Cytomegalovirus (CMV) infection is a common complication of renal, liver, and cardiac allograft transplantation. The morbidity of this infection may be related to an ability of CMV to facilitate allograft rejection. The proposed studies are based upon the central hypothesis that active CMV infection of allograft endothelial cells results in upregulation of their cytokine-inducible immune inflammatory properties, with subsequent facilitation of allograft rejection. Thus, the long term objectives of this research program are to investigate the effects of CMV infection on human endothelial cell immunobiology, particularly baseline and cytokine-inducible immune inflammatory properties.
The specific aims of this study are as follows: I. To further characterize infection of cultured human endothelial cells (ECs) by nonattenuated (clinical) CMV isolates. These experiments will test the hypothesis that clinical isolates are more ineffective than laboratory strains, particularly in nonconfluent cultures, as verified by detection of viral antigens, viral DNA, and a fibroblast plaque-forming assay. These experiments will provide a firm basis for the remaining specific aims. II. To characterize the effect of CMV infection on endothelial cell HLA Class I and II antigen expression. These experiments will test the hypothesis that CMV infection of ECs upregulates baseline, gamma interferon (IFN-y), and tumor necrosis factor (TNF)-induced, HLA Class I and class II antigen expression. These experiments will utilize immunohistochemistry, Cell-ELISA, and flow cytometry. III. To characterize the effect of CMV infection on endothelial cell interleukin-1 (IL-1) synthesis. These experiments will test the hypothesis that CMV infection of ECs upregulates baseline and TNF-induced IL-1 synthesis, as assessed by an immunohistochemical assay, Cell-ELISA, and flow cytometry. IV. To characterize the effect of CMV infection on endothelial adhesion for T lymphocytes. These experiments will test the hypothesis that CMV infection of ECs upregulates baseline, TNF, and IFN-y-inducible adhesion. Operative receptor/ligand molecules will be studied by inhibition with monoclonal antibodies to adhesion molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI029002-05
Application #
2064781
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1990-01-01
Project End
1994-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Ohio State University
Department
Pathology
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Knight, D A; Waldman, W J; Sedmak, D D (1999) Cytomegalovirus-mediated modulation of adhesion molecule expression by human arterial and microvascular endothelial cells. Transplantation 68:1814-8
Orosz, C G; Huang, E H; Bergese, S D et al. (1997) Prevention of acute murine cardiac allograft rejection: anti-CD4 or anti-vascular cell adhesion molecule one monoclonal antibodies block acute rejection but permit persistent graft-reactive alloimmunity and chronic tissue remodelling. J Heart Lung Transplant 16:889-904
Knight, D A; Waldman, W J; Sedmak, D D (1997) Human cytomegalovirus does not induce human leukocyte antigen class II expression on arterial endothelial cells. Transplantation 63:1366-9
Waldman, W J; Knight, D A; Huang, E H et al. (1995) Bidirectional transmission of infectious cytomegalovirus between monocytes and vascular endothelial cells: an in vitro model. J Infect Dis 171:263-72
Waldman, W J; Knight, D A; Adams, P W et al. (1995) In vitro induction of endothelial adhesion molecule and MHC antigen expression by cytomegalovirus-activated CD4+ T cells. Transplant Proc 27:1269-71
Sedmak, D D; Chaiwiriyakul, S; Knight, D A et al. (1995) The role of interferon beta in human cytomegalovirus-mediated inhibition of HLA DR induction on endothelial cells. Arch Virol 140:111-26
Ng-Bautista, C L; Sedmak, D D (1995) Cytomegalovirus infection is associated with absence of alveolar epithelial cell HLA class II antigen expression. J Infect Dis 171:39-44
Adams, P W; Lee, H S; Waldman, W J et al. (1994) Alloantigenicity of human endothelial cells. III. Quantitated indirect presentation of endothelial alloantigens to human helper T lymphocytes. Transplantation 58:476-83
Huang, E H; Morgan, C J; Sedmak, D D et al. (1994) Alloantigenicity of human endothelial cells. IV. Derivation, characterization, and utilization of gonadal vein endothelia to control endothelial alloantigenicity during lymphocyte-endothelial interactions. Transplantation 57:703-11
Sedmak, D D; Guglielmo, A M; Knight, D A et al. (1994) Cytomegalovirus inhibits major histocompatibility class II expression on infected endothelial cells. Am J Pathol 144:683-92

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