A novel in vivo regulatory role of P-glycoprotein in alloimmunity
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- 作者：Atsushi Izawa ; Tobias Schatton ; Natasha Y. Frank ; Takuya Ueno ; Kazuhiro Yamaura ; Shona S. Pendse ; Armen Margaryan ; Martin Grimm ; Martin Gasser ; Ana Maria Waaga-Gasser ; Mohamed H. Sayegh ; Markus H. Fra
- 关键词：P-glycoprotein ; Immunity ; Transplantation ; T cell ; Antigen presenting cell ; CD86
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2010
- 出版时间：9 April 2010
- 年：2010
- 卷：394
- 期：3
- 页码：646-652
- 全文大小：2108 K
文摘
P-glycoprotein (P-gp) is required for adaptive immunity through defined functions in T cell activation and antigen presenting cell (APC) maturation. The potential role of P-gp as an in vivo regulator of alloimmunity is currently unknown. Here we show that P-gp blockade prolongs graft survival in a murine heterotopic cardiac allotransplantation model through in vivo inhibition of the T helper 1 (Th1) cytokine IFN-γ and the Th2 product IL-4, and via downregulation of the APC-expressed positive costimulatory molecule CD80. In vitro, the P-gp antagonist PSC833, a non-calcineurin-inhibitory cyclosporine A analogue, specifically inhibited cellular efflux of the P-gp substrate rhodamine-123 in wild-type CD3+ T cells and MHC class II+ APCs but not their P-gp knockout counterparts that lacked rhodamine-123 efflux capacity. Additionally, P-gp blockade significantly inhibited murine alloimmune T cell activation in a dose-dependent fashion. In vivo, P-gp blockade significantly prolonged graft survival in Balb/c recipients of C57BL/6 cardiac allografts from 8.5 ± 0.5 to 11.7 ± 0.5 days (P < 0.01), similar in magnitude to the effects of monotherapy with cyclosporine A. Moreover, P-gp blockade, compared to controls, attenuated intragraft expression of CD3 and CD80, but not CD86, and inhibited IFN-γ and IL-4 production (P < 0.05). In the setting of systemic CD86 inhibition, P-gp blockade suppressed IFN-γ and IL-4 production significantly further (to 98 % and 89 % inhibition, respectively) compared to either P-gp or anti-CD86 blockade alone, and markedly prolonged allograft survival compared to anti-CD86 blockade alone (40.5 ± 4.6 versus 22.5 ± 2.6 days, respectively, P < 0.01). Our findings define a novel in vivo regulatory role of P-gp in alloimmunity and identify P-gp as a potential therapeutic target in allotransplantation.