Cow milk allergy represents one of the most common causes of food hypersensitivity in children. The mechanisms responsible for the induction of food hypersensitivity are poorly understood. Cow milk allergy is an interesting problem since while the gastrointestinal tract is constantly exposed to numerous antigens, immune response are held in check by the gut-associated lymphoid tissue to ensure that overwhelming inflammation does not occur. Intestinal epithelial cells constitutively express major histocompatibility complex (MHC) class II molecules and, in addition to their physiologic roles in digestion, are capable of processing and presenting antigens to stimulate CD-8+ T suppressor cells as opposed to conventional antigen presenting cells (APC) which stimulate predominantly CD-4+T cells. The development of humoral and cellular allergic responses to cow milk allergens may be related to differences in antigen handling by the IEC. This proposal seeks first to determine if cow milk allergens traffic differently than conventional antigens in IECs. We will utilize primary epithelial cells from cow milk patients and then cell lines derived from the same epithelial cells. To determine if cow milk proteins follow a route similar to other antigens in IEC we will use real trafficking. We will co-localize cow milk proteins in organelles associated with antigen processing and will attempt to alter trafficking with cytokines that may be present locally in allergic responses including IL-4, IL-10, and IL13. We will also determine whether gamma-IFN and IL-12 have the opposite effect. We will then study the nature of the antigen processing of the IEC of cow milk allergic and non-allergic patients by comparing peptide fragments in the different processing compartments. If distinct epitopes are generated by the cow milk allergic IEC, such peptides might selectively induce the production of cow milk protein reactive T cells which may promote allergic humoral (IgE) and attempt to restore antigen specific responses in primed T cells or T cell clones. We will phenotypically analyze the T cells generated in response to cow milk proteins to determine if there induction of CD-4+ or CD-8+ T cells. This approach to understanding the mechanisms of cow milk is unique as it directs attention at the inductive site rather than the effector site. Results from these studies may lead to improved treatments for cow milk allergic children.
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