Attenuated cardiac allograft vasculopathy in mice with targeted deletion of the transcription factor STAT4

Background-To study transcription factor signaling pathways that mediate ca rdiac allograft vasculopathy, we used mice with targeted gene deletion of s ignal transducer and activator of transcription (STAT)4 and STAT6 as recipi ents in our mouse cardiac transplant model of chronic rejection. Methods and Results-At day 55 after transplantation, cardiac grafts placed into STAT4 -/- (n=10) had reduced frequency (24+/-2%) and severity (9+/-4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70/-12% [P<0.001], severity 25+/-6% [P<0.05]). This decrease was associated w ith reduced intragraft expression (P-32 RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-gamma (P<0.001) and interleukin (IL )-2 (P<0.001). Furthermore, cardiac grafts in STAT4 -/- had fewer infiltrat ing CD45(+) mononuclear cells (99+/-27 cells/mm(3) compared with 551+/-168 cells/mm(3) in wild-type controls [P<0.05]) and reduced expression of P-sel ectin (P<0.001) and E-selectin (P<0.01) ligand, recently shown to regulate Th1 cell recruitment. In contrast, in grafts placed into STAT6 -/- (n=11), the development of cardiac allograft vasculopathy (frequency 62+/-8%, sever ity 28+/-6%) and Th2 cytokine profiles (IL-4, IL-10) were comparable to tho se in wild-type controls. Conclusions Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1 specific lymphocyte recrui tment, activation, and effector functions.