Accelerated graft atherosclerosis, a manifestation of chronic rejection, is the leading cause of late graft failure in patients surviving the first year post transplantation. The development of antibodies to donor HLA antigens is a major risk factor associated with transplant atherosclerosis. The overal goal of this proposal is to determine the mechanism(s) through which anti-HLA antibodies stimulate endothelial cell (EC) and smooth muscle cell (SMC) activation and proliferation.
In specific aim 1, the investigators will establish whether exposure of endothelial cells to anti-HLA antibodies from patients with transplant atherosclerosis is accompanied by the production of growth factors. Donor EC will be treated with recipient anti-HLA antibodies and the production of basic fibroblast growth factor (bFGF) will be assessed. The ability of anti- HLA antibodies to upregulate growth factor ligand binding will be evaluated using bFGF radioligand binding assays. The investigators will also determine whether exposure of endothelial cells to anti-HLA antibodies leads to increased permeability of the EC monolayer and de novo expression of adhesion molecules. The interaction of anti-HLA antibodies with the endothelium in the presence of cytokines will be examined.
In specific aim 2, the investigators will determine whether anti-HLA antibodies stimulate the proliferation of primary cultures of donor SMC. These experiments will assess whether anti-HLA antibodies induce EC to secrete growth factors that stimulate proliferation of SMC and second whether anti-HLA antibodies bind to and stimulate SMC proliferation directly. The ability of inflammatory cytokines to augment proliferative effects of anti-HLA antibodies on SMC will be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI042819-01A1
Application #
2759476
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Prasad, Shiv A
Project Start
1999-01-01
Project End
1999-08-31
Budget Start
1999-01-01
Budget End
1999-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Salehi, Sahar; Sosa, Rebecca A; Jin, Yi-Ping et al. (2018) Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection. Am J Transplant 18:1096-1109
Pearl, Meghan H; Zhang, Qiuheng; Palma Diaz, Miguel Fernando et al. (2018) Angiotensin II Type 1 receptor antibodies are associated with inflammatory cytokines and poor clinical outcomes in pediatric kidney transplantation. Kidney Int 93:260-269
Jin, Yi-Ping; Valenzuela, Nicole M; Zhang, Xiaohai et al. (2018) HLA Class II-Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection. J Immunol 200:2372-2390
Zhang, Qiuheng; Hickey, Michelle; Drogalis-Kim, Diana et al. (2018) Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients. Transplantation 102:e431-e438
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Valenzuela, Nicole M; Thomas, Kimberly A; Mulder, Arend et al. (2017) Complement-Mediated Enhancement of Monocyte Adhesion to Endothelial Cells by HLA Antibodies, and Blockade by a Specific Inhibitor of the Classical Complement Cascade, TNT003. Transplantation 101:1559-1572
Weng, Patricia L; Alejos, Juan Carlos; Halnon, Nancy et al. (2017) Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients. Pediatr Transplant 21:
Pearl, Meghan H; Nayak, Anjali B; Ettenger, Robert B et al. (2016) Bortezomib may stabilize pediatric renal transplant recipients with antibody-mediated rejection. Pediatr Nephrol 31:1341-8
Wallace, William Dean; Li, Ning; Andersen, Claus B et al. (2016) Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies. J Heart Lung Transplant 35:40-8
Pizzo, Helen P; Ettenger, Robert B; Gjertson, David W et al. (2016) Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatr Nephrol 31:2345-2352

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