Fc receptors for IgG (Fc gamma R's) on cells of the immune system play a central role in the linkage of the humoral system with effector cells, such as monocytes and macrophages, neutrophils, and NK cells. The heterogeneity of Fc-gamma R's on murine and human cells is becoming evident, but detailed structural analysis of many of these proteins is still wanting. Therefore, we propose to isolate monoclonal antibodies (MAb's) that will make further structural and functional characterization possible. We have preliminary evidence that the Fc-gamma-R on murine B cells is different from that on macrophages, although both bear a common epitope recognized by MAb 2.4G2. We will attempt to make B cell specific MAb's to further study the source of the heterogeneity, and to compare by peptide mapping and gel analysis the two receptors. We will also make MAb's directed against the largely uncharacterized murine receptor specific for IgG2a (Fc-gamma-2aR), thought to be important in antibody-dependent tumor cytotoxicity. Using another monoclonal antibody, 1B4C, we have found an epitope shared by murine Fc-gamma R and a set of other proteins of unknown function. We will continue to analyse the human high avidity Fc receptor (Fc gamma Rhi) using new MAb's recently derived. These MAb's will be used to define the cell types bearing the receptor, to study function in cell-cell interactions in which Fc-gamma R's are thought to play a role, and to isolate sufficient Fc gamma Rhi for structural analysis and comparison to the low avidity receptor present on human neutrophils. As a consequence of our studies search for a cDNA clone coding for Fc gamma Rhi in a cDNA library from gamma-interferon (IFN-gamma) induced U937 cells, we have isolated a gene coding for a 10,000 Mr, IFN-gamma induced peptide with structural homology to platelet factor 4 and beta-thromboglobulin. We will purify this new peptide, termed gamma IP-10, make MAb's directed against it, study the conditions for its release, and attempt to determine the role it plays in IFN-gamma activation of the immune system. Among the parameters we will test are chemotaxis, priming of monocytes for release of H2O2, induction of class II MBC determinants, stimulation of mitosis, and anti-thrombin activity.
| Portnoy, D A; Erickson, A H; Kochan, J et al. (1986) Cloning and characterization of a mouse cysteine proteinase. J Biol Chem 261:14697-703 |
| Clarkson, S B; Kimberly, R P; Valinsky, J E et al. (1986) Blockade of clearance of immune complexes by an anti-Fc gamma receptor monoclonal antibody. J Exp Med 164:474-89 |
| Clarkson, S B; Bussel, J B; Kimberly, R P et al. (1986) Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody. N Engl J Med 314:1236-9 |
| Unkeless, J C (1986) Heterogeneity of human and murine Fc gamma receptors. Ciba Found Symp 118:89-101 |
| Luster, A D; Unkeless, J C; Ravetch, J V (1985) Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 315:672-6 |
| Young, J D; Unkeless, J C; Cohn, Z A (1985) Functional ion channel formation by mouse macrophage IgG Fc receptor triggered by specific ligands. J Cell Biochem 29:289-97 |
