Research on principle of benzoxazole derivative PO-291 inhibiting T cell proliferation / 中国药理学通报

ABSTRACT

Objective To investigate the immunosup-pressive activity of benzoxazole derivative PO-291 in inhibiting human activated T cell proliferation and function. Methods Human T cells were isolated and purified by the immunomagnetic microbeads and acti-vated by anti-CD3/anti-CD28 mAbs or alloantigen. Cell proliferation, the expression of CD25 and CD69, cell cycle and apoptosis were measured by flow cytome-try. Secretion levels, including IL-2, IL-4, IL-6, IL-10, IL-17 and IFN-γ were determined by ELISA. The expression and phosphorylation of STAT5 and p70S6K of activated T cells were detected by Western blot. Re-sults PO-291 significantly inhibited human T cell proliferation with anti-CD3/anti-CD28 mAbs or alloan-tigen stimulation without obvious cytotoxicity. PO-291 did not affect CD25, CD69 and IL-2 expression, but induced T cell cycle arrest in G0/G1 phase. PO-291 significantly inhibited IL-17, IFN-γ and IL-6 expres-sion, but not IL-2, IL-4 and IL-10. PO-291 did not affect STAT5 and p70S6K expression, but inhibited STAT5 phosphorylation and enhanced p70S6K phos-phorylation. Conclusions PO-291 inhibits human ac-tivated T cell proliferation by affecting the JAK3/STAT5 pathway. PO-291 represents a potential lead compound for the design and development of new im-munosuppressive drugs for the treatment of organ trans-plantation and autoimmune diseases.