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A novel in vivo regulatory role of P-glycoprotein in alloimmunity.

Abstract：

: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-gamma 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-gamma and IL-4 production (P<0.05). In the setting of systemic CD86 inhibition, P-gp blockade suppressed IFN-gamma 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.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Izawa A,Schatton T,Frank NY,Ueno T,Yamaura K,Pendse SS,Margaryan A,Grimm M,Gasser M,Waaga-Gasser AM,Sayegh MH,Frank MH

doi

10.1016/j.bbrc.2010.03.040

subject

Has Abstract

pub_date

2010-04-09 00:00:00

pages

646-52

issue

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(10)00478-X

journal_volume

394

pub_type

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A novel in vivo regulatory role of P-glycoprotein in alloimmunity.