Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis

The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.

[1]  R. Pedotti,et al.  An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide , 2001, Nature Immunology.

[2]  M. V. von Herrath,et al.  Plasmid Vaccination with Insulin B Chain Prevents Autoimmune Diabetes in Nonobese Diabetic Mice1 , 2001, The Journal of Immunology.

[3]  D. Baker,et al.  Encephalitogenic and immunogenic potential of myelin-associated glycoprotein (MAG), oligodendrocyte-specific glycoprotein (OSP) and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) in ABH and SJL mice , 2002, Journal of Neuroimmunology.

[4]  L. Boon,et al.  Prevention of Experimental Autoimmune Encephalomyelitis in the Common Marmoset (Callithrix jacchus) Using a Chimeric Antagonist Monoclonal Antibody Against Human CD40 Is Associated with Altered B Cell Responses1 , 2001, The Journal of Immunology.

[5]  L. Hood,et al.  Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity , 1993, Cell.

[6]  R. Knobler,et al.  T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination , 1985, Nature.

[7]  R. Tisch,et al.  Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice , 1993, Nature.

[8]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[9]  L Steinman,et al.  Multiple Sclerosis: A Coordinated Immunological Attack against Myelin in the Central Nervous System , 1996, Cell.

[10]  Rolf M. Zinkernagel,et al.  Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes , 1998, Nature.

[11]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Rewers,et al.  Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Ulmer,et al.  Heterologous protection against influenza by injection of DNA encoding a viral protein. , 1993, Science.

[14]  H. Garren,et al.  Suppressive immunization with DNA encoding a self-peptide prevents autoimmune disease: modulation of T cell costimulation. , 1999, Journal of immunology.

[15]  R. Webster,et al.  Disquisitions of Original Antigenic Sin. I. Evidence in man. , 1966, The Journal of experimental medicine.

[16]  V. Tuohy,et al.  Spontaneous Regression of Primary Autoreactivity during Chronic Progression of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis , 1999, The Journal of experimental medicine.

[17]  R. Webster,et al.  Protection against a lethal influenza virus challenge by immunization with a haemagglutinin-expressing plasmid DNA. , 1993, Vaccine.

[18]  S. Hauser,et al.  Late Complications of Immune Deviation Therapy in a Nonhuman Primate , 1996, Science.

[19]  E. Sercarz,et al.  Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen , 1992, Nature.

[20]  P. Brown,et al.  Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions , 2001, Genome Biology.

[21]  R. Tisch,et al.  Insulin-Dependent Diabetes Mellitus , 1996, Cell.

[22]  W. Robinson,et al.  Millennium Award Recipient Contribution Proteomics for the Development of Dna Tolerizing Vaccines to Treat Autoimmune Disease , 2022 .

[23]  W. Cowden,et al.  DNA vaccines for the treatment of autoimmune disease , 1997, Immunology and cell biology.

[24]  N. Sarvetnick,et al.  Vaccination with glutamic acid decarboxylase plasmid DNA protects mice from spontaneous autoimmune diabetes and B7/CD28 costimulation circumvents that protection. , 2001, Clinical immunology.

[25]  H. Garren,et al.  Immunization with DNA encoding an immunodominant peptide of insulin prevents diabetes in NOD mice. , 2001, Clinical immunology.

[26]  P. Brown,et al.  Autoantigen microarrays for multiplex characterization of autoantibody responses , 2002, Nature Medicine.

[27]  J. Bluestone,et al.  Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. , 1995, Immunity.

[28]  S. Miller,et al.  Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis , 1995, The Journal of experimental medicine.

[29]  L. Steinman,et al.  Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: the minimal B-cell epitope and a model of its features. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Fontoura,et al.  Combination of gene delivery and DNA vaccination to protect from and reverse Th1 autoimmune disease via deviation to the Th2 pathway. , 2001, Immunity.

[32]  V. Tuohy,et al.  A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease , 1996, The Journal of experimental medicine.

[33]  J. Goverman,et al.  T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. , 1994, Science.

[34]  S. Hauser,et al.  Identification of autoantibodies associated with myelin damage in multiple sclerosis , 1999, Nature Medicine.

[35]  U. Utz,et al.  Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein , 1996, Nature.

[36]  J. Harley,et al.  Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity , 1995, The Journal of experimental medicine.

[37]  M. Shlomchik,et al.  From T to B and back again: positive feedback in systemic autoimmune disease , 2001, Nature Reviews Immunology.

[38]  G. B. Thornton,et al.  Antibody production to the nucleocapsid and envelope of the hepatitis B virus primed by a single synthetic T cell site , 1987, Nature.

[39]  H. Wekerle.  Remembering MOG: Autoantibody mediated demyelination in multiple sclerosis? , 1999, Nature Medicine.

[40]  L. Steinman.  Absence of  “Original Antigenic Sin” in Autoimmunity Provides an Unforeseen Platform for Immune Therapy , 1999, The Journal of experimental medicine.

[41]  John D. Storey.  A direct approach to false discovery rates , 2002 .