DC, B cells and Treg (CD11c+DC: 3.83 x 10⁵ vs 1.76 x 10⁶ cells; p<0.01, B cells: 54 x 10⁶ vs 102 x 10⁶; p<0.05, CD4+,CD25+,Foxp3+: 1.7X10⁶ vs 2.5X10⁶ cells; p<0.05) on day 7 post transplant. Unlike RAPA, which selectively preserved both granulocytic (CD11b+, MHC-ClassII-,Ly6Cint, Ly6G+) and monocytic myeloid-derived suppressor cells (CD11b+,MHC-ClassII-,Ly6C+,Ly6G-) in the spleen on Day 7 post transplant (7.13×10⁶ vs 8.47X10⁶ cells and 1.7X10⁶ vs 1.69X10⁶ cells), AZD2014 suppressed these populations (2.74X10⁶ vs 8.47X10⁶ cells; p<0.01 and 6.05X10⁵ vs 1.69X10⁶ cells; p<0.1).

Conclusions: Based on these early results that demonstrate both a long-lasting inhibitory effect of a short course of dual mTORC inhibition on graft survival and different immunoregulatory properties compared to RAPA, further investigation of the influence of novel TORKinibs on anti-donor T cell and Ab-mediated responses and on chronic allograft rejection are justified.

CITATION INFORMATION: Fantus D, Ono Y, Yokota S, Komatsu C, Turnquist H, Thomson A. The Impact of a Novel Dual Adenosine Triphosphate-Competitive mTOR Inhibitor (TORKinib) on Alloimmunity and Transplant Survival. Am J Transplant. 2016;16 (suppl 3).

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