The PI3K family of dual lipid and protein kinases phosphorylates Akt into pAkt, triggering kinase cascades downstream that play a central role in cell proliferation and survival. While the wide tissue distribution of PI3K expression hindered any significant advancement of drug therapy, discovery of the PI3K subunits and development of novel compounds that specifically target the leukocyte-restricted Δ subunit are promising advances to establish PI3KΔ as a safe therapeutic target for solid organ transplantation. Using a PI3KΔ-/- mouse and a novel specific inhibitor for PI3KΔ, we show a preferential role of this pathway in alloreactive T and B cell survival compared to regulatory T cells. The balance between effector memory and regulatory lymphocytes has been shown to determine the outcome of the alloimmune response. We analyzed by phospho-FACS and western blot Akt phosphorylation in splenoctyes of allogeneic heart recipients compared to syngeneic heart recipients. We found that the PI3K pathway is highly activated in alloreactive T and B cells. Splenic CD4+pAkthigh, CD8+pAkthigh T cells and B220+pAkthigh increased in allogeneic heart recipients over time and peaked at day 4 post-transplantation preceding clinical heart rejection. Interestingly, the expression of pAkt was preferentially higher in effector T cells compared to regulatory T cells. Furthermore, inhibition of this pathway using PI3KΔ-/- T cells or a novel specific PI3KΔ inhibitor (PI3K-i), induced Treg generation in vitro and in vivo while signficantly suppressed the proliferation of effector memory T cells and the production of inflammatory cytokines(Th1/Th17). PI3KΔ-/- recipients of BALB/c (H-2d) heart allografts showed a significant prolongation of heart allograft survival (MST: 43 days vs 7 day, respectively, p=0.0002) and notable protection against chronic rejection compared to wild type. This prolongation was associated with a reduced percentage and absolute number of effector/memory CD4+ and CD8+ T-cells in the spleen and draining lymphnodes of PI3KΔ-/- recipients along with a suppression of Th1/Th17 cytokines. The splenic marginal zone B cells were signficantly reduced in the PI3KΔ-/- recipients of BALB/c hearts compared to WT. Furthermore, the production of donor specific antibodies was reduced more than four folds. We show for the first time a critical role for PI3KΔ in T and B cell alloimmune responses in the context of solid organ transplantation.

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