A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis

Background: T cell receptor (TCR) peptide vaccination is a novel approach to treating multiple sclerosis (MS). The low immunogenicity of previous vaccines has hindered the development of TCR peptide vaccination for MS. Objective: To compare the immunogenicity of intramuscular injections of TCR BV5S2, BV6S5 and BV13S1 CDR2 peptides in incomplete Freund’s adjuvant (IFA) with intradermal injections of the same peptides without IFA. Methods: MS subjects were randomized to receive TCR peptides/IFA, TCR peptides/saline or IFA alone. Subjects were on study for 24 weeks. Results: The TCR peptides/IFA vaccine induced vigorous T cell responses in 100% of subjects completing the 24-week study (9/9) compared with only 20% (2/10) of those receiving the TCR peptides/saline vaccine (P =0.001). IFA alone induced a weak response in only one of five subjects. Aside from injection site reactions, there were no significant adverse events attributable to the treatment. Conclusions: The trivalent TCR peptide in IFA vaccine represents a significant improvement in immunogenicity over previous TCR peptide vaccines and warrants investigation of its ability to treat MS.

[1]  S. Ziegler,et al.  Decreased FOXP3 levels in multiple sclerosis patients , 2005, Journal of neuroscience research.

[2]  J. Lünemann,et al.  Cross-sectional and longitudinal analysis of myelin-reactive T cells in patients with multiple sclerosis , 2004, Journal of Neurology.

[3]  Clare Baecher-Allan,et al.  Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis , 2004, The Journal of experimental medicine.

[4]  D. Bourdette,et al.  Specificity of regulatory CD4+CD25+ T cells for self‐T cell receptor determinants , 2004, Journal of neuroscience research.

[5]  C. Baecher-Allan,et al.  Human CD4+CD25+ regulatory T cells. , 2004, Seminars in immunology.

[6]  R. Simon,et al.  Expansion and Functional Relevance of High-Avidity Myelin-Specific CD4+ T Cells in Multiple Sclerosis , 2004, The Journal of Immunology.

[7]  Arthur A. Vandenbark,et al.  TCR Peptide Therapy in Human Autoimmune Diseases , 2001, Neurochemical Research.

[8]  David H. Miller,et al.  A controlled trial of natalizumab for relapsing multiple sclerosis. , 2003, The New England journal of medicine.

[9]  A. Vandenbark,et al.  Inhibitory Effects of Incomplete Freund's Adjuvant on Experimental Autoimmune Encephalomyelitis , 2002, Autoimmunity.

[10]  D. Bourdette,et al.  Diminished frequency of interleukin‐10‐secreting, T‐cell receptor peptide‐reactive T cells in multiple sclerosis patients might allow expansion of activated memory T cells bearing the cognate BV gene , 2001, Journal of neuroscience research.

[11]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[12]  R. Moss,et al.  Vaccination with a CDR2 BV6S2/6S5 peptide in adjuvant induces peptide-specific T-cell responses in patients with multiple sclerosis. , 2001, Journal of neuroscience research.

[13]  Massimo Filippi,et al.  European/Canadian multicenter, double‐blind, randomized, placebo‐controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis , 2001, Annals of neurology.

[14]  M. D'hooghe,et al.  T‐cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls , 2001, Journal of neuroscience research.

[15]  M. Pender,et al.  Surges of Increased T Cell Reactivity to an Encephalitogenic Region of Myelin Proteolipid Protein Occur More Often in Patients with Multiple Sclerosis Than in Healthy Subjects1 , 2000, The Journal of Immunology.

[16]  J. Frank,et al.  Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand , 2000, Nature Medicine.

[17]  R Kikinis,et al.  Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis. , 2000, Archives of neurology.

[18]  A. Waisman Immunity to T-cell receptor : suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor. , 2000, Methods in molecular medicine.

[19]  B. Diamond,et al.  Autoimmune diseases , 2000, Bone Marrow Transplantation.

[20]  V. Prasad,et al.  T Cells On , 1998, Science.

[21]  T. C. Adamson,et al.  T cell receptor peptide vaccination in rheumatoid arthritis : A placebo-controlled trial using a combination of Vβ3, Vβ14, and Vβ17 peptides , 1998 .

[22]  A. Ben-nun,et al.  T-cell responses to myelin antigens in multiple sclerosis; relevance of the predominant autoimmune reactivity to myelin oligodendrocyte glycoprotein. , 1998, Journal of autoimmunity.

[23]  D. Bourdette,et al.  Immunity to T cell receptor peptides in multiple sclerosis. III. Preferential immunogenicity of complementarity-determining region 2 peptides from disease-associated T cell receptor BV genes. , 1998, Journal of immunology.

[24]  P. Calabresi,et al.  Characterization of MRI response to treatment with interferon beta-1b: Contrast-enhancing MRI lesion frequency as a primary outcome measure , 1997, Neurology.

[25]  Larry R. Smith,et al.  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 TCRVβ6 CDR2 peptide , 1997, Journal of Neuroimmunology.

[26]  Larry R. Smith,et al.  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 , 1997, Journal of Neuroimmunology.

[27]  R. Karr,et al.  HPRT mutant T-cell lines from multiple sclerosis patients recognize myelin proteolipid protein peptides , 1997, Journal of Neuroimmunology.

[28]  D. Bourdette,et al.  Therapeutic application of T cell receptor peptides , 1997 .

[29]  D. Bourdette,et al.  Treatment of multiple sclerosis with T–cell receptor peptides: Results of a double–blind pilot trial , 1996, Nature Medicine.

[30]  D. S. Sivia,et al.  Data Analysis , 1996, Encyclopedia of Evolutionary Psychological Science.

[31]  D. Bourdette,et al.  MHC‐restriction, cytokine profile, and immunoregulatory effects of human T cells specific for TCR Vβ CDR2 peptides: Comparison with myelin basic protein‐specific T cells , 1996, Journal of neuroscience research.

[32]  A. Vandenbark,et al.  Idiotypic regulation directed at T-cell receptor determinants. , 1995, Chemical Immunology.

[33]  A. Vandenbark,et al.  Immunity to T cell receptor peptides: theory and applications , 1994, Regulatory Peptides.

[34]  D. Bourdette,et al.  Immunity to TCR peptides in multiple sclerosis. II. T cell recognition of V beta 5.2 and V beta 6.1 CDR2 peptides. , 1994, Journal of immunology.

[35]  D. Bourdette,et al.  Immunity to TCR peptides in multiple sclerosis. I. Successful immunization of patients with synthetic V beta 5.2 and V beta 6.1 CDR2 peptides. , 1994, Journal of immunology.

[36]  H. Weiner,et al.  Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis , 1994, The Journal of experimental medicine.

[37]  E. Sercarz,et al.  The involvement of T cell receptor peptide-specific regulatory CD4+ T cells in recovery from antigen-induced autoimmune disease , 1993, The Journal of experimental medicine.

[38]  A. Begovich,et al.  Selection for T-cell receptor Vβ–Dβ–Jβ gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis , 1993, Nature.

[39]  D. Bourdette,et al.  Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis , 1992, Journal of Neuroimmunology.

[40]  W. Karpus,et al.  Studies of Vβ8 T cell receptor peptide treatment in experimental autoimmune encephalomyelitis , 1992, Journal of Neuroimmunology.

[41]  G. Nedwin,et al.  Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[42]  T. Olsson,et al.  Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls , 1991, European journal of immunology.

[43]  A. Vandenbark,et al.  T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. , 1991, Science.

[44]  H. Weiner,et al.  T-cell recognition of an immuno-dominant myelin basic protein epitope in multiple sclerosis , 1990, Nature.

[45]  R J Albertini,et al.  T cells responsive to myelin basic protein in patients with multiple sclerosis. , 1990, Science.

[46]  D. Carlo,et al.  Vaccination against experimental allergic encephalomyelitis with T cell receptor peptides. , 1989, Science.

[47]  A. Vandenbark,et al.  Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis , 1989, Nature.

[48]  A. Filouš [Diagnosis of multiple sclerosis]. , 1989, Ceskoslovenska neurologie a neurochirurgie.

[49]  J. Antel,et al.  Defective suppressor cell function mediated by T8+ cell lines from patients with progressive multiple sclerosis. , 1986, Journal of immunology.

[50]  C. Taswell Limiting dilution assays for the determination of immunocompetent cell frequencies. III. Validity tests for the single-hit Poisson model. , 1984, Journal of immunological methods.

[51]  J. Kurtzke Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[52]  C. Taswell,et al.  Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. , 1981, Journal of immunology.

[53]  I. Mackay,et al.  Autoimmune diseases. , 1981, Scientific American.