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THE COUNCIL FOR '.TOBACCO RESEARCH-U.S.A., INC. JOO TIIIRD AVENUE NEW YORK. N.Y. 10022 Mem orandum To: Dr. H.McAllister and Staff Fro:n: D.H.Ford Re: Site visit with Dr. E.E.M'arcantonio, Columbia University, C ol lege of Phys i ci ans and Surge ons , May 11 , 1994. Site visitors: Drs. A.Eisenberg and D.Ford Grant No. 2906A entitled. "Integrins/arthritis/col-lagen/ T-lymphocytes." Hypothesis: That lymphocytes use an d i(3 2 recept or to adhere to collagen type II and that this interaction leads to activation of lymphocytes and further degradation of collagen and thus perpetuates the -inflammatory process. Goals: To further understand the role of changes in integrins and the subsequent changes in adhesion which occur as related to the migration of normal and ma lign ant ce l ls . This leads to a 2nd goal; the role of integrins in the pathcgenesis of a variety of human diseases. His overall orie_,ntation is to better understand the molecular nature of integrin activation and how it may be controlled. Further, he hopes to determin the role of oC 1 integrins in the hormal develcpment and haning of T-lymphocytes. His major focus at this time is to determin the role of integrins.in the pathogenesis of rheumatoid arthritis. Proctress: Inasmuch as his progress for his first 3 years of support by CTR is well covered in his 3rd year progress report, I will not elaborate further. In this report he lists one pub licati-cn for 1993 and one which has been accepted, as well as two manuscripts in prep- aration. Observations made during our discussion:The binding of the cytoplasmic portion,,of the integrin receptor to the cytoskeleton of a T-cell probably p lays ' s ane role in its ability to change shape and perhaps to penetrate through vascular walls and into tissue. Further, increasing interaction of the a 1 62 f orm of the integrin re cept or to the T-cell cytoskeleton probably has sane influence on the biologic functions of a T-cel.l. Dr. Marcantonio had mentioned in his proposal that integrin receptors could influence embryologic development and morphogenesis. However, just how this was achieved is unknown. Whether or not this might be associated with the growth hcrmone present in lymphocytes also appears to be unknown. Integrins, like neuronal receptors appear to exhibit a considerable diversity, the significance of which is still to be ascertained. As yet it is not known whether different types of T-cell have different forms of the receptor or whether a cell may have more than one type of recept or . Summary: This is an intriguing investigation which promises to shed light on a number of pathogenic processes. However, it is evident that there is a great deal more to be learned about these lymphocyte receptors. Frem our discussion with Dr. Marcantcnio, he appears to have the tools, insight and enthusiasum to pursue this project, which appears to grow in canplexity with each new finding. Thus, the observaticn that these receptors are involved in a number of

-2- nhysi clogic nrccesses, such as hemostasis and thrcmbosis, wound hea ling , malignant trans f_ ormati on and in the functi cxi of leuk o- cvte helper and killer function and that they may possibly play a role in MS (as suggested by the large number of lymphocytes which cluster around vessels in EPE (Experimental alergic enceph- alanalacia) ) indicate the biologic significance of this family of lymphocyte recept ors . DHF