演題詳細

一般口演 / Oral Session

一般口演 22 (Oral Session 22) :造血幹細胞移植:基礎

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日程
2013年10月11日(金)
時間
15:25 - 16:25
会場
第5会場 / Room No.5 (さっぽろ芸文館 3F 清流)
座長・司会
村田 誠 (Makoto Murata):1
1:名古屋大学医学部附属病院 血液内科
 
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Inhibition of c-Rel activity diminishes alloactivation without compromising anti-tumor activity

演題番号 : OS-1-110

庄野 雄介 (Yusuke Shono):1、Marcel van den Brink:1

1:Memorial Sloan-Kettering Cancer Center

 

We investigated the role of c-Rel during GVHD in murine HSCT models. c-Rel-/- T cells caused significantly less GVHD than wildtype T cells. Proliferation/activation of c-Rel-/- T cells was impaired and pSTAT5 expression was decreased, resulting in less expansion of donor derived effector T cells by day 7 after transplant. Surprisingly, serum levels of IL-2 were increased on day 7, likely secondary to decreased pSTAT5-mediated negative feed back on IL-2 secretion. By day 14 we observed increased numbers of donor derived Tregs with increased CD25 expression in recipients of c-Rel-/- T cells, suggesting that the increased IL-2 levels primarily benefited the expansion of Tregs. Consistent with this hypothesis, in vivo depletion of donor Tregs in recipients of c-Rel inhibited Foxp3DTR transgenic T cells exacerbated GVHD.
GVT activity in c-Rel-/- T cells recipients was intact in the absence of GVHD in various tumor models. Using syngeneic GVT models we could demonstrate strong anti-tumor activity in the absence of T-cell alloactivation, reinforcing the notion of separation of GVHD from GVT activity through inhibition of c-Rel signaling.
T cells that were pre-treated with a recently developed small molecule c-Rel inhibitor compound reproduced our above described effects on GVHD and antitumor activity.
Our findings identify c-Rel as a promising target for the development of a clinical strategy to prevent GVHD while preserving GVT activity, and to possibly even enable adoptive T-cell therapy across MHC barriers that would be incompatible with a conventional transplant approach.

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