Anti-MHC class I antibody activation of proliferation and survival signaling in murine cardiac allografts.
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.
Jindra
Peter T
PT
UCLA Immunogenetics Center and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA.
Hsueh
Aileen
A
Hong
Longshen
L
Gjertson
David
D
Shen
Xiu-Da
XD
Gao
Feng
F
Dang
Julie
J
Mischel
Paul S
PS
Baldwin
William M
WM
Fishbein
Michael C
MC
Kupiec-Weglinski
Jerzy W
JW
Reed
Elaine F
EF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006084:Graft Rejection / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006183:H-2 Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D064532:Histocompatibility Antigen H-2D; D007116:Immunization, Passive; D007518:Isoantibodies / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; C024755:H-2K(K) antigen; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D007518:Isoantibodies; D048049:Extracellular Signal-Regulated MAP Kinases