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(Circulation. 2000;101:1034.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Attenuated Cardiac Allograft Vasculopathy in Mice With Targeted Deletion of the Transcription Factor STAT4

Jörg Koglin, MD; Troels Glysing-Jensen, BS; Silpa Gadiraju; Mary E. Russell, MD

From the Cardiovascular Biology Laboratory, Harvard School of Public Health (J.K., T.G.-J., S.G., M.E.R.); Brigham and Women’s Hospital (M.E.R.); and Harvard Medical School (M.E.R.), Boston, Mass.

Correspondence to Jörg Koglin, MD, Medizinische Klinik I, Universitätsklinikum Grosshadern, Marchioninistraße 15, 81377 Munich, Germany. E-mail joerg.koglin{at}med1.med.uni-muenchen.de

Background—To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients 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 with reduced intragraft expression (³²P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon- (P<0.001) and interleukin (IL)-2 (P<0.001). Furthermore, cardiac grafts in STAT4 -/- had fewer infiltrating CD45⁺ mononuclear cells (99±27 cells/mm³ compared with 551±168 cells/mm³ in wild-type controls [P<0.05]) and reduced expression of P-selectin (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%, severity 28±6%) and Th2 cytokine profiles (IL-4, IL-10) were comparable to those 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 recruitment, activation, and effector functions.

Key Words: lymphocytes • transplantation • immune system • cytokines • cell adhesion molecules

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