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TIjr•. CoUmaF. FoH TolsAcco Ri:sLaxcu-U.S.A., INC. August 31, 1976 MEMORANDUM TO: Drs. Hockett, Jacobson, Sommers, Stone and Wyatt FROM: W. U. Gardner !{M1& , _ , 'i 'I q 1. SIIf3JECT: Site Visit. Application 1105. Irving P. Crawford, M.D., Microbiology Department, Scripps Clinic and Research Foundation, La Colla, California. "Leukocyte E.lastase-Complement Interactions in the Etiology of Emphysema." Drs. Crawford and Hugli (Department of Microbiology and Department of Molecular Biology respectively) are really co-investigators. David Stone had talked earlier with Dr. Crawford about his work on the purifica tion of AAT, and later Stone and Lisanti had seen him. Crawford is really a medical geneticist and spends approximately half time on human genetics and half on microbiological genetics. He was interested in the genetics of AAT and hence his initial studies. When he heard about Hugli's work on C3a and -Q5 he became concerned with the possible effects of proteases on these and hence the application. Crawford's first worYk on AAT was vitn two sibs - 3R-year deceased women and severe emphysema, men 50-years alive and not too greatly handicanped, both smokers. Dr. Kidokoro from Dr. Moser's lab contacted him and Crawford and, a fellow, now at Mayo's, collaborated in a study of AAT deficient male patients and compared pulmonary deficiency with levels of ATT. Variables other than age and smoking seemed important. This l.~ork^is in press and preprint available. Dr. Hugli has trained and is now associated in Dr. Miller Eberhard's department. 'rhe latter has been associated with 93 _and CS complen.ent for years, some work being done with Dr. Cochrane. Thes@ compleIDent rnmponents can produce ---- AnOphylotoxjns (shock inducing substances). Dr. Hug li has developed a unique method of getting an evaluation of PMN chemotoxis. Plastic valium caps are taped to scarified (epidermis removed by electric razor with no bleeding) filled with media to which inhibitors or stimulators, CS or its derivatives, are added and the PrIIN's counted for 1, 2 & 3 or more hours. Two hours usually gives reliable numbers. Hugli had at least ten rounced marks on his arm. As many as 18 tests can be run simultaneously on the same rabbit and two on a mouse. Crawford has been studying human leukocytic elastase (HLE) and a method of evoking and quar.titating PMN chemotoxis was available and a protease - C5 derivative was a powerful chemotactic agent.

W - 2 - , ffK~l ~:~; 1O~' The objectives are listed on pages 2b and 2c and were reiterated. The possibility exists of (1) 3etermining persons who may be at risk ane possibly preventing progress of emphysena. The approach is primarily basic PMN elastolytic $gtiui.ty . - The pulmonary section at Scripps has increased from 1/2 to 2 1/2 persons recently. They have adequate human material with blood bank resources combined. Dr. Moser's facility will not be needed. This was a most im z~~ssive visit. We met the technician (Coryill) at the amino acid sequencer. The plasma for CS and PMN elastase are quite expensive. W. U. Gardner WUG:ek