|Fang, H - UNIF SERV BETHESDA MD|
|Liu, Q - UNIF SERV BETHESDA MD|
|Nguyen, D - UNIF SERV BETHESDA MD|
|Ekkens, M - BRISTOL MYERS SQUIBB NJ|
|Chen, S - UNIF SERV BETHESDA MD|
|Donaldson, D - GENET INST MASS|
|Peach, R - BRISTOL MYERS SQUIBB NJ|
Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 1, 1999
Publication Date: April 15, 2000
Citation: Urban Jr, J.F., Fang, H., Liu, Q., Nguyen, D., Byrd, C., Ekkens, M.J., Chen, S.J., Donaldson, D.D., Peach, R. 2000. B7 costimulation is required for il-4 but not il-13 responses: interactionsamong b7, il-4, il-13, and ifn-gamma determines the host's ability to expel the nematode parasite, trichuris muris. Journal of Immunology. 164:4252-4256 (2000) Interpretive Summary: Infection of livestock with gastrointestinal (GI) nematode parasites is a significant economic concern to producers, and certain infections posse a threat to the safe ingestion of animal tissues by the public. The nature of the immune response to GI parasites is complex but vaccination is a desirable control strategy because it eliminates the risk of drug residues and can provide long-term protection. Basic studies on the mechanism of protective immunity to GI parasites reveal a molecular target that controls the initial interaction between antigens and the cells that are stimulated to develop immunity. Antigens react with specific cell surface receptors but further development of the response is dependent on co-stimulatory molecules that trigger these cells to develop. The current study demonstrates that the B7 molecule is required during a response to a GI nematode parasite but there is an additional intricate balance between extracellular proteins that ultimately determines the effectiveness of the immune response. The proteins IL-4, IL-13, and IFN-gamma are components of this interaction along with T cells, antigens, antigen receptors and B7. Although these interactions are complex, they are ordered and predictable and subject to manipulation. This information will be of value to government, academic and industrial scientists that consider improvements in the development of effective vaccines against parasitic worms.
Technical Abstract: Protective immunity to gastrointestinal parasites requires B7 stimulation of CD4+ T cells and is associated with production of the type 2 cytokines IL-4 and IL-13. These cytokines promote additional type 2-cytokine production by stimulating Th2 differentiation and clonal expansion and induce IgG1 and IgE secretions and parasite expulsion. Blocking B7 ligand interactions inhibited protective immunity to T. muris, suppressed IL-4 production, enhanced IFN-gamma production, but did not affect IL-13 production. IL-13 is required for expulsion in immunologically intact mice and in mice was both IFN-gamma and B7 are blocked, while IL-4 mediates expulsion in the absence of both IL-13 and IFN-gamma. These studies demonstrate that: 1) both IL-4 and IL-13 are required to expel T. muris in the presence of IFN-gamma, while either expel in the absence of IFN-gamma; 2) B7 costimulation is required to induce IL-4, but not IL-13 responses; and 3) increased IL-13 production, in the absence of IL-4 production, is not associated with an IgE response, even in the absence of IFN-gamma.