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Principal Investigator: Dr. Margaret Bynoe
Contact Information: E-mail: msb76@cornell.edu
- Phone: 607-253-4023
Sponsor: NIH-NIAID
Grant Number: 1 K22AI057854-01A1
Title: Tolerance Induction in EAE by Epicutaneous Immunization
Annual Direct Cost: $150,000
Project Period: 09/01/05-07/31/07
The human disease multiple sclerosis (MS) is an inflammatory
and demyelinating neurological disease that is mediated by T helper-1 (Th1)
cells. (EAE) is the most well-established animal model for the study of MS. EAE
can be actively induced in certain inbred mouse strains following immunization
with myelin protein autoantigens such as myelin basic protein (MBP),
proteolipid protein (PLP) or myelin oligodendrocyte protein (MOG) in adjuvant.
Recently, we found that when we immunize transgenic mice carrying a MBP
specific T cell receptor via the epicutaneous (skin) route with MBP peptides in
a patch prior to immunizing them with the same peptide to induce disease, such
mice were protected from EAE. This protection was antigen-specific, antigen
dose-dependent and was mediated by CD4 T cells that transferred protection to
naive recipients. In addition, epicutaneous immunization with myelin-derived
self-peptides protected normal mice from developing EAE in an antigen-specific
and antigen dose-dependent manner including in a relapsing-remitting model of
the disease. However, when these same mice are epicutaneously immunized with
their cognate peptide in adjuvant, disease was accelerated. This proposal
describes three specific aims that will attempt to elucidate the mechanism(s)
by which the epicutaneous administration of self-peptide induces dominant
tolerance in mice. Some aims focus on determining the role of skin dendritic
cells in the induction of tolerance in both the transgenic and non-transgenic
mouse models. Proposed studies will also investigate the mechanism(s) by which
tolerance is induced and operates in normal mice. In normal mice, we will
explore whether Th2 cytokines are involved in mediating protection fromdisease:
specifically in the (SJLxPL/J)F 1 mouse model. Finally, we will carry out
experiments to test whether epicutaneous immunization with autoantigenic
peptides is capable of ameliorating EAE.
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