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Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts¹

Peter T. Jindra^*,, Aileen Hsueh^*,, Longshen Hong, David Gjertson^*, Xiu-Da Shen, Feng Gao, Julie Dang, Paul S. Mischel, William M. Baldwin, III, Michael C. Fishbein, Jerzy W. Kupiec-Weglinski and Elaine F. Reed^2,*,

^* University of California Los Angeles (UCLA) Immunogenetics Center and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095; Department of Surgery, University of California, Los Angeles, CA 90095; and Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205

Anti-MHC class I alloantibodies have been implicated in the process of acute and chronic rejection because these Abs can bind to endothelial cells and transduce signals leading to the activation of cell survival and proliferation pathways. To characterize the role of the MHC class I-signaling pathway in the pathogenesis of Ab-mediated rejection, we developed a mouse vascularized heterotopic cardiac allograft model in which B6.RAG1 KO hosts (H-2K^b/D^b) received a fully MHC-incompatible BALB/c (H-2K^d/D^d) heart transplant and were passively transfused with anti-donor MHC class I Ab. We demonstrate that cardiac allografts of mice treated with anti-MHC class I Abs show characteristic features of Ab-mediated rejection including microvascular changes accompanied by C4d deposition. Phosphoproteomic analysis of signaling molecules involved in the MHC class I cell proliferation and survival pathways were elevated in anti-class I-treated mice compared with the isotype control-treated group. Pairwise correlations, hierarchical clustering, and multidimensional scaling algorithms were used to dissect the class I-signaling pathway in vivo. Treatment with anti-H-2K^d Ab was highly correlated with the activation of Akt and p70S6Kinase (S6K). When measuring distance as a marker of interrelatedness, multidimensional scaling analysis revealed a close association between members of the mammalian target of rapamycin pathway including mammalian target of rapamycin, S6K, and S6 ribosomal protein. These results provide the first analysis of the interrelationships between these signaling molecules in vivo that reflects our knowledge of the signaling pathway derived from in vitro experiments.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant RO1AI42819 and American Heart Association Grant 0555081Y (to E.F.R.) and National Institutes of Health Grants RO1AI23847 and RO1AI42223 (to J.K.-W.).

² Address correspondence and reprint requests to Dr. Elaine F. Reed, UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095. E-mail address: ereed{at}mednet.ucla.ed

³ Abbreviations used in this paper: AMR, Ab-mediated rejection; CAV, coronary allograft vasculopathy; EC, endothelial cell; FAK, focal adhesion kinase; S6RP, S6 ribosomal protein; mTOR, mammalian target of rapamycin; KO, knockout; MDS, multidimensional scaling; FcRn, neonatal FcR; mTORC, mTOR complex; Raptor, regulatory associated protein of mTOR.