T helper 2 (Th2) effector cells, through Th2 cytokine production, can mediate resistance to helminthic parasite infection. Understanding the cell and molecular interactions that lead to their differentiation is therefore important for the development of therapies and vaccines that promote host protective immune responses. We have begun to examine the innate response that initially develops following infection of mice with nematode parasites to identify cell populations or signals that may be important in promoting adaptive immunity that leads to the developing of IL-4 producing Th2 cells. Global gene expression analyses of draining lymph nodes shortly after parasite infection showed pronounced increases in chemokines, including MCP-1 and CXCR3 ligands. Both chemokines are known to recruit monocytes and granulocytes. Gr-1 is a cell surface marker shared by these cell populations and also plasmacytoid dendritic cells. Draining lymph nodes showed pronounced increases in Gr1+ cells at 4 and 16 hours after inoculation with the intestinal nematode parasite, N. brasiliensis. Treatment with anti-GR-1 antibody caused marked increases in lymph node IFN-y expression at 18 hours after N. brasiliensis inoculation and decreased IL-4 expression and host resistance was observed at 7 days after inoculation. In the proposed studies, we will examine the function of Gr1+ cells in promoting the development of Th2 effector cells in vivo. Specifically, we propose to identify the chemokine/chemokine receptors that mediate the recruitment of Gr1+ cells to the peripheral lymph nodes at early stages of the immune response to N. brasiliensis. We will also elucidate the mechanism of how Gr1+ cells suppress IFN-y elevations and promote Th2 cell development leading to host resistance by examining Gr1+ cell interactions with developing Th2 cells in situ. Finally, we will address in two parasite models, N. brasiliensis and H. polygyrus, the role of Gr1+ cells in the development of the host protective primary and memory response. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI066188-01A1
Application #
7105715
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Wali, Tonu M
Project Start
2006-03-15
Project End
2011-02-28
Budget Start
2006-03-15
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$388,750
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Gause, William C; Wynn, Thomas A; Allen, Judith E (2013) Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol 13:607-14
Chen, Fei; Liu, Zhugong; Wu, Wenhui et al. (2012) An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med 18:260-6
Mishra, Pankaj K; Wu, Wenhui; Rozo, Cristina et al. (2011) Micrometer-sized titanium particles can induce potent Th2-type responses through TLR4-independent pathways. J Immunol 187:6491-8
Harris, Nicola; Gause, William C (2011) To B or not to B: B cells and the Th2-type immune response to helminths. Trends Immunol 32:80-8
Patel, Nirav; Kreider, Timothy; Urban Jr, Joseph F et al. (2009) Characterisation of effector mechanisms at the host:parasite interface during the immune response to tissue-dwelling intestinal nematode parasites. Int J Parasitol 39:13-21
Pesce, John T; Liu, Zhugong; Hamed, Hossein et al. (2008) Neutrophils clear bacteria associated with parasitic nematodes augmenting the development of an effective Th2-type response. J Immunol 180:464-74
Kreider, Timothy; Anthony, Robert M; Urban Jr, Joseph F et al. (2007) Alternatively activated macrophages in helminth infections. Curr Opin Immunol 19:448-53
Anthony, Robert M; Rutitzky, Laura I; Urban Jr, Joseph F et al. (2007) Protective immune mechanisms in helminth infection. Nat Rev Immunol 7:975-87
Liu, Qian; Liu, Zhugong; Rozo, Cristina T et al. (2007) The role of B cells in the development of CD4 effector T cells during a polarized Th2 immune response. J Immunol 179:3821-30