Inflammatory Th1 cells reacting to tissue/myelin derived
antigens likely contribute to the pathogenesis of diseases such as
multiple sclerosis (MS),
rheumatoid arthritis (RA), and
psoriasis. One regulatory mechanism that may be useful for treating
autoimmune diseases involves an innate second set of Th2 cells specific for portions of the
T cell receptor of clonally expanded pathogenic Th1 cells. These Th2 cells are programmed to respond to internally modified V region
peptides from the
T cell receptor (TCR) that are expressed on the Th1 cell surface in association with major histocompatibility molecules. Once the regulatory Th2 cells are specifically activated, they may inhibit inflammatory Th1 cells through a non-specific bystander mechanism. A variety of strategies have been used by us to identify candidate disease-associated TCR V genes present on pathogenic Th1 cells, including BV5S2, BV6S5, and BV13SI in MS, BV3, BV14, and BV17 in RA, and BV3 and BV13S1 in
psoriasis. TCR
peptides corresponding to the mid region of these BV genes were found to be consistently immunogenic in vivo when administered either i.d. in saline or i.m. in
incomplete Freund's adjuvant (IFA). In MS patients, repeated injection of low doses of
peptides (100-300 microg) significantly boosted the number of TCR-reactive Th2 cells. These activated cells secreted
cytokines, including
IL-10, that are known to inhibit inflammatory Th1 cells.
Cytokine release could also be induced in TCR-reactive Th2 cells by direct cell-cell contact with Th1 cells expressing the target V gene. These findings indicate the potential of regulatory Th2 cells to inhibit not only the target Th1 cells, but also bystander Th1 cells expressing different V genes specific for other
autoantigens. TCR
peptide vaccines have been used in our studies to treat a total of 171 MS patients (6 trials), 484 RA patients (7 trials), and 177
psoriasis patients (2 trials). Based on this experience in 824 patients with
autoimmune diseases, TCR
peptide vaccination is safe and well tolerated, and can produce significant clinical improvement in a subset of patients that respond to immunization. TCR
peptide vaccination represents a promising approach that is well-suited for treating complex
autoimmune diseases.