Studies of Immune Regulation for Autoimmune Diseases
Experimental Medicine
Darcy B. Wilson, Ph.D.
Scientific Director
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Studies of Immune Regulation for Autoimmune Diseases
Research efforts in this laboratory extend from basic studies of the immunobiology of thymus derived (T) lymphocytes and their involvement in the immune response mechanism to clinical studies that explore means for down-regulating T cell activity in autoimmune disease. It is possible to silence selected clones of activated, disease-causing T cells by vaccination with small peptides that represent a portion of the antigen-specific receptor molecules on the surface of these T cells.
Multiple sclerosis is a chronic inflammatory disease of the central nervous system (CNS) in humans. While the initial events involved in the onset of the disease remain obscure, there is much evidence suggesting that disease progression is caused by an episodic attack by T lymphocytes in the body's immune system against one or more neural proteins of the CNS. This autoimmune attack in the CNS leads to a patchy loss of the myelin sheath surrounding principal nerves, in turn causing an interruption of their normal function.
As appears to be true for EAE, the T lymphocytes responsible for MS in humans use a particular b chain as part of the T cell antigen receptor (TCRVb6) that triggers these cells to become activated and pathogenic. We have shown that a small fragment of this TCRVb6 protein chain can, when used as a vaccine in MS patients, eliminate all presumed disease causing T lymphocytes from the cerebral spinal fluid. This promising result may be the basis for a novel approach for the treatment of MS.
Key References
1. Wilson, D.B., Pinilla C., Wilson, D.H., Schroder, K., Boggiano, C., Judkowski, V., Kaye, J., Hemmer, B., Houghten, R.A., and Martin, R. Immunogenicity. I. Use of peptide libraries to identify epitopes that activate clonotypic CD4+ T cells and induce T cell responses to native peptide ligands. J. Immunol. 163:6424-6434 1999.
2. Sun, D., Whitaker, J.N. and Wilson, D.B. Regulatory T cells in experimental allergic encephalomyelitis. I. Frequency and specificity analysis in normal and immune rats of a T cell subset that inhibits disease. Intl. Immunol. 11:307-315, 1999.
3. Sun, D., Whitaker, J.N. and Wilson, D.B. Regulatory T cells in experimental allergic encephalomyelitis. II. CD8+ T cells functionally antagonistic to CD4+ encephalitogenic MBP-specific T cells show persistent expression of FasL1. J. Neuroscience Res., in press, 1999.
4. Sun, D., Whitaker, J.N. and Wilson, D.B. Regulatory T cells in experimental allergic encephalomyelitis. III. Comparison of disease resistance in Lewis and Fischer 344 rats. Eur. J. Immunol. 29:1101-1106, 1999.
5. Pinilla, C., Martin, R., Gran, B., Appel, J.R., Boggiano, C., Wilson, D.B., and Houghten, R.A. Exploring immunological specificity using synthetic peptide combinatorial libraries. Current Opinion in Immunol. 11:193-202, 1999.
6. Wilson, D.B., Golding, A.B., Smith, R.A., Dafashy, T., Nelson, J., Smith, L., Carlo, D.J., Brostoff, S.W., and Gold, D.P. Results of a phase I clinical trial of a T cell receptor peptide vaccine in patients with multiple sclerosis. I. Analysis of T cell receptor utilization in CSF cell populations. J. Neuroimmunol. 76: 15-28, 1997.
7. Gold, D.P., Smith R.A., Golding, A.B., Morgan, E.E., Dafashy, T., Nelson, J., Dively, J., Laxer, J.A., Richieri, S.P., Carlo, D.J., Brostoff, S.W., and Wilson, D.B. Results of a phase I clinical trial of a T cell receptor vaccine in patients with multiple sclerosis. II. Comparative analysis of TCR utilization in CSF T cell populations before and after vaccination with a TCRVb6 CDR2 peptide. J. Neuroimmunol. 76: 29-38, 1997