Earlier studies from several groups including ours have documented that patients with multiple sclerosis (MS) have over-expression of activated T-cells from specific TCR V beta families, including BV6S2/S5 (Kotzin et al. [1991] Proc. Natl. Acad. Sci. USA 88:9161--9165; Gold et al. [1997] J. Neuroimmunol. 76:29--38). It has also been established in the rat EAE model that peptide vaccines to the over-expressed V beta 8.2 TCR can prevent MBP induced disease (Vandenbark et al. [1989] Nature 341:541--544). In the current clinical study, 10 patients were vaccinated with 300 microg of BV6S2/6S5 peptide emulsified in incomplete Freund's adjuvant (IFA) and monitored for safety and immunogenicity in a 48-week multicenter, open-label trial. The peptide vaccine was well tolerated and no serious adverse events were observed. Vaccinations induced cell-mediated immunity to the immunizing peptide in eight of 10 patients as demonstrated by lymphocyte proliferation assay (LPA) and delayed-type hypersensitivity (DTH) skin test responses. In summary, these results demonstrate that immunization with TCR BV6S2/6S5 peptide vaccine in MS patients is safe and immunogenic, and supports a larger double-blind placebo controlled trial to determine the clinical efficacy of this approach.

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 BV13S1 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 μg) 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.

Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA).A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20.Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection.IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

We report here the results of a phase I trial of a T-cell receptor (TCR) Vβ6 CDR2 region peptide vaccine in 10 patients with multiple sclerosis who showed biased over-representations of Vβ6 mRNA among T-cells in their cerebrospinal fluids (CSF). One group of 5 patients was immunized twice during a four week period with 100 μg of the TCRVβ6 peptide 39-LGQGPEF LTYFQNEAQLEKS-58 emulsified in incomplete Freund's adjuvant (IFA); the second group of 5 MS patients received 300 μg of the same peptide in IFA over a similar time period. Patients were monitored for adverse events, immunogenicity of the peptide and changes in their CSF T-cell populations. The results indicate that this peptide was immunogenic (T-cell proliferation assays and recall DTH responses) in some of the patients, although none of the immunized patients produced detectable anti-peptide antibodies. More importantly, we show that the 5 patients treated with higher doses of the vaccine displayed a slight decrease in CSF cellularity, a lack of growth of CSF cells in cytokine supplemented expansion cultures that implies a significant absence of a subset of activated CD4 T-cells and a marked diminution in Vβ6 mRNA levels among T-cells in these cultures. By comparison, in 5 patients receiving the lower dosage of the vaccine, CSF cellularity was the same or slightly increased over pre-vaccination levels, CSF cells from 1 patient failed to grow in expansion cultures and cultured CSF cells from 2 patients underwent a change from an oligoclonal Vβ6 pattern to one that was more polyclonal. These results justify a more thorough exploration of the use of TCR peptide vaccines as a possible therapeutic treatment for MS.

OBJECTIVE:To determine whether modulation of activated T cells occurs in patients with rheumatoid arthritis (RA) after immunization with T cell receptor (TCR) V beta 17 peptides, a phase I trial was initiated to investigate the safety and feasibility of TCR peptide immunization as a therapeutic approach in RA.METHODS:15 patients with moderate to severe RA were given an intramuscular injection of one of 4 doses (10, 30, 100, and 300 micrograms) of the V beta 17 peptide vaccination, followed by a booster injection of the same dose of vaccine 3 weeks later. Patients were followed for 48 weeks.RESULTS:The product was well tolerated and no serious adverse events attributable to the vaccine were observed. This was an uncontrolled phase I trial, however; decreases in patients joint scores were observed at all followup visits starting at 4 weeks after primary immunization. Activated V beta 17 T cells (IL-2R+) in peripheral blood were decreased (> or = 20%) in 3/5 patients in the 100 micrograms group after initial measurement at Week 2 and 3/4 patients in the 300 micrograms group 3 weeks after immunization. Lymphocyte proliferation in response to the V beta 17 peptide was detected at 6 weeks or later after primary inoculation in 6/15 patients (40%) immunized.CONCLUSION:Further controlled studies are required to assess the biologic and clinical efficacy of this treatment approach.

Annals of the New York Academy of SciencesVolume 756, Issue 1 p. 211-214 Vβ17 T-Cell Receptor Peptide Vaccine Results of a Phase I Dose-Finding Study in Patients with Rheumatoid Arthritis L. W. MORELAND, L. W. MORELAND The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorL. W. HECK Jr., L. W. HECK Jr. The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorW. J. KOOPMAN, W. J. KOOPMAN The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorP. A. SAWAY, P. A. SAWAY The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorT. C. ADAMSON, T. C. ADAMSON Sharp Rees-Stealy Medical Group 2001 Fourth Avenue San Diego, California 92101Search for more papers by this authorZ. FRONEK, Z. FRONEK Sharp Rees-Stealy Medical Group 2001 Fourth Avenue San Diego, California 92101Search for more papers by this authorR. D. O'CONNOR, R. D. O'CONNOR Sharp Rees-Stealy Medical Group 2001 Fourth Avenue San Diego, California 92101Search for more papers by this authorE. E. MORGAN, E. E. MORGAN The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorJ. P. DIVELEY, J. P. DIVELEY The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorN. M. CHIEFFO, N. M. CHIEFFO The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorT. D. FREEMAN, T. D. FREEMAN The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorS. R. RICHIERI, S. R. RICHIERI The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorD. J. CARLO, D. J. CARLO The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorS. W. BROSTOFF, Corresponding Author S. W. BROSTOFF The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Author to whom correspondence should be addressed.Search for more papers by this author L. W. MORELAND, L. W. MORELAND The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorL. W. HECK Jr., L. W. HECK Jr. The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorW. J. KOOPMAN, W. J. KOOPMAN The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorP. A. SAWAY, P. A. SAWAY The University of Alabama at Birmingham 068 Spain Rehabilitation Center 1717 Sixth Avenue South Birmingham, Alabama 35294–0006Search for more papers by this authorT. C. ADAMSON, T. C. ADAMSON Sharp Rees-Stealy Medical Group 2001 Fourth Avenue San Diego, California 92101Search for more papers by this authorZ. FRONEK, Z. FRONEK Sharp Rees-Stealy Medical Group 2001 Fourth Avenue San Diego, California 92101Search for more papers by this authorR. D. O'CONNOR, R. D. O'CONNOR Sharp Rees-Stealy Medical Group 2001 Fourth Avenue San Diego, California 92101Search for more papers by this authorE. E. MORGAN, E. E. MORGAN The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorJ. P. DIVELEY, J. P. DIVELEY The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorN. M. CHIEFFO, N. M. CHIEFFO The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorT. D. FREEMAN, T. D. FREEMAN The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorS. R. RICHIERI, S. R. RICHIERI The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorD. J. CARLO, D. J. CARLO The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Search for more papers by this authorS. W. BROSTOFF, Corresponding Author S. W. BROSTOFF The Immune Response Corporation 5935 Darwin Court Carlsbad, California 92008Author to whom correspondence should be addressed.Search for more papers by this author First published: July 1995 https://doi.org/10.1111/j.1749-6632.1995.tb44514.xCitations: 6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume756, Issue1T-Cell Receptor Use in Human Autoimmune DiseasesJuly 1995Pages 211-214 RelatedInformation