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Dir•. CovNciL Foe TosACCO I2aaLAdic1-1 -U:S.A., lNc. May 20, 1981 H M®1 1b7007 --br. 41.w_~ HET'IORAAIDUM SUEJDC.3': Site Visit to E. C. Lawrence, M.D., Baylor College of Medicine, Houston, Teazas Grant No. 1215A "Effects of Cigarette Srrroking on Pulnonary Alvaolar Macrophage Nbdulation of In Vitro Ilmnmoglobulin Secretion" DATE OF VISIT: May 13, 1981 SITE VISI'PORS: Drs. Ford and Stone BACKCROUND Work by Dr. R. Martin had earlier sharal that IgG in lavage fluids from cigarette smokers was increased over that found for non-sarokers. Dr. Lawrenee, who had developed a method (reverse hertolytic plaque assay) for estimating the number of Ig secreting cells, cmtinued the Martin finding by attempting to de- termi.ne whether the increased IgG was due to an increase in the nunber of secret- ing cp-lls or to an increased secxetion and/or synthesis per cell. Originally, an the basis that the lung is an organ capable of innnme respcsnse, Dr. Lawrence had proposed to investigate and oaPare levels of cells secreting IgG, IgA, IgH and IgE in both perpheral blood and broncheoalveolar lavage fluids from healthy srmkers and izon-smokers, as well as frnxn patients with interstitial lung disorders and lw`ig canoer. 7hese studies were recent]y focussed (present Grant) on the modulator effects of PAH's on Ig levels in the lung, on the basis that immaie response of lyrrphocytes residing in the lung should be subjected to similar 'helper' and 'suppressor' actions as found in iir[rnmoregulation in general. Interstitial lung disorders, as seen clinically, are being used as 'indicators' of disorders in lung imnumoregulation. DISC[ISSICN Dr. Lawrence presented two reprints (see reprints 1 and 2 - attached). Reprint No. 1 is essentially on studies acomplished when Dr. iaiwrence was at NIH. Reprint No. 2 aanistitutes the main effort so far, and that is on the mark- edly increased nunbers of IgG secreting cells, in the lung, in interstitial lung diseases including saroordosis and idiopathic pulnunary fibrosis. There appears to be a correlation of level of disease activity and markers of IgG secreting cells (see also Abstract A). Zfie data also suggzst that patients who will re- spond to eortioosteroid treatment show decreases in IgG secreting cells to nor- mal range, while unresponders exhibit no change in nudUers of IgG cells. (Yhe- ther these results are due to increases in IgG secreting cells or synthesis/ secreticn of IgG is still not )nawn).

E. C. Lawrence, M.D. Page 2 May 20, 198r Tiir•. Cot;NccL Fon Tosacco Ri:Scnncn-L'.S.A.. Bc. H K11 1670( Also lookirog for markers which correlate with disease activity eg. not only ntambers of IgG secreting cells, but also senan Angioterisin ooiiverting enzyme (ie. relates to lung damage and oonsequent leakage) and Gallium lung scans (see Abstract A). Over the past period, the nvmber of patients studiec7 has been increased to a total of 87, but rain effort is on total Ig and on IgG - litt~.le has been ,accomplished on spectrtm of Ig in the various conditions (ie IgA, M and E). Also ancluded is rheumatoid arthritis with lung involvement and is identifying rheumatoid factors in the lavage fluids. T4ii.s in collaboration with imn=logist Dr. Roger Rawson. Also mentioned same work (not supported by CTR) by a post-doctoral fellow (Dr. Harvey MeClung) on effects of a rnsite asbestos on Ig secretion and possible relationship to interst3tial fibrosis induoed by annsits (see Abstract B). Other wark mentio?ed was a ecnparison of PAM's and blood monocytes, frcen ~~rokers and non-smokers, in their abilities to mediate anti.bady - dependent eellu- lar cyl-otoxicity. Manos exhibited much greater activity than PAM's (no differences between smkers and non-smokers): (See Abstract D). A manuscript (see attac:fiment 3) entitled "Regulation of Ig Secretion by Eiivnchoalveolar Cells" was also introduoed by Dr. Iawrenee. This prepublication contains much of what was in the last progress report (Jan. 1, 1979-June 30, 1980) and data which was mot included. Essentially, the manuscri.pt,discussed the regu- lation (both enhanoenent and suppression) of lymphocytes (including T cells) by PAM's. Present studies suggest that Ia positive PAM's may be helpers in Ig secretion by peripherall blood,lymphocytes while Ia negative PAM's suppress poke- weed mitogen induced Ig secretion (see attachment 3). Also see Abstract C on PAM suppressor effects on Ig secretion by B lym- phocytes (as in last Progress Report). Evture work will involve attenpts to separate Ia positive and negative PP;M's, and attenpt to elucidate factors in the regulation of both B and T lym- piocyt:es by Ia positive and negative PAMs. Hfien methods have been worked-up, it is hoped that investigations wil]l focus on srakers v. nmn-smkers. At the conclusion of the discussion, Dr. Martin briefly presented smre of his recent data zElating to high levels of cten.ilumiesoenoe in PAM's and PHN's from satooa'd patients as aaqmred to normal subjects. Tttat is, indicates activation of these cells in this disease, and to production of reactive oxygen radicals (see Abstract E) SUGGE.S'1'ION BY SITE VISIZtORS Acti.vation of cells is involved in Ig production, may or may not be depen- dent upon free radical formation, eg activation ~ free radicals by latex particle I , membeane changes Ig Secretion "Pm/Lymphocyte° interactior

-3- Tjir•. Coi.Ncm Fun To$ncco REsenacn-L°.S.A., Nc.. H I(11167009 so that vitamins E and C ray reduoe free radical action on mmnbranes and, therefore, alter (teduoe or increase) I9 production. • CC1lJCWSIQIJ OF VISIT: S1ow pragress - but interesting. Wbrthy of another year. /agm