This proposal attempts to determine the biologic importance and therapeutic potential of a more thorough understanding of autacoids as immune modulators in man. There are two cornerstones of this proposal: 1) the observation that some mediators of inflammation may modulate immunity; and 2) that chemical modification of selected mediators of inflammation (histamine and catecholamines) can result in formation of tissue and effect specific immune modulators. Furthermore, it is becoming evident in studies of mouse systems that sources of histamine may be within lymphocytes in addition to mast cells; that release mechanisms for histamine may be complex but controllable and organized; that receptors for the two autacoids mentioned are non-randomly distributed on subsets of lymphyocytes; that expression of autacoid effects are dependent on the lymphocytic cells in the environment and the stage of immune response; and that the effects of autacoids on subsets of cells and their physiologic interactions are possible. The proposed study attempts to: 1) determine whether the data from mice can be extrapolated and extended to man by using human cells in vitro and both histamine and catecholamines as well as their congeners and conjugates as experimental probes; and 2) to set the stage for determining the appropriateness and feasibility of using congeners and conjugates of autacoids as therapeutic immune modulators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023463-02
Application #
3135588
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1986-06-01
Project End
1989-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Qiu, R; Melmon, K L; Khan, M M (1994) Effects of lymphokines and mitogens on a histamine derivative-induced intracellular calcium mobilization and inositol phosphate production. Biochem Pharmacol 47:2097-103
Qiu, R; Melmon, K L; Khan, M M (1993) Cyclic AMP is not a direct regulator of calcium flux and hydrolysis of phosphoinositides in human lymphocytes. Immunopharmacology 25:37-49
Qiu, R; Melmon, K L; Khan, M M (1993) A histamine derivative increases intracellular calcium mobilization and oxidative metabolism in HL-60 cells. Immunopharmacology 26:213-24
Khan, M M; Melmon, K L (1991) Histamine and its congener derivatives as immune modulators. Agents Actions Suppl 33:365-79
Qiu, R; Melmon, K L; Khan, M M (1990) Effects of histamine-trifluoromethyl-toluidide derivative (HTMT) on intracellular calcium in human lymphocytes. J Pharmacol Exp Ther 253:1245-52
Khan, M M; Tran, A C; Keaney, K M (1990) Forskolin and prostaglandin E2 regulate the generation of human cytolytic T lymphocytes. Immunopharmacology 19:151-61
Silverman, E D; Somma, C; Khan, M M et al. (1990) Abnormal T suppressor cell function in juvenile rheumatoid arthritis. Arthritis Rheum 33:205-11
Simon, M R; Kamlay, M T; Khan, M et al. (1989) Angiotensin II binding to human mononuclear cells. Immunopharmacol Immunotoxicol 11:63-80
Khan, M M; Fishwild, D M; Melmon, K L et al. (1989) A subset of human rosetted lymphocytes contains previously unidentified histamine. Clin Immunol Immunopathol 52:147-59
Khan, M M; Keaney, K M; Melmon, K L et al. (1989) Histamine regulates the generation of human cytolytic T lymphocytes. Cell Immunol 121:60-73

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