In this revised application, Dr. Mosser proposes to study the mechanisms by which ligation of selected receptors on macrophages and dendritic cells influences the subsequent development of Type-1 and Type-2 responses from T cells. The hypothesis to be tested is that the ligation of some receptors on antigen presenting cells favors the production of cytokines that promote Type-1 responses, whereas ligation of other receptors may favor the production of cytokines that elicit Type-2 responses. Data in support of this hypothesis comes from a well-developed model system in which ligation of the FcR1 receptors on murine bone marrow-derived macrophages suppresses the production of IL-12 when these cells are later stimulated with LPS. This suppression is specific, because ligation of complement receptors does not lead to down-regulation of LPS-induced IL-12 production. Furthermore, this down-regulation of IL-12 expression is regulated at the transcriptional level. In contrast, ligation of the FcgR1 receptors leads to the enhancement of LPS-induced IL-10 production. These investigators have gone on to show that suppression of IL-12 production can occur by two distinct mechanisms, one which requires extracellular calcium fluxes and the other which is mediated by IL-10. Together, these two mechanisms may lead to diminished Type-1 responses, augmented Type-2 responses, and a suppression of macrophage pro-inflammatory responses in vivo. Both published and preliminary data are provided to demonstrate the capacity of FcgR1 ligation to suppress pro-inflammatory responses in several in vitro and in vivo models. The goal of this application is to determine the extent to which macrophage-and dendritic cell-derived cytokines can influence T-cell responses. There are four specific aims.
The first aim will examine the cytokine profile of macrophages and dendritic cells following specific receptor ligation and stimulation via engagement of CD14 or CD40.
The second aim will define on the intracellular events that suppress the production of IL-12 following receptor ligation.
The third aim will examine the extent to which macrophages and dendritic cells can influence T cell responses to antigens in vitro. Antigens will be targeted to specific receptors on these APCs, and lymphokine production by defined T cell clones will be measured.
The fourth aim will examine the extent to which macrophages and dendritic cells can influence T cell responses to antigens in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046805-02
Application #
6170725
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Ash-Shaheed, Belinda
Project Start
1999-05-15
Project End
2000-10-31
Budget Start
2000-05-01
Budget End
2000-10-31
Support Year
2
Fiscal Year
2000
Total Cost
$161,956
Indirect Cost
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Fleming, Bryan D; Mosser, David M (2011) Regulatory macrophages: setting the threshold for therapy. Eur J Immunol 41:2498-502
Mosser, David M; Zhang, Xia (2011) Measuring opsonic phagocytosis via Fc? receptors and complement receptors on macrophages. Curr Protoc Immunol Chapter 14:Unit 14.27
Gallo, Paul; Gonçalves, Ricardo; Mosser, David M (2010) The influence of IgG density and macrophage Fc (gamma) receptor cross-linking on phagocytosis and IL-10 production. Immunol Lett 133:70-7
Anderson, Charles F; Mosser, David M (2002) A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol 72:101-6
Anderson, Charles F; Mosser, David M (2002) Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors. J Immunol 168:3697-701
Tietzel, Illya; Mosser, David M (2002) The modulation of macrophage activation by tyrosine phosphorylation. Front Biosci 7:d1494-502
Grazia Cappiello, M; Sutterwala, F S; Trinchieri, G et al. (2001) Suppression of Il-12 transcription in macrophages following Fc gamma receptor ligation. J Immunol 166:4498-506
Gerber, J S; Mosser, D M (2001) Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J Immunol 166:6861-8
Kane, M M; Mosser, D M (2001) The role of IL-10 in promoting disease progression in leishmaniasis. J Immunol 166:1141-7