Immune responses must induce the proper effector mechanisms to protect animals against infections. Specific cytokines are often required to induce the proper effector mechanisms. The cytokine IL-4, which is produced in response to nematode infections, is important in protective immunity against gastrointestinal nematodes. We have demonstrated that the ability of mice to limit a challenge infection with a nematode that causes a chronic gastrointestinal infection, Heligmosomoides polygyrus, is dependent upon production of IL-4, that treatment with IL-4 can cure a primary H. polygyrus infection, and that IL-4-induced cure is dependent upon an intact immune system. In contrast, the cytokine IFN-gamma, which often opposes the effects of IL-4, exacerbates H. polygyrus infections. The cytokines IL- 2 and IL-4 promote the differentiation of naive T cells into IL-4 secreting cells. Consequently, we want to determine if treatment of mice with these cytokines can influence the T cell response to H. polygyrus to enhance the production of IL-4 and other Th2-associated cytokines and to limit challenge infections with this parasite. Our experimental approach will utilize complexes of IL-4 or IL-2 with neutralizing monoclonal antibodies, which have a much greater in vivo cytokine agonist effect and half-life than the free cytokines. We will study the ability of IL-4 and IL-2 complexes, alone and in combination, to enhance protective immunity induced by immunization with H. polygyrus antigens or by an initial infection with H. polygyrus and to modify cytokine production in response to a challenge infection with H. polygyrus. Doses, ratios of cytokine to anticytokine antibody in complexes, routes of cytokine administration, and administration schedules will be optimized. Effects of cytokine complexes on antibody, mast cell, and eosinophil responses will be investigated. The relative roles of T cells and B cells in cytokine-promoted immunity will be examined. The ability of cytokine complexes to protect mouse strains that are normally particularly susceptible to H. polygyrus will be determined. These studies should define methods that can be used to promote immunity to gastrointestinal nematodes of the genera Necator, Ancylostoma, Ascaris, Trichuris, and Strongyloides, which infect approximately one billion people worldwide and are believed to cause approximately 1,000,000 deaths a year.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI037180-01
Application #
2073820
Study Section
Special Emphasis Panel (SRC (58))
Project Start
1994-09-30
Project End
1995-06-30
Budget Start
1994-09-30
Budget End
1995-06-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817
Finkelman, F D; Morris, S C (1999) Development of an assay to measure in vivo cytokine production in the mouse. Int Immunol 11:1811-8
Urban Jr, J F; Noben-Trauth, N; Donaldson, D D et al. (1998) IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8:255-64
Morris, S C; Coffman, R L; Finkelman, F D (1998) In vivo IL-4 responses to anti-IgD antibody are MHC class II dependent and beta 2-microglobulin independent and develop normally in the absence of IL-4 priming of T cells. J Immunol 160:3299-304
Else, K J; Finkelman, F D (1998) Intestinal nematode parasites, cytokines and effector mechanisms. Int J Parasitol 28:1145-58
Brunet, L R; Finkelman, F D; Cheever, A W et al. (1997) IL-4 protects against TNF-alpha-mediated cachexia and death during acute schistosomiasis. J Immunol 159:777-85
Tedder, T F; Tuscano, J; Sato, S et al. (1997) CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu Rev Immunol 15:481-504
Hizi, A; Kamath-Loeb, A S; Rose, K D et al. (1997) Mutagenesis by human immunodeficiency virus reverse transcriptase: incorporation of O6-methyldeoxyguanosine triphosphate. Mutat Res 374:41-50
Finkelman, F D; Shea-Donohue, T; Goldhill, J et al. (1997) Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models. Annu Rev Immunol 15:505-33
Lu, P; Urban, J F; Zhou, X D et al. (1996) CD40-mediated stimulation contributes to lymphocyte proliferation, antibody production, eosinophilia, and mastocytosis during an in vivo type 2 response, but is not required for T cell IL-4 production. J Immunol 156:3327-33
Finkelman, F D (1995) Relationships among antigen presentation, cytokines, immune deviation, and autoimmune disease. J Exp Med 182:279-82