Eliciting Autoimmunity to Ovarian Tumors in Mice by Genetic Disruption of T Cell Tolerance Mechanisms
Abstract
Research in the fields of basic immunology and autoimmunity has identified several distinct mechanisms through which immune tolerance is established and maintained in the normal host, and additional mechanisms will likely be identified in future. We hypothesize that ovarian tumors are recognized in an antigen-specific manner by T cells but induce immunologic tolerance through one or more of these homeostatic mechanisms, which have evolved to protect the host from autoimmune attack. We further hypothesize that tolerance to ovarian tumors can be overcome by disrupting critical components of tolerogenic pathways through genetic manipulation of T cells. To test this hypothesis, we proposed to develop a murine model for ovarian cancer that will allow, for the first time, precise monitoring of the functional responses of naive, tumor-specific CD4+ and CD8+ T cell clones to ovarian tumors. Multiple properties of tumor-reactive T cells will be assessed in vivo, including their localization, activation, anergic status, proliferation and apoptosis. Differential responses and anti-tumor activities of the CD4+ and CD8+ T cell subsets will be investigated. Finally, the model will be used to evaluate the functional responses of tumor-specific CD4+ and CD8+ T cells that are genetically pre-disposed to autoimmune activity. The first tolerogenic pathway tested will be that involving the Cbl-b gene, as T cells lacking Cbl-b have a greatly reduced requirement for CD28 co-stimulation and demonstrate hyperactivity in vivo with profound autoimmune sequelae.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2005
- Accession Number
- ADA447683
Entities
People
- Brad H Nelson
Organizations
- L. J. Blackmore Cancer Research Centre