Cardiac transplant recipients exhibiting a humoral immune response to the allograft demonstrate increased risk of antibody-mediated rejection and transplant arteriosclerosis. HLA class I and class II signaling pathways have been implicated in this process because ligation of class I and class II molecules by anti-HLA antibodies initiates intracellular signals in endothelial cells that synergize with growth factor receptors to elicit cell survival and cell proliferation. Activation of anti-apoptotic and cell survival machinery in endothelial cells is augmented when cells are exposed to low concentrations of anti-HLA antibodies. In contrast, treatment of endothelial cells with high concentrations of anti-HLA antibodies stimulates cell proliferation. This suggests that lower levels of anti-HLA antibody binding to HLA may be beneficial to graft survival by activating survival signaling pathways that promote graft accommodation. On the other hand, high levels of anti-HLA antibody binding may have a detrimental effect on graft survival by upregulating FGFR expression, stimulating cell proliferation and increasing risk for development of transplant arteriosclerosis. We believe these findings are clinically relevant and may explain differences in transplant outcome in cardiac transplant patients producing anti-donor HLA antibodies. The overall goals of this proposal are to elucidate whether the intracellular signaling events initiated by antibody ligation of class I and class II molecules are influenced by the specificity and concentration of the HLA antibody and to determine the clinical relevance of class I and II signaling pathways in cardiac transplantation. Patient samples to be used in the proposed research will be obtained from the """"""""CTOT-05 Observational Study of Alloimmunity in Cardiac Transplant Recipients"""""""". The CTOT-05 study is a prospective, non-randomized, multicenter, observational clinical trial in cardiac transplant recipients.
Under Aim 1, we will characterize the ability of anti-HLA class I and class II antibodies in sera from heart allograft recipients to mediate proliferative and/or cell survival signals in endothelial cells. The IgG fraction of the serum will be tested for its ability to transduce signals via MHC class I and class II molecules in donor and surrogate endothelial cells bearing the relevant HLA antigen(s).
Under Aim 2 we will assess the expression of anti-HLA antibody induced protein phosphorylation, fibroblast growth factor receptors and anti-apoptotic proteins in clinical biopsy specimens from cardiac allografts with and without anti-HLA antibody production. Understanding the class I and class II signaling pathways in the context of antibody mediated rejection and transplant arteriosclerosis is of importance for the development of new diagnostic tools and therapeutic strategies to improve patient management and cardiac transplantation outcome. Relevance to Public Health: Studying anti-HLA antibody mediated signal transduction in samples from the CTOT-05 clinical trial will permit us to establish the importance of the class I and class II signaling pathways in cardiac transplant outcome. These studies will identify key signaling proteins mediating acute and chronic antibody-mediated rejection and may permit the development of new treatment strategies. This study will develop and test class I and class II antibody mediated signal transduction as reliable indicators of transplant outcome and provide insight into mechanisms underlying antibody mediated graft injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090995-03
Application #
7788849
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Shah, Monica R
Project Start
2008-05-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$385,000
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Valenzuela, N M; Trinh, K R; Mulder, A et al. (2015) Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and Fc?RIIa polymorphisms. Am J Transplant 15:1502-18
Tsai, E W; Reed, E F (2014) MHC class I signaling: new functional perspectives for an old molecule. Tissue Antigens 83:375-81
Valenzuela, Nicole M; McNamara, Jeffrey T; Reed, Elaine F (2014) Antibody-mediated graft injury: complement-dependent and complement-independent mechanisms. Curr Opin Organ Transplant 19:33-40
Jin, Y-P; Valenzuela, N M; Ziegler, M E et al. (2014) Everolimus inhibits anti-HLA I antibody-mediated endothelial cell signaling, migration and proliferation more potently than sirolimus. Am J Transplant 14:806-19
Valenzuela, N M; Hong, L; Shen, X-Da et al. (2013) Blockade of p-selectin is sufficient to reduce MHC I antibody-elicited monocyte recruitment in vitro and in vivo. Am J Transplant 13:299-311
Valenzuela, Nicole M; Mulder, Arend; Reed, Elaine F (2013) HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and, depending on subclass, by engaging Fc?Rs. J Immunol 190:6635-50
Zhang, Xiaohai; Valenzuela, Nicole M; Reed, Elaine F (2012) HLA class I antibody-mediated endothelial and smooth muscle cell activation. Curr Opin Organ Transplant 17:446-51
Ziegler, Mary E; Souda, Puneet; Jin, Yi-Ping et al. (2012) Characterization of the endothelial cell cytoskeleton following HLA class I ligation. PLoS One 7:e29472
Zhang, Xiaohai; Reed, Elaine F (2012) HLA class I: an unexpected role in integrin ?4 signaling in endothelial cells. Hum Immunol 73:1239-44
Ziegler, Mary E; Jin, Yi-Ping; Young, Steven H et al. (2012) HLA class I-mediated stress fiber formation requires ERK1/2 activation in the absence of an increase in intracellular Ca2+ in human aortic endothelial cells. Am J Physiol Cell Physiol 303:C872-82

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