Self proteins are processed and presented, albeit constitutively, in the same manner as any foreign antigen. Both self and foreign antigens possess determinants that are well processed and presented (dominant) and those that are poorly processed and presented or not at all (cryptic). The investigator's earlier studies suggest that tolerance is induced to the dominant but not cryptic self determinants of a native antigen. Moreover, the display of cryptic self determinants can be upregulated during inflammation and other immune-stimulating conditions. Several tumor antigens are now known to be unmutated, normal self proteins. A major problem in treatment of many tumors might be imposed by the induction of tumor antigen-specific T cell tolerance. We predict that the T cells potentially directed against cryptic determinants within a self (tumor) antigen would have escaped tolerance induction, and thereby be available in the mature T cell repertoire. Therefore, peptides comprising the cryptic determinants of tumor antigens could be employed for raising anti-tumor immune responses for therapeutic purposes. Their proposed study is based on a model self protein, mouse lysozyme (ML) but the principles elucidated from this work would be equally well applicable to a tumor antigen. The long term objective of their study is to better understand the induction of self tolerance, and how to harness the force of self reactivity efficiently and in a positive way to treat cancer. This study is aimed at: 1) a) validating the relationship between MHC binding and immunogenicity/tolerogenicity of self (ML) determinants in ML-knock-out mice (in these mice, ML would behave like a foreign antigen); and b) determining the constitutive (without addition of exogenous ML) display hierarchy of self determinants of ML on different types of antigen presenting cells (APQ of normal (ML sufficient) mice; 2) exploring three different approaches to enhance the display of cryptic determinants of ML a) treatment of APC in vitro by interferon-g /interleukin12 (IL-l2)/IL-4/IL-6 etc.; b) altering the physical form of native ML by cleavage with different cathepsins or cyanogen bromide, and c) introduction at defined positions within ML of 'dibasic' sites, which are targets of proteolytic enzymes; and 3) testing the practical utility of these approaches in vivo in mice for induction of T cell response to the cryptic determinants of ML upon challenge with native antigen. They believe that such predetermined, experimentally programmed control of the display hierarchy of cryptic self determinants would pave the way for novel immunotherapeutic strategies for prevention and treatment of cancer.
