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THI; COUNCIL FoR TOBACCO RESEARCH-U.S.A., INC. May 12, 1986 TO: DR. S. C. SOMMERS AND STAFF FROM: D. H. Ford RE: Site visit with Dr. B. Cii2Yr.~4 University of Pennsylvania, Philadelphia, April 22, 1986. Grant No. 1646R2 entitled "Immune Injury of Human Endothelial Cells" GOAL To determine if vasculitis in humans is associated with immune injury or viral attack of the endothelial cells, which then leads to the inflammation of the vessels accompanied by the presence of immunoglobulins, complement and leucocytes within the vessel wall, occasionally leading to vessel destruction. OVERVIEW Vasculitis is a heterogeneous disorder varying in site from organ to organ as to vessel involved (veins vs. arteries). Is this because vessels at different sites have different antigenic properties? What normally protects the endothelium from inflammation and clot formation? Do specific vessels develop characteristic receptors to antigens in their membranes in response to injury (viral attack, persistent low-grade hypertension, toxic agents)? Dr. Cines's biomolecular approach to these questions suggests (as does the work of others) that endothelial cells from different sites do indeed possess different antigenic properties, which may possibly be induced by the nature of the surrounding tissue matrix. RESULTS Endothelial cells, normally, have only a limited ability to bind IgG. However, when venous umbilical cord endothelial cells in culture are infected with Herpex Simplex virus (HSV), the cells develop IgG and IgMC receptors. The IgMC receptor appears to be for complement. (HSVI also induces formation of FC and C3 receptors.) Conceivably, the virus may leave a part of its own structure in the walls of these cells when it infects them and thus provides for the receptors, or it may induce receptor protein synthesis by the endothelial cells. In order to investigate soluble immune complexes, Dr. Cines has studied patients with Systemic lupus erythromatosus (SLE). These patinets show an increase in IgG binding to embryonic umbilical vein endothelial cells in culture. IgA and IgM was also elevated. Another area of interest to Dr. Cinces relates to observations that heparin is associated with thrombocytopenia/thrombosis. In these patients, there is a low platelet level induced by heparin. Their vessels then become clotted following the second or third exposure to hcparin some 7-10 days after the first exposure. This occurred in about 1% of the cases when porcine heparin was used and about 5% of the cases following use of bovine heparin. Up to 10-25% of the patients in some hospitals were reported to demonstrate this phenomenum. The duration of time between the first exposure to

Site Visit - Dr. Cines Page 3 COMMENT An enthusiastic investigator pursing several interesting subjects dealing with the biological role of endothelial cells in vasculitis, clotting, carposi sarcoma and atherosclerosis, as well as in the maturation of bone marrow cells and the function of PMNs and macrophages induced by CSF. While these different lines of investigation appear somewhat divergent, they appear to converge and be intrinsically related in the manner in which Dr. Cines considers them, particularly in relation to technique. Further, he appers to be making progress along all of the various areas of interest. The study is relevant to the interests of CTR and merits contined support. DHF and DS