This proposal will take advantage of several unique observations made in understanding the properties of self proteins that regulate the development of autoimmune responses. In attempts to define cryptic self peptides of lupus autoantigens, we found that a particular post-translational modification of a self peptide elicited strong B and T cell autoimmunity. The post-translational peptide modification, termed isoaspartyl, occurs when the carboxyl (2') carbon of an aspartic acid side chain forms a cyclic intermediate with the neighboring primary amine group within a protein. Immunity to tumors may be viewed in the context of """"""""autoimmunity"""""""" since many tumor antigens are found on other self tissues and cells. This proposal will attempt to initiate and perpetuate an """"""""autoimmune"""""""" response to tumors utilizing a novel strategy of tumor peptide immunization. Isoaspartyl forms of self proteins have the ability to stimulate both autoimmunity and anti-tumor immunity in a manner where the """"""""normal"""""""" aspartyl form of the self protein fails. The present proposal will exploit these observations in attempts to stimulate anti-tumor B and T cell immunity. Preliminary studies indicate that the isoaspartyl peptide of a melanoma protein, TRP-2, stimulates anti-tumor immunity in animal models. We will further examine the mechanisms of the anti-tumor response and utilize other modified tumor peptides to elicit anti-tumor immunity in animal models of melanoma. It is anticipated that this approach will lead to novel immunotherapies for the treatment of human tumors.
| Doyle, Hester A; Mamula, Mark J (2012) Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr Opin Immunol 24:112-8 |
