Oral administration of soluble protein antigens typically induces antigen specific systemic nonresponsiveness. However, the PI has found that when a model food protein, ovalbumin (OVA), is orally administered to mice infected with a nematode parasite (Heligmosomoides polygyrus), this normally tolerogenic stimulus primes for a systemic OVA specific Th2 response. We have shown that the polarized Th2 cytokine response induced by this enteric infection plays a central role in determining whether or not tolerance to OVA is induced. We have also found that H. polygyrus infection potentates the response to oral antigen by enhancing T cell clonal expansion and upregulating costimulatory molecule expression on mucosal antigen presenting cells (APC).
In Specific Aim 1, we will further explore the mechanistic basis for this effect by examining the influence of infection on various APC populations which can present orally administered antigens in mucosal and peripheral lymphoid tissue. To examine the ways in which helminth infection alters the OVA specific T cell response, T cells from OVA specific TCR transgenic mice will be adaptively transferred into normal BALB/c mice and their response will be tracked in vivo. In addition to providing insight into the ability of an infection to bias the response to other antigens, these experiments will provide basic information on antigen presentation in the mucosal immune system and the means by which it orchestrates decisions concerning tolerance and immunity. Since parasitic infection is endemic in many parts of the Third World, our observations have important clinical implications. The ability of Th2 biased infections to deviate the immune response to other antigens is well documented. Our model extends these findings in a novel direction by showing that enteric infection can elicit a Th2-biased immune response to a normally tolerogenic form of antigen. This suggests that helminth infection may pre-dispose for allergic phenomena and may affect the response to oral vaccines.
In Specific Aim 2, we will therefore examine the ability of helminth infection to prime for an allergic response to a food antigen and explore the relevance of these findings to clinical food allergy. We will also examine the practical implications of mucosal parasitic infection for oral vaccination. If helminth infection biases for a Th2 response to oral vaccination, the success of oral vaccination campaigns in developing countries may hinge upon controlling the ability of these infections to alter responses to vaccine antigens. Characterization of the influence of mucosal infection on the response to oral vaccination using this murine model may suggest methods for maximizing the desired response to oral vaccines.
