The human disease multiple sclerosis (MS) is an inflammatory and demyelinating neurological disease that is mediated by T helper-1 (Th1) cells. Experimental allergic encephalomyelitis (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 from disease: 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
1K22AI057854-01A1
Application #
6818486
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2005-09-01
Project End
2007-07-31
Budget Start
2005-09-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$159,600
Indirect Cost
Name
Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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