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THE COUNCIL FOR TOBACCO F.ESEARCH-U.S.A., INC. 000 THIRD AVENUE NEW YORK. N.Y. 10022 Memorandum To:. Dr. J. F. Glenn From: D.H.Ford and D.Stone Re: Site visit with Dr.S-K. Oh, Boston University School of Medicine, Boston, Sept.22, 1988 Grant No. 1992R2 entitled "Role of SER immunosuppressor in pulmonary inflammation and malignancy." Goals: To determinethe extent to which SER is involved in smoke-induced inflammation of the lung and to assess its role in immune surveillance mechanisms. Introduction: Dr. Oh and her colleagues have identified an immune suppressor from the body fluids of cancer patients, which suppresses E-rosetting, hence the term SER. Her recent studies have shown that SER is a mixture of alpha-l-acid glyco- protein (AGP, 3 to 10%) and haptoglobin (90%), both of which are acute phase reactants. It was shown to suppress by 50% the mitogenic response to phytohemagglutinin, which may be due to its ability to compete with I1-1 in T-cell activation. The association of SER with haptoglobin may be of special interest because smoking elevates levels of haptoglobin and because there is a high frequency (50%) of cancer patients with hapto- globin type 2-1 found in can cer fluids. Recent Results:There is no doubt but that Dr. Oh is an extremely busy, enthusiastic investigator who is undertaking many approaches to determine the Role of -SER.She has purified the SER-hapto- globin. SER exhibited a broad spectr'um on non-specific immune suppression on T-dependent responses, natural killer cells and on the phagocytic activity of macrophages in a dose-dependent manner. Her group has also obtained and purified normal hapto- globin from tumor-bearing patients and noted that it causes a non-specific immune suppression both in vitro and in vivo. Clinical testing: Dr. Oh has tested to determine the levels of acute phase reactants~in the sera of patients with renal cell carcinoma, melanoma and in bronchial fluid from patients with pulmonary disease. In these patients, levels of AGP and hapto- globin fall to normal following successful immunotherapy. Multi- variate analysis of the levels of the two proteins could predict the outcome of therapy with an accuracy of 90% ( A failure to respond to the therapy was reflected by a failure of the AGP-haptoglobin levels to return to normal. With the pulmonary lavage fluid, Dr.Oh noted that there were elevated levels of SER present in close association with reactive bronchial cells or multinucleated histiocytes in patients with pulmonary disorders, while I1-1 activity was found only in the bronchial fluid of heavy smokers. .

-2- Dr. Oh's most recent findings indicate that SER is a polymeric form of haptoglobin, analagous to a fetal.form. Further, as an immune suppressor it is at least 100 to 1000 times more potent than normal serum haptoglobin. It appears to be an oxidized form of haptoglobin produced by activated macrophages during an inflammation. Native haptoglobin has about 100 binding sites/PMN and effectively depresses the amount of 02 produced by them. This may be assoc- iaUd with the fact that haptoglobin depresses intracellular Ca flux. Haptoglobin also inhibits the generation of 02 from PMNs activated by Con A, arachadonic acid and other membrane activators. It had no effect, however, on PMA, which acts within the cytoplasm on protein kinase C. Denatured haptoglobin had a depressing effect only on Con A, which binds to a glyco- protein, presumably by competitive inhibition, since the hapto- globin also binds to a glycoprotein. Comment: Dr. Oh impresses'one has being an extremely bright individual with a considerable expertise in biochemistry, molecular biology, immunology and oncology. As she presents her work, it is difficult to judge where one level of expertise ends and another begins. She is currently collaborating with a number of investigators in the US and abroad. While it might appear that she is involved in a variety of different invest- igations, it becomes apparent that all of these in reality focus on the same goal: to understand the role of SER in health and disease. This is an exciting program dealing with an area of immunology of interest to CTR. DHF