During the past several years it has become clear that there are three distinct Fc receptors for IgG (Fc gamma R) which are associated with human myeloid cells and thus potentially involved in antibody dependent killing (ADK) by these cells. With the development of monoclonal antibodies (MAb) to each of these Fc gamma R, it has now become possible to explore in a definitive way the properties and functional capabilities of each receptor. We have been involved in the development of MAb to these Fc gamma R which have been used by us and by other investigators to develop a substantial base of information on the functional properties of each of these receptors. We now propose to use these MAb and the hybridoma cells that produce them to systematically explore the functional properties of the different Fc gamma R. In particular, we propose to use Ig bearing hybridoma cells as targets to further define the cytotoxic potential of different effector cells and trigger molecules as well as to develop insights into the triggering events, their requirements and mechanisms. To facilitate our studies on one of these receptors, Fc gamma R II, we would develop a panel of MAb to Fc gamma RII comparable to those we have already prepared against Fc gamma RI. MAb which react with Fc gamma RII at epitopes other than the ligand binding site would be used in an analysis of the initial events associated with ADK through this receptor. Studies would be carried out on the ability of MAb specific for different Fc gamma R to modulate the expression of these receptors. The conditions for, and effects of, triggering of each of the Fc gamma R on different effector cells would be examined. This analysis would include studies of early signaling, superoxide generation, enzyme and monokine release and phagocytosis. The ability of various biological mediators to modulate the expression and cytotoxic capabilities of each of the Fc gamma R and the effector cells with which they are associated would also be determined. Finally, we would prepare and use heteroantibodies for dissection of the functional activities of the different Fc gamma R. Specifically, we would investigate the capability of each Fc gamma R and their associated effector cells to mediate killing and/or phagocytosis of red blood cell, bacterial, parasite and nucleated cell targets. These studies should permit us to clearly define the functional properties of each of the Fc gamma R, their capability to mediate killing of a variety of target cells, and their associated cytotoxic mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019053-11
Application #
3128498
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1981-09-01
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Guyre, C A; Keler, T; Swink, S L et al. (2001) Receptor modulation by Fc gamma RI-specific fusion proteins is dependent on receptor number and modified by IgG. J Immunol 167:6303-11
Wallace, P K; Tsang, K Y; Goldstein, J et al. (2001) Exogenous antigen targeted to FcgammaRI on myeloid cells is presented in association with MHC class I. J Immunol Methods 248:183-94
Guyre, C A; Barreda, M E; Swink, S L et al. (2001) Colocalization of Fc gamma RI-targeted antigen with class I MHC: implications for antigen processing. J Immunol 166:2469-78
Wallace, P K; Romet-Lemonne, J L; Chokri, M et al. (2000) Production of macrophage-activated killer cells for targeting of glioblastoma cells with bispecific antibody to FcgammaRI and the epidermal growth factor receptor. Cancer Immunol Immunother 49:493-503
Wallace, P K; Keler, T; Guyre, P M et al. (1997) Fc gamma RI blockade and modulation for immunotherapy. Cancer Immunol Immunother 45:137-41
Wallace, P K; Keler, T; Coleman, K et al. (1997) Humanized mAb H22 binds the human high affinity Fc receptor for IgG (FcgammaRI), blocks phagocytosis, and modulates receptor expression. J Leukoc Biol 62:469-79
Benoit, N E; Wade, W F (1996) Increased inhibition of proliferation of human B cell lymphomas following ligation of CD40, and either CD19, CD20, CD95 or surface immunoglobulin. Immunopharmacology 35:129-39
Ely, P; Wallace, P K; Givan, A L et al. (1996) Bispecific-armed, interferon gamma-primed macrophage-mediated phagocytosis of malignant non-Hodgkin's lymphoma. Blood 87:3813-21
Valone, F H; Kaufman, P A; Guyre, P M et al. (1995) Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu. J Clin Oncol 13:2281-92
Wallace, P K; Howell, A L; Fanger, M W (1994) Role of Fc gamma receptors in cancer and infectious disease. J Leukoc Biol 55:816-26

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