Acute rejection is the most important factor causing allograft loss, which remains a challenge for patients undergoing organ transplantation. There is considerable evidence indicating that the activity of PI3K and its downstream positive and negative regulators plays a major role in regulating the activation of different subsets of effector CD4+ T cells. Thus, we investigated whether class A PI3Ks are involved in the development of acute allograft rejection, we found that p110α protein expression levels in the allograft group were significantly up-regulated on day 7 post-transplantation, while p110β and p110δ expression was significantly increased on days 5 and 7 post-transplantation. Treatment with PIK and IC but not TGX significantly prolonged allograft survival and altered pathological grades. The percentages of Th1 and Th2, Th17 and Tfh cells/monocytes in the spleens from the IC treatment group were all down-regulated. In contrast, the percentage of Treg cells in the spleens from IC treatment group was remarkably increased. IL-17A and IL-21 and IFN-γ expression levels were significantly decreased in the IC group. Moreover, IC significantly reduced P70 S6 Kinase β and 4E-BP1 protein expression. In conclusion, small-molecule inhibitors of p110δ and p110α suppress acute heart allograft rejection in mice. These inhibitors may play a role in anti-rejection by impacting the phosphorylation and expression of proteins in the AKT/mTOR pathway to modulate CD4+ T cell subsets levels in recipients, reduce proinflammatory factor expression and increase anti-inflammatory cytokine expression. These findings indicate that some small-molecule inhibitors of p110 can serve as novel targets in acute allograft rejection treatment.
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