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UBC Theses and Dissertations

The mechanism of anti-proliferation of Halofuginone in T cells. Chu, Tony Lok Heng


Inactivation of T cells is a widely used strategy for immunosuppression. Halofuginone (HF) is an antiprotozoal agent for treating parasites in veterinary medicine, and has been demonstrated to inhibit collagen type 1 synthesis, T helper 17 cell differentiations and cytokine production in activated T cells. The present study was designed to examine its actions against T cell proliferation, and in a combined therapy with conventional immunosuppressant rapamycin. To examine the anti-proliferative ability of HF, T cell proliferation in cultured murine splenocytes, cell apoptosis, and cell cycle analysis as well as autophagy markers were investigated. The expression of cleaved Poly ADP ribose polymerase and DNA fragmentation were further to characterize apoptosis. Here, I showed that addition of HF in naïve splenocyte cultures significantly suppressed cell proliferation in response to antigen- or anti-CD3 antibody or in activated T cell cultures in response to Interleukin (IL)-2 in a dose-dependent manner with activation of apoptosis, and cell cycle arrest at S phase. Further studies showed that proline supplement in cell culture medium significantly prevented HF-mediated suppression of T cell proliferation by reducing cell apoptosis and proliferation arrest. In addition, HF synergistically enhanced the anti-proliferative ability of rapamycin, which was correlated with increased induction of apoptosis in T cell cultures. My data suggests that HF interferes proline incorporation in protein synthesis machinery resulting in apoptosis and autophagy-induced cell cycle arrest via amino acid starvation response in T cells. The data of this study suggest that HF may be a potential adjuvant that can enhance anti-proliferative activity of rapamycin in preventing T cell proliferation.

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