Identification of immune responses against neuronal proteins in patients with cancer and neurologic disorders (paraneoplastic neurologic disorders [PNDs]) has uncovered the existence of antigens (onconeuronal proteins) shared by some cancers and the nervous system. These onconeuronal proteins are targets of humoral and cell mediated immune responses, which result in degeneration of discrete or multifocal areas of the nervous system, producing severe neurologic deficits and often death. Tumors that elicit PND appear to be more indolent than tumors from patients without PND and usually remain elusive to clinical detection. In 1999, we reported on two related proteins (Mal and Ma2) that are targets of immunity associated with certain cancers and PND. Since then, we have identified 16 new patients with immunity to Ma proteins and isolated another protein member (Ma3). We believe that the Ma proteins comprise a large family of onconeuronal antigens targeted by immune responses associated with PND. We hypothesize that the expression of Ma proteins by the tumor is able to break immune tolerance for these proteins, resulting in the production of autoreactive immune B and T-cells against the tumor and the nervous system; that the type of PND depends on which Ma proteins are recognized by the immune response; and that T-cell mechanisms are involved.
In Aim 1, we will identify additional Ma family members and determine the identity and sequence of the Ma proteins expressed by normal tissues and tumors.
In Aim 2, we will identify the immunodominant regions of the Ma proteins and determine the extent of disease protein specificity.
In Aim 3, we will isolate the mouse Ma sequences and develop a model of anti-tumor immunity and neuronal injury using Ma cDNA and protein vaccination. Our methods will include immunohistochemical and other antibody-related studies, standard molecular biology techniques, and small animal surgery. These studies will provide insights into the role of Ma proteins in the development of PND and will generate immunodominant protein fragments to be used for diagnosis of PND, with prognostic and possibly therapeutic implications. The development of an animal model of PND will help to understand these disorders and is an absolute requirement for developing therapeutic strategies.
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