The human gastrointestinal antigen (Ag) GA733 is a potential target for active immunotherapy against these tumors. A suitable animal model of active immunotherapy against this (Ag), however, has thus far been lacking. Such a model should take into account the frequently observed immunological tolerance of cancer patients' lymphocytes to (Ag), including the GA733 Ag, expressed by their own tumors. This tolerance is related to expression of the (Ag) by normal tissues. Recently, murine epithelial glycoprotein 314 (mEGP), with 82% sequence homology to human GA733 (Ag), has been identified. The mEGP mRNA is expressed in normal murine epithelial tissues, similar in distribution to that of human GA733, and the two molecules share immunologic cross-reactivity. Thus, mice provide a promising model for experimental active cancer immunotherapy against the human GA733 (Ag) in the immunologically tolerant host. The major goal is to compare the capacity of various forms of mEGP native, and to induce humoral and cellular immunity and to protect against tumors in this mouse model. This model is ideally suited to study the potential side effects of active immunization against a tumor associated cell surface (Ag) that is also expressed on normal tissues. The specific aims are: (1) To determine the distribution of mEGP in normal mouse tissues, and the presence of immunological tolerance of mice to the (Ag); (2) To compare native and recombinant mEGP in their ability to induce humoral and cellular immune responses and in potential side effects; and (3) To determine tumor protective effects of mEGP vaccines and the mechanism(s) underlying these effects. The proposed studies are important for the rational design of recombinant vaccines to overcome immunological tolerance to tumor associated (Ags) which are also expressed on normal tissues. These studies will provide insight into the mechanism(s) of vaccine action and provide a basis for the clinical application of recombinant human GA733 (Ag) vaccines.
NIH ExPorter
NIH ExPorter