Therapeutic Interventions

The understanding that the autoimmune disease is caused by an immune response directed against self points to possible modes of therapeutic interventions.

Following this understanding, it was possible to prevent or treat EAE by

1. Blocking MHC class II molecules

• By antibodies that are specific to the MHC or to the complex of particular MHC molecules with the pathogenic peptide embedded in its binding groove.

• Using peptides that bind the MHC and do not activate the pathogenic T cells; thus, the peptides block the interaction between the pathogenic T cells and the MHC.

• Using peptides that bind both the MHC and the pathogenic TCR, but the effect of this interaction is silencing of the T cells. Such peptides are termed TCR antagonists. A related group of peptides, called altered peptide ligands, also bind the MHC and TCR, but the result of stimulation modifies or changes the effector function of the T cell, inducing the secretion of different cyto-kines or the creation of T cells incapable of mediating disease.

2. In addition to the TCR contacting its appropriate peptide in the MHC, efficient T cell activation needs an interaction called ''the second signal'' or T cell costimulation. In other words, the signal delivered to the T cell by the interaction of its TCR with the peptide-MHC complex is not sufficient to cause activation, and another trigger to a simultaneously bound surface molecule on the T cell is needed to enable the stimulation to proceed. This second signal is termed a costimula-tory signal. Blocking this interaction by decoy molecules prevents T cell costimulation. Such interventions in animal models of autoimmune disease result in prevention or cure of the disease.

3. Blocking the TCR, using anti-TCR antibodies, either against a specific disease-causing TCR or against a family of TCRs known to be involved in the disease.

4. Tolerance induction by administering the pathogenic antigen in a form that will abort the immune response to it. An example is administering the antigen orally or intravenously.

5. Recently, several researchers have examined the possibility of using DNA instead of protein or peptides to induce forms of tolerance. Using DNA encoding the TCR V b 8.2, EAE was prevented and the anti-MBP T cell response was shifted from Th1 (secreting interferon g and IL-2) to Th2 (secreting IL-4 and -5). Others have used DNA-encoding myelin antigens to prevent EAE.

6. After pathogenic T cells have been activated in the periphery, they have to cross the blood-brain barrier to enter the site of the disease. The adhesion of activated T-cells to endothelial cells is mediated by the T cell molecule very late antigen type-4 (VLA-4; a protein expressed on the surface of T cells late after activation) interacting with the vascular cell adhesion molecule (a member of intercellular adhesion molecules) on endothelial cells. Blocking this interaction by monoclonal antibodies can prevent EAE. Clinical studies with a humanized version of anti-VLA-4 are now in phase II clinical trials in MS. The migration of T cells across the extra cellular matrix involves the secretion of enzymes such as matrix metalloproteinases. Inhibition of these enzymes is another way of treating EAE.

7. Once the pathogenic T cells have reached the target tissue, the damage is inflicted in part by cytokines secreted by these cells. Thus, one way to treat autoimmune diseases involves the neutralization of cytokine effects (e.g., anti-tumor necrosis factor antibodies or IL-1 antagonists). These treatments were found to be successful in patients with rheumatoid arthritis.

8. An additional mode of immunointervention is to enhance the immune regulation over the pathogenic T cells by procedures such as T cell vaccination and TCR peptide vaccination or by injection of anti-idiotypic T cell lines (T cells that are specific for the TCR of the pathogenic cell and have the functional capacity to suppress the disease causing-cell).

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