Characterization of regulatory T cells generated in DNA Abeta42 immunized mice

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the most common form of dementia found in the elderly and disease progression has been strongly associated with build-up of the self peptide Amyloid beta 1-42 (A¿42) in brain. The possibility of an immune mediated approach as a preventive or therapeutic intervention that reduces amyloid plaques without causing brain inflammation has great impact for future clinical use. Immunizations with A¿42 peptide have been shown to reduce amyloid burden in brain and improve cognitive function in transgenic mouse models for AD. A clinical trial with early AD patients which received A¿42 peptide vaccinations, however, was discontinued after occurrence of meningoencephalitis in 6% of patients due to a Th1 autoimmune response. A follow-up of study participants showed that A¿42 peptide vaccination did lead to a reduction in plaque load in patients who had been treated with A¿42 peptide compared to the placebo control patients providing proof that it is possible to remove brain amyloid by immunotherapy. Genetic immunization, in which the immunizing agent is DNA encoding A¿42, has great potential because the immune response differs quantitatively and qualitatively from the immune response elicited by peptide immunization. Our previous findings showed a predominantly Th2-type antibody response and the disappearance of an A¿42 specific T cell response at later immunization time points. Further characterization of cellular components of the immune response against A¿42 is needed for an understanding of how an inflammatory cellular response against the self antigen A¿42 can be avoided by use of this full-length DNA A¿42 immunization approach. We hypothesize that a polarized T helper 2 (Th2) cellular immune response following genetic immunization leads only to the production of a beneficial and therapeutic antibody response. The low level of T cell proliferation in DNA A¿42 trimer immunized mice might be due to increased numbers of regulatory T cells (Tregs) which dampen the cellular response found at later immunization time points. To test this we will perform phenotypic and functional analyses of the immune response to DNA A¿42 trimer and the comparison to the immune response elicited by A¿42 peptide with special emphasis on the characterization of a possible regulatory T cell response elicited via the DNA A¿42 trimer immunization route.