The anti-idiotypic regulatory network comprised of anti-idiotypic (anti-id) T cells and antibodies is critical in the regulation of autoreactive T cells and B cells, and can be stimulated by immunization with inactivated autoreactive T cells (T cell vaccination). T cell vaccination with irradiated autologous myelin basic protein (MBP)-reactive T cells that are implicated in the pathogenesis of multiple sclerosis (MS) results in depletion of MBP-reactive T cells and correlates with clinical improvement in patients with MS. It has been shown that T cell vaccination induces anti-id T cell and B cell responses in recognition of the variable and hypervariable sequences of the T cell receptor (TCR) expressed by the immunizing MBP-reactive T cells in MS patients. This project is proposed to define the complete distribution pattern of the idiotypic epitopes and to identify the dominant idiotypic epitopes responsible for eliciting anti-id immune responses in T cell vaccination. In particular, the study is designed to evaluate whether TCR (hyper)variable regions most frequently used among MBP-reactive T cells in MS patients contain dominant idiotypic epitopes for anti-idiotypic B cells and T cells and whether TCR peptides incorporating the identified dominant idiotypic epitopes are effective in inhibiting MBP-reactive T cells by up-regulating anti-idiotypic immune responses. The project has three specific aims.
Aim 1 : Recombinant full-length TCR incorporating the most frequently utilized (hyper)variable regions among MBP-reactive T cells will be made to generate and select anti-idiotypic B cell lines and T cell lines from immunized MS patients.
Aim 2 : The resulting anti-id antibodies and T cell lines recognizing the full-length TCR will be examined to map the complete idiotypic epitopes and determine whether the (hyper)variable sequences contain the dominant idiotypic epitopes using overlapping TCR peptides. The antibodies and T cell lines will be further characterized for the reactivity to the whole immunizing T cells and the regulatory properties on the immunizing MBP-reactive T cells.
Aim 3 : The selected TCR peptides will be evaluated in vitro for the ability to stimulate anti-idiotypic B cells and T cells in relationship to their inhibitory effect on MBP-reactive T cells derived from MS patients. The results will help to determine the value of the TCR peptides in therapeutic regulation of MBP-reactive T cells in a subset of MS patients where the T cells express the common TCR sequence features. The long-term goal of the study is to define the mechanism of T cell vaccination and develop a practical peptide-based vaccination approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041289-04
Application #
6738119
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Utz, Ursula
Project Start
2001-06-15
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$338,625
Indirect Cost
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030