THE ROLE OF OX40L INTERACTION IN THE DEVELOPMENT OF THE PRIMARY AND MEMORY TH2 RESPONSE TO THE GASTROINTESTINAL NEMATODE PARASITE HELIGMOSOMOIDES POLYGYRUS

Authors: EKKENS, MELINDA - USUHS; LIU, ZHUGONG - USUHS; LIU, QIAN - USUHS; FOSTER, ANTHONY - USUHS; EHITMIRE, JEANETTE - USUHS; PESCE, JOHN - USUHS; VANNOY, JANSIE - USUHS; SHARPE, ARLENE - USUHS; Urban, Joseph; GAUSE, WILLIAM - USUHS

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/13/2002
Publication Date: 1/1/2003
Citation: Ekkens, M., Liu, Z., Liu, Q., Foster, A., Ehitmire, J., Pesce, J., Vannoy, J., Sharpe, A., Urban Jr, J.F., Gause, W. 2003. The role of ox40l interaction in the development of the primary and memory th2 response to the gastrointestinal nematode parasite heligmosomoides polygyrus. Journal of Immunology. 170:384-393 (2003)

Interpretive Summary: The immune response that is activated by infection with parasitic worms is very similar to the body's response to allergens. Thus, a response to an allergen like ragweed pollen may be considered as the body's attempt to eliminate a foreign invader. This response requires regulation to keep the response appropriate to the severity of the infection and not to become inappropriate and result in allergic disease. The immune response requires specific signals to focus on a specific targets, but there are down stream regulators that control the intensity of the response. The current study examines one of these regulators that exist as a family of molecules on the surface of immune and other presentation cells called the OX40/OX40L series. When one of these molecules, OX40L, is eliminated from cells by genetic manipulation, then the intensity of the response to a parasitic worm is reduced. This results in a higher number of worms that establish in the host. Although this may not be an appropriate consequence to a worm infection, it may be useful as a tool to reduce the intensity of an allergic reaction to environmental allergens. Worm infections in the United States are not considered as a major health problem, but responses to allergens cost the nation in terms of patient care and lost productivity. Targeting these regulatory molecules could offer a novel therapeutic approach to the control of allergic disease, but it also provides basic information on regulation of immunity and disease that can be used to design better preventative procedures that include the use of nutritional interventions.

Technical Abstract: In these studies, we examined the effects of OX40L deficiency on the development of Th2 cells during the primary and memory immune responses to the intestinal nematode parasite Heligmosomoides polygyrus. Elevations in IL-4 production and total and Ag-specific serum IgE levels were inhibited during both the primary and memory immune responses to H. polygyrus in OX40L-/- mice. The host protective memory response was compromised in OX40L-/- mice as decreased worm expulsion and increased egg production was observed compared to H. polygyrus-inoculated OX40L+/+ mice. To further examine the nature of the IL-4 defect during priming, adoptively transferred DO11.10 T cells were analyzed in the context of the H. polygyrus response. Although Ag-specific T cell IL-4 production was reduced in the OX40L-/- mice following immunization with OVA peptide plus H. polygyrus, Ag-specific T cell expansion, cell cycle progression, CXCR5 expression, and migration were comparable between OX40L+/+ and OX40L-/- mice inoculated with OVA and H. polygyrus. These studies suggest an important role for OX40/OX40L interactions in specifically promoting IL-4 production, and associated IgE elevations, during both the primary and memory Th2 responses to H. polygyrus. However, OX40L interactions are not required for serum IgG1 elevations, increases in GC formation, and Ag-specific Th2 cell expansion and migration to the B cell zone.