We have shown that human platelet factor 4 alleviates Con A-induced or pneumococcal-specific immunosuppression in mice, an effect of potential clinical value. The activity can be removed from human or mouse serum or platelet releasates by T cells of the suppressor phenotype, and suppressor cells can be removed from spleen cell suspensions by """"""""planning"""""""" on PF4-coated surfaces. If serine protease activity is arrested immediately after the platelets have secreted the releasates and PF4 prepared from it are not active, although the amount of PF4 measured by radioimmunoassay is not affected. Monoclonal antibodies will be sought that identify activity and used in an attempt to develop an in vitro assay. The enzymatic changes that activate PF4 will be established and the enzyme localized in platelet organelles and characterized. Cells with receptors for PF4 will be identified in human an mouse blood, spleen or lymph nodes by sue of fluorescence cell analysis with PF4 and antibodies to PF4 and the cells will be characterized with monoclonal antibodies to surface determinants. The binding kinetics of active radiolabeled PF4 to T cells of the suppressor phenotype will be assessed. Since PF4 does not act on suppression in vitro, it may sequester suppressor cells away from lymphoid organs, e.g., on the heparan sulfate on vascular endothelium. Therefore, the distribution of III indium-labeled T cells of the suppressor phenotype will be explored with and without PF4 and/or heparin injection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL027752-08
Application #
3485920
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1981-12-01
Project End
1992-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
McPherson, J; Zucker, M B; Mauss, E A et al. (1991) The effect of agonists and antagonists of platelet aggregation on von Willebrand factor-mediated platelet agglutination. Thromb Haemost 65:573-7
Zucker, M B; Katz, I R (1991) Platelet factor 4: production, structure, and physiologic and immunologic action. Proc Soc Exp Biol Med 198:693-702
Zucker, M B; Puszkin, E G; Sussman, I I et al. (1990) Inhibition of von Willebrand factor-induced platelet agglutination by ADP does not result from reduced binding of total von Willebrand factor or its larger multimers. J Lab Clin Med 116:305-14
Puszkin, E G; Mauss, E A; Zucker, M B (1990) Assembly and GPIIIa content of cytoskeletal core in platelets agglutinated with bovine von Willebrand factor. Blood 76:1572-9
Zucker, M B; Katz, I R; Thorbecke, G J et al. (1989) Immunoregulatory activity of peptides related to platelet factor 4. Proc Natl Acad Sci U S A 86:7571-4
Puszkin, E G; Mauss, E A; Milot, D C et al. (1989) Effect of the thiol group inhibitor monobromobimane and other inhibitors on the composition of the platelet cytoskeletal core and its association with glycoprotein IIIa. J Cell Biochem 39:339-54
Zucker, M B; Mauss, E A (1988) Erythrocyte aggregation in iohexol and other nonionic media. Invest Radiol 23 Suppl 2:S340-5
Yin, J Z; Zucker, M B; Clarke, D et al. (1988) Prevention by a platelet-derived factor (platelet factor 4) of induction of low dose tolerance to pneumococcal polysaccharides. Cell Immunol 115:221-7
Barone, A D; Ghrayeb, J; Hammerling, U et al. (1988) The expression in Escherichia coli of recombinant human platelet factor 4, a protein with immunoregulatory activity. J Biol Chem 263:8710-5
Zucker, M B; Brownlea, S; McPherson, J (1987) Insights into the mechanism of platelet retention in glass bead columns. Ann N Y Acad Sci 516:398-406

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