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  • CURRICULUM VITAE February 14, 2006 Claude Paul Genain, M.D. Department of Neurology- C 440 University of California San Francisco, CA 94143-0114 Ph: (415) 514-3591 Fax: (415) 634-1653 E-Mail: claudeg@itsa.ucsf.edu, genain@sbcglobal.net Place of Birth: Paris, France Immigration status: US Citizen EDUCATION 1970: Baccalaureate C (Mathematics) & A (Literature), Pasteur High School, Neuilly/Seine, France. 1983: Medical Degree: Xavier Bichat College of Medicine University of Paris.Thesis defended in May 1984 Certification: ECFMG, FLEX. Active License: California Past Licenses: Kentucky, Massachusetts. ACADEMIC APPOINTMENTS 1996-present: Assistant Professor, Neurology; University of California, San Francisco. ACADEMIC HONORS 1976: Interne des Hopitaux, Paris, rank 5th of 370 nominees (1,500 applicants). 1984: Silver medal cor thesis-Graduated with Doctorate in Medicine cum laude 1996: Harry Weaver Neurosciences Scholarship from the National Multiple Sclerosis Society. RESIDENCIES 1979-1983: Internal Medicine, Assistance Publique of Paris. Interne des Hopitaux (Equivalent of Resident) 1987-1988: University of Kentucky. Intern. Department of Internal Medicine 1988-1991: University of Kentucky. Resident. Department of Neurology RESEARCH EXPERIENCE 10/76-6/77: Leave of absence for volunteer work in biomedical research. INSERM laboratory, Hopital Claude Bernard, Paris (under Prs. Jean-Jacques Poccidalo and Rene Gourgon).
  • 07/77-9/79: French Military Service, Detached by the Ministry of Defense as a Research Associate in Cardiovascular Physiology. Montreal Heart Institute, Montreal, Canada (Pr. Martial G. Bourassa). 1980-1983. Biochemistry and Hypertension. INSERM laboratory (Prs. Pierre Corvol and Joel Menard). 1984-1986. University of Kentucky, Lexington, KY. Post-doctoral Fellow. Department of Medicine, Endocrine Division (Dr. Theodore A. Kotchen). 1986-1987. University of Kentucky, Lexington, KY. Post-doctoral Fellow. Department of Biochemistry (Pr. Charles J. Waechter). 1991-1992. Massachusetts General Hospital, Boston, MA. Post-Doctoral Fellow, Department of Neurology (Pr. Stephen L. Hauser). 1992-1995. University of California, San Francisco. Post-doctoral Fellow, Department of Neurology (Pr. Stephen L. Hauser) PROFESSIONAL ACTIVITIES Memberships in Professional Organizations 1989-present: American Academy of Neurology 1994-present: American Association for the Advancement of Science 2001-present American Neurological Association Service to Professional Publications Referee for: Journal of Neuroimmunology; Annals of Neurology; Journal of Immunology; Journal of Endotoxin Research; Proceedings of the National Academy of Sciences-USA; Multiple Sclerosis; Journal of Clinical Investigation. Ad hoc reviewer for: International Immunology; Nature Medicine; New England Journal of Medicine; Nature Genetics; Trends in Neurosciences, Trends in Molecular Medicine. INVITED PRESENTATIONS, LECTURES AND SEMINARS National June 1993: Active and passively transferred experimental allergic encephalomyelitis in the common marmoset Callithrix Jacchus . Berlex Biosciences, Richmond, CA August 1993: Experimental allergic encephalomyelitis in Callithix Jacchus marmosets: a model to test future therapies for multiple sclerosis. Athena Neurosciences, CA April 7 1995: Future therapeutic strategies for multiple sclerosis. Midyear Educational Meeting, American College of Osteopathic Neurologists and Psychiatrists. Phoenix, Arizona.
  • July 31 1995: Experimental allergic encephalomyelitis in the common marmoset. An overview of the model and its applicability to development of future strategies to treat human multiple sclerosis. Berlex Biosciences, Richmond, CA. Nov 1995: Genetic models: demyelinating experimental allergic encephalomyelitis in non human primates. Symposium on the Impact of Glial Biology and Immunology on Multiple Sclerosis and Other Demyelinating Diseases. UCLA seminar series. June 19 1996: The pathophysiology of multiple sclerosis-like lesions in a non human primate. IBC conference, San Francisco, CA October 1996: Experimental allergic encephalomyelitis in common marmosets: its applications to future therapeutic trials for human multiple sclerosis. Parkinson's Institute, Mountain View, CA. April 18 1997: Mechanisms of autoimmune demyelination in common marmosets: a new model for multiple sclerosis and its implications for future therapeutic strategies. Boehringer-Ingelheim, Ridgefield, CT. June 12 1997: Prevention of autoimmune demyelination by phosphodiesterase type IV- inhibitors. FASEB Summer Research Conference on "Cytokines and Lipid Mediators". June 7-12, Saxton's River, VT. July 2 1997: Allergic encephalomyelitis in the common marmoset: complex pathogenesis for a multiple sclerosis-like lesion and implications for therapeutic strategies. La Jolla Institute for Allergy and Immunology, San Diego, CA. Sept. 30 1997: Immune deviation strategies in a non human primate model for autoimmune demyelination. IBC Conferences, Autoimmune Diseases: Exploiting Mechanisms for Drug Development and Diagnosis, San Francisco, CA. Oct. 1 1997: Experimental allergic encephalomyelitis in the common marmoset Callithrix jacchus. Roche Biosciences, Palo Alto, CA. Nov. 11 1997: Mechanisms of immunologic tolerance in non human primates. Department of Microbiology and Immunology, University of California, San Francisco (Immunology Retreat), Tiburon, CA. Mar. 10 1998: Prevention of EAE in non human primates by a type-IV phosphodiesterase inhibitor that suppresses tumor necrosis factor. IBC Conferences, Cytokine Inhibitors:Anti-inflammatory Drug Discovery, Philadelphia, PA. June 10 1998: New developments and therapeutic perspectives in multiple sclerosis. Neurology Grand Rounds, Department of Neurology, Stanford University, Palo Alto, CA. Oct. 30 1998: Magnetic Resonance Imaging in a non human primate model for human multiple sclerosis. Brown Bag Lecture Seminars, Department of Radiology, University of California, San Francisco, CA. Mar. 25 1999: A novel model of autoimmune demyelination in the common marmoset: advantages in preclinical trials for multiple sclerosis and efficacy of type-IV phosphodiesterase inhibition. ICOS Corporation, Bothell, WA. Sept. 13 1999: Multiple Sclerosis. Genetics and the Immune System. Dean's Research Seminar Series, University of California, San Francisco, CA. Oct. 8 1999: The model of EAE in the common marmoset. Biogen Inc., Cambridge, MA. Dec. 8 1999: Multiple Sclerosis As A Heterogeneous Disease: Contribution Of Antibody- Dependent Mechanisms To Autoimmune Demyelination. Neurology Grand Rounds. Oregon Health Sciences University, Portland, OR. Jan. 5 2000: Mechanisms of Antibody-Mediated Autoimmune Demyelination: Implications for Tailored Therapeutic Strategies in Multiple Sclerosis. Grand Rounds, Department of Neurology, University of California, San Francisco, CA. Jan. 27 2000: Role of Autoantibodies in CNS demyelinating disorders. Winter Conferences On Brain Research, Beckenbridge, CO.
  • Sep. 15 2000: Complexity of Autoimmune Demyelination and Emerging Therapeutic Targets for Multiple. Protein Design Laboratories, Fremont, CA. Oct. 14 2000: Therapeutic Benefits of Nerve growth Factor in Non-Human Primate Encephalomyelitis. Symposium "The Neurobiology and immunobiology of Multiple Sclerosis", Boston, MA. Jan. 8 2001: Molecular Grand Rounds. Multiple sclerosis. Physician Scientist Training Program, University of California, San Francisco, CA. May 7 2001: Aventis Pharmaceuticals, Bridgewater, NJ. "Autoimmune demyelination in a non human primate: a model for identification of genes involved in MS pathogenesis". May 9 2001: Merck Research, Rathway, NJ. "Allergic encephalomyelitis in the common marmoset: pathophysiology of demyelinating plaques and use in preclinical trials" Jun 14 2001: Visiting Professor Rounds, Mayo Clinic, Rochester, MN. "Encephalomyelitis in the common marmoset: a model to study the complex pathophysiology of multiple sclerosis and novel therapeutic strategies". Jun 15 2001: Research Seminar, Mayo Clinic, Rochester, MN. “Therapeutic Potential of Nerve Growth factor for Demyelinating Disorders.” Jul 19 2001: National Multiple sclerosis Society advisory Board, California Chapter. “New therapeutic avenues for Multiple Sclerosis”. Dec 19 2001: Visiting Professor Rounds, University of Medical and Dental School, New Jersey, Newark, New Jersey. “Allergic encepholomyelitis in common marmosets: a model to study the complex pathophysiology of multiple sclerosis and validate novel immunotherapies”. Jan 10 2003: Nancy Davis Without Walls Winter Symposium. “Significance of autoantibodies to myelin in CNS autoimmune demyelination”. Feb 10 2003: Genentech Symposium. “Role of B cells and humoral immunity in CNS autoimmune demyelination”. Feb 28 2003: Genentech Advisory Board. “Role of B cells in Multiple Sclerosis and Rationale for use of Rituxan”. Apr 12 2003: FASEB (Satellite Symposium American Association of Anatomists). “Nerve Growth Factor is a Tissue Specific Regulatory Cytokine in CNS inflammation”. San Diego, CA. Sept 15 2003: Boehringer-Ingelheim Advisory Board. MS Therapeutics: “Value of MS disease models and marmoset EAE”. New York, NY. Oct 28 2003: Adventis advisory board. Strategic planning for development of future therapies. “Immunological aspects of MS and EAE”. New York, NY. Dec 03 2003: First International B cell Summit. Marmoset model to study the role of B cells in MS. Carlsbad CA. June 14 2004: Keynote Speaker, First Symposium of the Marmoset Group of America.. Primate models of inflammation with emphasis on multiple sclerosis. Madison, WI. July 14 2004: California Pacific Medical Center Research Institute. Research Seminar. Aug 18 2004: University of Kentucky, Lexington, KY. Neurology Grand Rounds. Oct 28 2004 Archemix: Pre-clinical use of the Marmoset Model of experimental Allergic Encephalomyelitis. Oct 29 2004: Washington University, St Louis, MI. Neurology Grand Rounds: CNS- targeted humoral immunity as a factor of phenotypic expression and a novel biomarker in multiple sclerosis. Feb 03 2005: Torrey Pines Institute for Molecular Studies, La Jollia, CA. Myelin Autoantibodies: Translating Bench Research to Patient Bedside and Back. April 30 2005: Advisory Meeting of the HHV6 Foundation. Marmoset model of HHV6 infection and its use for elucidation of MS pathogenesis. Bethesda, MD.
  • May 26 2005: Diabetes Seminar Series, UCSF. Modeling Interactions Between Human Herpesvirus-6 Exposure and Multiple Sclerosis. San Francisco, CA. June 4 2005: MS Consortium Annual Symposium. Humoral responses to CNS antigens and their significance in MS. Orlando, FL Jan 20 2006: Models of Interactions Between Exposure to Ubiquitous Childhood Viruses, Autoimmunity, and Neurodegeneration. Grand Rounds, Buck Institute for Aging, Novato, CA. International Dec. /91: Perspectives therapeutiques dans la sclerose en plaques. Dept d’enseignement et de recherche de Neurosciences. CHU Henri Mondor, Creteil, France Oct. /94: Experimental allergic encephalomyelitis in the common: a novel model for human multiple sclerosis. Department of Neuroimmunology, Max Planck Institut fur Psychiatrie, Martinsried, Germany Feb. /96: Trials of Iloprost and Betaseron in marmoset experimental allergic encephalomyelitis. Symposium organized by Schering, A.G., Berlin, Germany. Sept. /96: Multiple Sclerosis: new therapeutic perspectives. Boehringer-Mannheim, Penzberg, Germany. Aug. 2/98: The molecular basis for autoimmune demyelination in primates. Symposium, Fifth International Congress of the Society of Neuroimmunology, Montreal, Quebec, Canada. April 13/99: EAE in non human primates. Symposium: Autoimmune demyelination in the CNS. Basic mechanisms and implications for MS. Clinica Puerta de Hierro, Hospital Universitario, Madrid, Spain. Nov. 12/00: Experimental Allergic Encephalomyelitis in the common marmoset. Philippe Laudat/INSERM Conference "Pathological Aspects and Therapeutic Approaches of Demyelinating Diseases", Nov 12-16, Aix-les-Bains, France. Nov. 15/00: Pathogenesis of Autoimmune Demyelination in a Non-Human Primate Model for Multiple Sclerosis: Implications for Defining New Therapeutic Targets. Cantab Pharmaceuticals, Cambridge, UK. May 19/02: Nerve growth factor suppresses allergic encephalomyelitis through CNS-specific immune deviation. NGF 2002, 7th International Conference on NGF and Related Molecules, Modena, Italy, May 15th-19th, 2002. Sept. 26/02: Therapies de Tolerance Immune au Course de la Sclerose en Plaques: Des Modeles Animaux a la Maladie Humaine. Neurology Grand Rounds, Hopital La Pitie Salpetriere, Paris, France. May 16/03: Role of B cells and Antibody Responses in Multiple Sclerosis”. Thematic Symposia: Autoantibodies in type 1 diabetes and neurological disease and shared principles of in the pathogenesis of MS and type 1 diabetes. FOCIS (Federation of Clinical Immunology Societies), Paris, France. Dec 12 2004: First Anti-myelin Antibody Workshop in Multiple Sclerosis, Innsbruck, Austria: Complexity of Autoantibody Responses to the MOG Protein in Human and Non-Human Primates. Dec 14 2004 Neurology Grand Rounds, University of Zurich, Zurich, Switzerland. Myelin Autoantibodies As Novel Biomarkers In Multiple Sclerosis.
  • May 5 2005 ESF Marie Network Conference. Anti-Myelin antibody responses. Status and Clinical Applications. Potenza, Italy. May 18 2005 Myelin Autoantibodies Symposium. Dubrovnik, Croatian Republic. July 2-2005 Second Anti-myelin Antibody Workshop in Multiple Sclerosis, Innsbruck, Austria: Comparison of Methods to Measure Serum Anti-MOG Antibodies and Prelimianry Evaluation of Results from 6 Independent Laboratories. SERVICE University Service: 01/00-05/00: Search Committee for Clinical Director of the Multiple Sclerosis Center 08/00-10/00: Search Committee for Junior Faculty, Multiple Sclerosis center 05/2001: Peer-Reviewer, Alzheimer's Disease Program, California Department of Health Services. 05/03-05/05: Committee on Animal Research, University of California 05/01-present: Peer-Reviewer, Biostar Program, University of California. Government Service 11/99-present: The National Multiple Sclerosis Society. Advisory Committee on Fellowships. 05/01 : Research Enhancement Award Program (REAP) Advisory Committee, Veterans Administration Hospital, Portland, OR. 06/04-present: National Institutes of Health (NINDS), NCBT 01 Study Section. Other: 05 /00: Immune Tolerance Network. Ad-Hoc Reviewer and advisor. 2002-2004: Ethics Committee, American Neurological Association. Advisory Boards (Industry): 09/01-present: Aventis Pharmaceuticals. 10/02-present: Genentech, South San Francisco, CA. 10/02-present: BiogenIdec, San Diego, CA. 03/03-present: Boehringer-Ingelheim, Ridgefield, CT. TEACHING EXPERIENCE:
  • Technician Supervision and training (full time): 1992-1995. My-Hoa Nguyen, SRA I. 07/95-11/96. Kristina Abel, SRA II. Graduated from Ph.D. program in Immunology, UC Davis, CA. Currently Faculty at UC Davis. 10/95-03/98. Nicole Belmar, SRA I. 01/97-05/98: Scott Mayfield, SRA II. Graduated from Medical school at Chapel Hill, North Carolina. Currently in Anesthesiology residency program at UCSF. 01/98-09/99. Mitra Jazayeri, SRA II 01/97-11/99. Nathan Heald, AHT III. 11/00-06/02: Antje Fuhrman, BSc. 05/98-present. Janeen Islar, SRA III. 11/99-present. Salomon Martinez, AHT III. 06/02-05/03: Stacey Bae, MS. 07/03-present: Drew Dover, SRA II. 10/03-present: Ishita Barman, SRA II. 10/03-present: Jerry Hernandez, SRA II. 02/05-present: Jennifer Gardell, SRA II. Post-Doctorates supervision and training (10 hours/week): 03/96-12/97. Pablo Diaz-Villoslada, M.D. – 664 hours. Currently Faculty at the University of Navarra, Pamplona, Spain. 06/96-08/97. Niklas Kohler, M.D. – 448 hours 12/97-10/99. Jean-Christophe Ouallet, M.D. – 664 hours. Currently Faculty at the University of Bordeaux, France. 03/98-01/03. Hans-Christian von Büdingen, M.D. – 1328 hours. Currently pursuing completion of Neurology Residency at the Universitätsspital Zurich, Zurich, Switzerland. 04/00-01/02. Naoyuki Tanuma, M.D. – 224 hours. Currently Faculty in the Department of Pediatrics, Metropolitan Fuchu Medical Center for Severe Motor and Intellectual Disabilities, Tokyo, Japan. 10/01-present. Til Menge, M.D. – 8 hours/week. 12/03-present. Patrice Lalive d’Epinay, M.D.- 8 hours/week. Students supervision and training: Summer 1994. Rachel Pearl, Stanford University, CA. 140 hours. Graduated from UCSF Medical School. Summer 1996. Robert Goertsches, University of Goettingen, Germany. 120 hours. Currently Associate in Dr. Villoslada’s group, Pamplona, Spain. Summer 1997. Sabine Cepok, University of Goettingen, Germany. 120 hours. Currently Faculty in Dr. B. Hemmer’s group, Dusseldorf, Germany. 9/96-06/98. Ling Shao, University of Berkeley, CA. 2 hours/week. 152 hours. Currently graduated from New York University Medical School, Mt Sinai, New York. 9/96-06/98. Andrew Shih, University of Berkeley, CA. 2 hours/week. 152 hours 09/96-08/97. Damon Chandler, Howard Hughes Fellow, Duke University, NC. 8 hrs/wk. 384 hrs. Graduating from M.D./Ph.D. program at Duke. 01/97-06/98. Chuan-Wei Lu, University of Berkeley, CA. 2 hours/week. 128 hours. 03/97-03/98. Monique Yao, University of Berkeley, CA. 2 hours/week.96 hours. 06/98-06/99. Michael Kim, University of Berkeley, CA. 2 hours/week. 96 hours. 06/99-08/99. Nina Garga, Albert Einstein College of Medicine, Bronx, NY. 2 hrs/week. 24 hrs. Currently Chief Resident in Neurology Residency program at UCSF.
  • 05/00-12/01. Cameron Nabavi, University of California, Berkeley, CA. 2 hours/week. 48 hrs. 12/00-01/01. Mercedes Paredes, University of California, San Francisco (MPTP student). Molecular Grand Rounds. Total 12 hours. 07/01-05/03 Joy Lee, University of California, Berkeley, CA. 2 hours/week. Currently in Ph.D. program at Northwestern University. 10/03-present Jennifer Wu, University of California, Berkeley, CA 3 hours/week. Formal Courses to Graduate Students: Nov 98: Bioengineering 280: Clinical aspects of bioengineering. 4 hours. May 99: MED I: Introduction to the Neurologic Examination. 4 hours. May 00: MED I: Introduction to the Neurologic Examination. 3 hours. Neurology Resident Teaching: Moffit Consult-Ward Attending: 15 days per year since 2001. One lecture per period.
  • PATENTS 1. US PAT NO. 6,333,033 B1. AUTOANTIBODY INHIBITORS. Issued December 25, 2001. Application No. 09/384,036, filed August 26, 1999. Provisional application No. 60/097,953, filed on August 26, 1998. 2. US Patent 6,573,236 B2. INHIBITING MOG-ANTIBODY BINDING. Issued June 3, 2003. Filed on December 21, 2001. Division of application No. 09/384,036, filed on August 26, 1999, now Patent No. No. 6,333,033. Provisional application No. 60/097,953, filed on August 26, 1998. Ref No. UCSF99-020-3. 3. US PAT NO. 6,569,431 B2. RECOMBINANT ANTIBODY FRAGMENTS AS AUTOANTIBODY ANTAGONISTS. Issued May 27, 2003. Application No. 09/899,896, filed on July 5, 2001. Continuation of application No. 09/691,654, field on October 17, 2000, now abandoned. 4. US Patent Application No. 09/854142. NGF FOR THE PREVENTION OF AUTOIMMUNE DEMYELINATION IN THE CENTRAL NERVOUS SYSTEM. Filed May 10, 2001. Ref No. SF2000-12-3. 5. PCT Patent Application No. PCT/US2003/032349. A METHOD FOR DIAGNOSIS AND PROGNOSIS OF MULTIPLE SCLEROSIS. Docket No. 305T-300410PC. Filed October 10, 2003. Provisional application No. 60/418.001, filed October 11, 2002. Ref No. UCSF2003-019-2. 6. US Patent Provisional Application No. 60/674,354 A METHOD FOR DIAGNOSIS AND PROGNOSIS OF MULTIPLE SCLEROSIS. Docket No. 305T-300420US. Filed April 21, 2005. Ref No. UCSF 2003-019-3. 7. US Patent provisional application. METHODS FOR ASSESSING ANTIBODY- MEDIATED CYTOTOXICITY. Filed on March 15, 2005. Ref No. SF05-054. 8. US Patent provisional application No. 60/698,519. COMPOSITION AND METHODS COMPRISING COMPLEX ALTERNATIVE SPLICE VARIANTS OF MYELIN/OLIGODENDROCYTE GENES (MOGs) AND ANTIBODIES DIRECTED THERETO. Docket No. 13333. 1003P. Filed July 11, 2005. 9. US non-provisional and PCT application. ANIMAL MODEL SYSTEMS FOR VIRAL PATHOGENESIS OF NEURODEGENERATION, AUTOIMMUNE DEMYELINATION, AND DIABETES. Docket No. 13333. 1001U and 13333. 1001PCT. Filed October 12, 2005. Provisional applications No. 60/618,277 filed on October 12, 2004 and No. 60/720,676 filed on September 26, 2005.
  • EDITORIALS FOR PUBLISHED WORK 1. McFarland, H. Significance of autoreactive T cells in diseases such as multiple sclerosis using an innovative primate model. J. Clin. Invest. 94, 921-922 (1994). 2. Raine, C. Multiple sclerosis: TNF revisited, with promise. Nature Med. 1, 244-248 (1995). 3. McFarland, H. Complexities in the treatment of autoimmune disease. Science 274, 2037-2038 (1996). 4. Wekerle, H. Remembering MOG: autoantibody mediated demyelination in multiple sclerosis? Nature Med. 5, 153-154 (1999). 5. McFarland, H. The path to damage in multiple sclerosis. Ann. Neurol. 46, 141-142 (1999). 6. Ransohoff, RM, Trebst, C. Surprising pleiotropy of nerve growth factor in the treatment of experimental autoimmune encephalomyelitis. J. Exp. Med. 191 (10): 725-729 (2000). 7. Mathey, E, Breithaupt, C., Schubart, AS, Linington, C. Sorting the wheat from the chaff: identifying demyelinating components of the myelin oligodendrocyte glycoprotein (MOG)- specific autoantibody repertoire. Eur. J. Immunol., 34:1-7 (2004). PUBLICATIONS Peer-Reviewed Articles 1. Syrota A, Xuan BB, Genain C, Theven D, Valois JM, Poccidalo JJ. Thermodynamic coefficients in capillary membrane of dog lung for small hydrophilic molecule transport evaluated by an osmotic bolus method.INSERM EUROMECH 92, Cardiovascular And Pulmonary, Joffrin MY (Ed) Vol 71: 291. 1977. 2. Fruchaud J, Guiomard A, Touche T, Genain C, Valois JM, Gourgon R. Comparative Hemodynamic effects of left heart bypass and cardiopulmonary bypass in experimental heart insufficiency. European Surgical Research, Clinical and Experimental Surgery, EURSERM (Suppl 1) I-147: 123. 1978. 3. Guiomard A, Touche T, Valois JM, Genain C, Fruchaud J. Derivations veino- arterielle et ventriculaire gauche. Effets compares au cours de l'insuffisance cardiaque aigue experimentale. Bull Eur Physiopathol Resp 14: 693. 1978. 4. Genain C, Tellier A, Syrota A, Poccidalo JJ, Hanss M. Infinite dilution conductimetry of plasma and urine: correlation with osmolality. Clin Chim Acta 88: 177. 1978. 5. Bourassa MG, Theroux P, Genain C, Thuilliez C et al. Effects of Diltiazem on myocardial ischemia in dogs. In: New Drug Therapy with a Calcium Antagonist, Diltiazem, Hormone Symposium. Experta Medica, Amsterdam. 1980. 6. Bourassa MG, Cote P, Theroux P, Tubau JF, Genain C, Waters DD. Hemodynamics and coronary flow following Diltiazem administration in anesthetized dogs and humans. Chest 78: 224. 1980. 7. Clauser E, Genain C, Bouhnik J, Corvol P, Menard J. Variations de l'angiotensinogene et du Desangiotensine I-angiotensinogene chez l'homme et chez le rat au cours de l'inhibition de l'enzyme de conversion. Arch Mal Coeur 75eme annee: 157. 1982. 8. Genain C, Aldigier JC, Guyenne TT, Corvol P, Menard J. Direct radioimmnoassay of renin and renin substrate during conversion enzyme inhibition. Clin Exp Hypertension-Theory and Practice 4A (11&12): 2193. 1982.
  • 9. Merillon JP, Fontenier GJ, Lerallut JF, Joffrin MY, Motte GA, Genain CP, Gourgon R. Aortic imput impedance in normal man and arterial hypertension: its modification during changes in aortic pressure. Cardiovasc Res 16: 646-652. 1982. 10. Genain C, Bouhnik J, Tewksbury D, Corvol P, Menard J. Characterization of plasma and cerebrospinal fluid angiotensinogen and des-angiotensin I-angiotensinogen by direct radioimmunoassay. J Clin Endocrinol Metab 59: 478. 1984. 11. Auzan C, Genain C, Corvol P, Menard J, Chrambach A. Evaluation of the capacity of gel electrophoresis, steady-state and transient state electrofocusing to resolve des- angiotensin Iangiotensinogen from angiotensinogen. Electrophoresis 6: 201. 1985. 12. Genain C, Van Loon GR, Kotchen TA. The distribution of renin activity and angiotensinogen in rat brain: effects of dietary NaC1 intake on brain renin. J Clin Invest 76: 1939. 1985. 13. Genain CP, Reddy SR, Ott CE, Van Loon GR, Kotchen TA. Failure of salt loading to inhibit tissue norepinephrine turnover in prehypertensive Dahl salt-sensitive rats. Hypertension 12: 568-573. 1988. 14. Nelson KR, Genain C. Duchenne de Boulogne and the muscle biopsy. J. Child Neurol. 4(N4):315, 1989. 15. Cheeseman, M, Genain, C, Smith, CD. Group C streptococcal meningitis with favorable recovery. A case report. J. Kentucky Medical Association, 88 (10): 545-546, 1990. 16. Genain CP, Waechter CJ. Separation of brain dolichol kinase from endogenous activating factors: evidence that phospholipid enhances the interaction between enzyme and dolichol. J Neurochem 54(3): 855-862. 1990. 17. Genain CP, Lee-Parritz D, Nguyen MH, Massacesi L, Joshi N, Ferrante R, Hoffman K, Moseley M, Letvin NL, Hauser SL. In Healthy Primates, Circulating Autoreactive T-cells mediate autoimmune disease. J Clin Invest 94: 1339-1345. 1994. 18. Massacesi L, Genain CP, Lee-Parritz D, Letvin NL, Cantfield D, Hauser SL Active and passively induced autoimune encephalomyelitis in common marmosets: a new model for multiple sclerosis. Ann Neurol 47: 519-530. 1995. 19. Genain CP, Roberts T, Davis RL, Nguyen MH, Uccelli A, Faulds D, Yi L., Hedgpeth J, Hauser SL. Prevention of autoimmune demyelination in non human primates by a cAMPspecific phosphodiesterase inhibitor. Proc Natl Acad Sci (USA) 92:3601-3605. 1995. 20. Genain CP, Nguyen MH, Pearl R, Linington C, Adelman M, Lees MB, Hauser SL. Antibody facilitation of multiple sclerosis-like lesions in a non human primate. J. Clin. Invest. 96: 29662974. 1995. 21. Genain CP, Abel K, Belmar N, Villinger F, Rosenberg DP, Linington C, Raine CS, Hauser SL. Late complications of immune deviation therapy in a non human primate. Science 274: 20542057. 1996. 22. Uccelli A, Oksenberg JR, Jeong M, Genain CP, Rombos T, Jaeger EEM, Giunti DE, Lanchbury JS, Hauser SL. Characterization of the TCRb chain repertoire in the New World monkey Callithrixjacchus. J. Immunol. 158: 1201-1207. 1997. 23. Genain, CP, Gritz, L, Panicali, D, Whitaker, JN, Letvin, NL, Hauser, SL. Inhibition of allergic encephalomyelitis in marmosets by vaccination with recombinant vaccinia virus encoding for myelin basic protein. J. Neuroimmunol. 79: 119-128. 1997. 24. Genain, CP, Cannella, B, Hauser, SL, Raine, CS. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Med., 5: 170-175. 1999 25. McFarland, HI, Lobito, A, Johnson, MM, Nyswaner, JT, Frank, JA, Palardy, GR, Tresser, N, Genain, CP, Mueller, JP, Matis, LA, Lenardo, MJ. Determinant
  • spreading associated with demyelination in a nonhuman primate model of multiple sclerosis. J. Immunol. 162: 2384-2390. 1999. 26. Diaz-Villoslada, P, Shih, A, Shao, L, Genain, CP, Hauser, SL. T-cell reactivity to myelin antigens: myelin/oligodendrocyte glycoprotein is a prevalent antigen. J. Neuroimmunol. 99: 36-43, 1999. 27. Raine, CS, Cannella, B, Hauser, SL, Genain, CP. Demyelination in non-human primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: a case for antigen-specific antibody mediation. Ann. Neurol. 46: 144-160, 1999. 28. Villoslada, P., Heald, N., Bartke, I., Unger, J., Fisher, S., Rosenberg, D., Cheung, S.W., Hauser, S.L., Genain, C.P. Human nerve growth factor protects common marmosets from autoimmune encephalomyelitis by switching the balance of Th1 and Th2 cytokines within the central nervous system. J. Exp. Med. 191 (10): 1799-1806, 2000. 29. Heeger, PS, Forsthuber, T, Shive, C, Biekert, E, Genain, C, Hofstetter, HH, Karulin, A,, Lehmann, PV. Revisiting tolerance induced by autoantigen in incomplete Freund's adjuvant. J. Immunol. 164(11):5771-81, 2000. 30. Uccelli, A, Giunti, D, Caroli, F, Fiorone, M, Seri, M, Mancardi, G, Hauser, SL, Genain, CP. Responses to myelin basic protein in an outbred non human primate model for multiple sclerosis. Eur. J. Immunol. 31:474-479, 2001. 31. Mohr, DC, Goodkin DE, Islar, J, Hauser, SL, Genain, CP. Treatment of depression is associated with suppression of non-specific and antigen-specific Th1 responses in multiple sclerosis. Arch. Neurol. 58: 1081-1086, 2001. 32. McFarland, H., A. Lobito, M. Johnson, G. Palardy, C. Yee, E. Jordan, J. Frank, N. Tresser, C. Genain, J. Mueller, L. Matis and M. Lenardo. 2001. Effective antigen- specific immunotherapy in the marmoset model of multiple sclerosis. J. Immunol. 166: 2116-2121, 2001. 33. Villinger, F, Bostik, P, King, CL, Genain, CP, Weiss, WR, Ansari, AA. Cloning, sequencing, and homology analysis of nonhuman primate Fas/Fas-ligand and co- stimulatory molecules. 2001. Immunogenetics, 53: 315-328. 34. von Büdingen, H-C, Hauser, SL, Nabavi, C, Genain, CP. Analysis of the immunoglobulin gamma heavy Chain repertoire in the New World monkey Callithrix jacchus jacchus. Immunogenetics 53:557-563, 2001. 35. Villoslada, P, Abel, K, Heald, N, Goersches, R, Hauser, SL, Genain, CP. Frequency, Heterogeneity and Encephalitogenicity of T cells specific for Myelin Oligodendrocyte Glycoprotein in Naive Outbred Primates. Eur. J. Immunol. 31:2942-2950, 2001. 36. Mesleh, MF, Belmar, N, Lu, CW, Krishnan, VV, Maxwell, RS, Genain, CP, Cosman, M. Marmoset B-cell and T cell epitope specificities mapped onto a homology model of the extracellular domain of human myelin oligodendrocyte glycoprotein. Neurobiology of Disease 9:160-172, 2002. 37. Scarisbrick, I, Blaber, S, Lucchinetti, C, Genain, C, Blaber, M, Rodriguez, M. Activity of a Newly Identified Serine Protease in CNS Demyelination. Brain 125:1283-1296, 2002. 38. Koehler, N, Genain, C.P., Giesser, B, Hauser, S.L. The human T cell response to myelin oligodendrocyte glycoprotein: a multiple sclerosis family-based study. J. Immunol. 168 (11): 5920-5927, 2002. 39. von Büdingen, H-C, Hauser, SL, Fuhrmann, A, Nabavi, C, Lee, JI, Genain, CP. Molecular characterization of antibody specificities against myelin oligodendrocyte glycoprotein in autoimmune demyelination. Proc. Natl. Acad.Sci. USA 99(12) 8207-8212, 2002.
  • 40. Pelletier D; Grenier D; Lu Y; Genain CP; Nelson SJ; and Goodkin DE: "3-D Echo Planar HMRS Imaging in MS: Metabolite Comparison from Supratentorial vs. Central Brain". Magnetic Resonance Imaging 20 (8), 599-606, 2002. 41. Robinson WH, Fontoura P, Lee BJ, Neuman de Vegvar HE, Tom J, Pedotti R, DiGennaro CD, Mitcjell DJ, Fong D, Ho P P-K, Ruiz PJ, Maverakis E, Stevens DB, Bernard CCA, Martin R, Kuchroo VK, van Noort JM, Genain CP, Amor S, Olsson T, Utz PJ, Garren H, Steinman L. Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis. Nature Biotechnology, 21(9):1033-1039, 2003. 42. Ohler, B, Graf, K, Bragg, R, Lemons, T, Coe, R, Genain, C, Israelachvili, J, Husted, C. Role of lipid interactions during autoimmune demyelination. Biochim. Biophys. Acta 1688(1), 10-17, 2004. 43. Mohr, D, Genain, CP. Social Support as a buffer in the relationship between treament for depression and T cell production of interferon gamma in patients with multiple slcerosis. J. Psychosom. Res. 57:155-158, 2004. 44. Oh J, Henry RG, Majumdar S, Genain CP, Nelson S, Pelletier D. Mechanisms of normal appearing corpus callosum injury related to pericallosal T1 lesions in multiple sclerosis using directional diffusion tensor and 1H MRS imaging. J. Neurol. Neurosurg. Psychiatry, 75: 1281-1286, 2004. 45. von Budingen H-C, Hauser SL, Ouallet J-C, Tanuma N, Menge T, Genain CP. Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences phenotype and antibody effector functions in autoimmune demyelination. Eur. J. Immunol., 34: 2072-2083, 2004. 46. Cox D, Pelletier D, Genain CP, Majumdar S, Lu Y, Nelson S, Mohr D. The unique impact of changes in normal appearing brain tissue on cognitive dysfunction in secondary progressive multiple sclerosis patients Mult. Scler., 10:626-629, 2004. 47. Hu Y, Doudevski I, Wood D, Moscarello M,, Husted C, Genain C, Zasadzinski JA, Israelachvili, J. Synergistic interactions of lipids and myelin basic proteins. Proc Natl Acad Sci USA, 101: 13466-13471, 2004. 48. Cree B, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology, 64:1270-72, 2005. 49. Menge T, Lalive d’Epinay P, von Budingen H-C, Hauser SL, Genain CP. Antibodies against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis. J. Allergy Clin Immunol., 116:453-459, 2005. 50. Herndon RM, Rudick RA, Munschauer FE 3rd, Mass MK, Salazar AM, Coats ME, Labutta R, Richert JR, Cohan SL, Genain C, Goodkin D, Toal M, Riester K. Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis. Mult Scler., 11:409-19, 2005. 51. Kauppinen, TM, Suh, SW, Genain, CP, Swanson, RA. Poly(ADP-ribose) Polymerase-1 Activation in a Primate Model of Multiple Sclerosis" by T.M. J. Neurosci. Research, 81:190-8, 2005. 52. Lalive P, Menge T, Barman I, Della Gaspera B, Delarasse C, Pham-Dinh D, Villoslada P, von Budingen H-C, Genain CP. Antibodies to Native Myelin/Oligodendrocyte Glycoprotein are Serologic Markers of Early Inflammation in Multiple Sclerosis. Proc Natl Acad. Sci USA, 103: 2280-2285, 2006. 53. von Büdingen H-C, Menge T, Hauser SL, Genain CP. Restrictive and Diversifying Elements of the Anti-Myelin/Oligodendrocyte Glycoprotein Antibody Response in Primate Experimental Allergic Encephalomyelitis. Immunogenetics, In Press 2006.
  • 54. Lalive P, Menge T, Barman I, Cree B, Genain CP. Identification of new serum autoantibodies in neuromyelitis optica using protein microarray techniques. Neurology, Accepted with minor revisions. I have personally planned and designed all experiments reported in the above publications since the year 1998, and been responsible for training teaching and supervision of all post-doctorates and students in my laboratory. I have personally applied for, secured, and administered all sources of support used for this research in my laboratory. Book Chapters, Invited reviews, Editorials 1. Kotchen TA, Genain CP, Carey RM. Neuro-endocrine regulation of the renin- angiotensinaldosterone system. In: Clinical Neuro-endocrinology, R Collu, GM Brown, GR Van Loon (Eds). Blackwell Scientific Publications, 352-366. 1988. 2. Genain CP, Hauser SL. Perpectives Therapeutiques dans la Sclerose en Plaques In Therapeutique et Neurologie. Defer G. (Ed.) Vol 2: 255-264. 1993. 3. Genain CP, Hauser SL. Allergic encephalomyelitis in common marmosets: pathogenesis of a multiple sclerosis-like lesion. Methods: A companion to Methods in Enzymology 10: 420-434. 1996 4. Genain CP, Hauser SL. Creation of a model for multiple sclerosis in Callithrix jacchus marmosets. J. Mol. Med. 75: 187-197. 1997. 5. Genain, CP., and S.L. Hauser. Autoimmune demyelinating diseases of the central nervous system. In Immunology of the nervous system. R.W. Keane and W.F. Hicke,y, Ed., Oxford University Press, New York Oxford. pp 703-26. 1997. 6. Genain, CP. MRI investigations in a non human primate model of multiple sclerosis. AJNR Am. J. Neuroradiol. 20: 955-957. 1999. 7. Genain, CP, Zamvil, SS. Specific Immunotherapy: One size does not fit all. Nature Medicine, 6 (10): 1098-1100.2000. 8. von Büdingen, H-C, Tanuma, N, Villoslada, P, Ouallet, J-C, Hauser, SL, Genain, CP. Immune Responses Against The Myelin/Oligodendrocyte Glycoprotein In Experimental Autoimmune Demyelination. J. Clin. Immunol. 21 (3): 155-170, 2001. 9. Genain, CP. Smart Therapies and Touchy T cells. Neuroimmunologia, 5(1):1-4, 2001. 10. Genain, CP, Hauser, SL. Experimental allergic encephalomyelitis in the New World monkey Callithrix jacchus. Immunological Reviews, 183: 159-172, 2001. 11. Genain, CP, Hauser, SL, Oksenberg, JR. Current concepts in the immunology and immunogenetics of multiple sclerosis. Neurosciences News 4(4-5), 82-92, 2002. 12. Stuve O, Cree BC, von Budingen H-C, Yousef S, Bowen JD, Genain CP, Hauser SL, Steinman L, Zamvil, SS. Approved and future pharmacotherapy for multiple sclerosis. The Neurologist 8: 290-301, 2002. 13. Villoslada P, Genain CP. Role of nerve growth factor and other trophic factors in brain inflammation. Prog. Brain. Res 146, 403-14, 2004.
  • 14. Genain, CP. Animal Models. In Ablashi, D, and Krueger, G. Human Herpes Virus 6 in Disease. Elsevier, In Press, 2006. Most Recent Significant Publications 1. von Büdingen, H-C, Hauser, SL, Fuhrmann, A, Nabavi, C, Lee, JI, Genain, CP. Molecular characterization of antibody specificities against myelin oligodendrocyte glycoprotein in autoimmune demyelination. Proc. Natl. Acad.Sci. USA 99(12) 8207-8212, 2002. 2. von Budingen H-C, Hauser SL, Ouallet J-C, Tanuma N, Menge T, Genain CP. Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences phenotype and antibody effector functions in autoimmune demyelination. Eur. J. Immunol., 34: 2072-2083, 2004. 3. Cree B, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology, 64:1270-72, 2005. 4. Menge T, Lalive d’Epinay P, von Budingen H-C, Hauser SL, Genain CP. Antibodies against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis. J. Allergy Clin Immunol., 116:453-459, 2005. 5. Lalive P, Menge T, Barman I, Della Gaspera B, Delarasse C, Pham-Dinh D, Villoslada P, von Budingen H-C, Genain CP. Antibodies to Native Myelin/Oligodendrocyte Glycoprotein are Serologic Markers of Early Inflammation in Multiple Sclerosis. Proc Natl Acad. Sci USA, In press. I am last author on all these publications because all work was peer-review funded, planned by me, and executed in my laboratory by post-doctoral trainees under my supervision. I have also been supervising the draft of the relevant manuscripts and was responsible for all final editorial decisions, submission and re-submission of revised manuscripts. 6. Genain, CP. Animal Models. In Ablashi, D, and Krueger, G. Human Herpes Virus 6 in Disease. Elsevier, In Press, 2006. and: 7. Tanuma N, Lalive P, Gardell J, Islar J, Menge T, Genain CP. Herpesvirus hominis causes autoimmune demyelination through de novo apoptotic mechanism on glial cells. The above two manuscripts are not published yet. However, they describe an exciting new model for studying human MS based on interactions with whole body system (marmoset), and common ubiquitous human viruses (human herpesvirus-6). Manuscripts Submitted 1. Ouallet, J-C, Hauser, SL, Genain, CP. Selective Expansion of Circulating B Cells Bearing Myelin Protein-Specific B Cell Receptors in Multiple Sclerosis. 2. Ouallet, J-C, Wendland, M, von Budigen, H-C, Baumann, N, Hauser, SL, Genain, CP. Successful Treatment Of Primate Experimental Autoimmune Encephalomyelitis With Intravenous Soluble Peptide. 3. Delarasse C, Della-Gaspera B, Lu C, Lachapelle F, Rodriguez D, Dautigny A, Genain C, Pham-Dinh D. Complex alternative splicing of the myelin/oligodendrocyte gene is unique to human and non-human primates.
  • 4. Lalive d’Epinay P, Menge T, von Budingen C, Genain CP. Antibody-mediated neuronal toxicity in multiple sclerosis. 5. Menge T, Lalive P, von Budingen C, Genain CP. Differential reactivity against solid-phase and liquid-phase myelin/oligodendrocyte glycoprotein in MS and EAE. 6. Tanuma N, Lalive P, Gardell J, Islar J, Menge T, Genain CP. Herpesvirus hominis causes autoimmune demyelination through de novo apoptotic mechanism on glial cells.
  • ABSTRACTS (selected) 1. Hauser SL, Lee-Parritz D, Nguyen MH, Massacesi L, Joshi N, Ferrante R, Hoffman K, Moseley M, Letvin NL, Genain CP. Myelin basic protein-reactive T-cells in normal peripheral blood are encephalitogenic. Neurology 44 (Suppl II) A 147. 1994. 2. Genain CP, Nguyen MH, Roberts T, Uccelli A, Moseley M, Hauser SL. Characterization of changes in cerebral white matter by magnetic resonance imaging and 1H spectroscopy during experimental allergic encephalomyelitis in primates. Neuroloy 44 (Suppl II) A 340. 1994. 3. Roberts TPL, Wong P, Stewart E, Nguyen MH, Hauser S, Genain C. MRI evaluation of cerebral white matter in a non-human primate model of experimental allergic encephalomyelitis. Proc of the Society of Magnetic Resonance, 2d Meeting, August 1994. 4. Genain CP, Nguyen MH, Faulds D, Uccelli A, Davis RL, Hedgpeth J, Hauser SL. Prevention of EAE in non human primates by a type IV phosphodiesterase inhibitor that suppresses tumor necrosis factor. J Neuroimmunol 54: 163. 1994. 5. Husted C, Nguyen MH, Hauser SL, Genain CP. Changes in myelin lipid fatty acid unsaturation during EAE in the common marmoset detected with carbon-13 magic angle spinning NMR spectroscopy. Neurology 45 (Suppl 4), A211. 1995. 6. Genain CP, Nguyen MH, Lees MB, Linington C, Hauser SL. Immune responses to myelin/oligodendrocyte glycoprotein are required for plaque formation during allergic encephalomyelitis in the common marmoset Callithrix Jacchus. Neurology 45 (Suppl 4), A210. 1995. 7. Genain CP, Nguyen MH, Lees MB, Linington C, Hauser SL. Immune responses to myelin/oligodendrocyte glycoprotein are required for plaque formation during allergic encephalomyelitis in the common marmoset Callithrix Jacchus. Neurology 45 (Suppl 4), A210. 1995. 8. Uccelli A, Nguyen MH, Hauser SL, Genain CP. The T-cell receptor repertoire in the common marmoset Callithrix Jacchus. Neurology 45 (Suppl 4), A210. 1995. 9. Genain CP, Nguyen MH, Linington C, Hauser SL. In common marmosets, immune responses to myelin/oligodendrocyte glycoprotein are required for autoimmune demyelination. 9th International Congress of Immunology, San Francisco. July 1995 10. Genain CP, Gritz L, Pannicali D, Letvin NL, Hauser SL. Inhibition of allergic encephalomyelitis in marmosets by vaccination with recombinant vaccinia virus encoding for myelin basic protein. Neurology 46 (Suppl.). 1996. 11. Genain CP, Belmar N, Abel K, Rosenberg D, Raine CS, Hauser SL. Suppression of Th1 responses in non-human primates exacerbates autoimmune demyelination. Society for Experimental Neuropathology; Biology of Disease Meeting. Brain Pathology 6: 351. 12. Genain CP, Belmar N, Abel K, Rosenberg D, Raine CS, Hauser SL. Suppression of Th1 responses in non-human primates exacerbates autoimmune demyelination. Society for Experimental Neuropathology; Biology of Disease Meeting. Brain Pathology 6: 351. 13. Genain CP, Abel K, Belmar N, Rosenberg DP, Raine CS, Hauser SL. Immune deviation worsens antibody-mediated experimental allergic encephalomyelitis in a non human primate. 121 st Annual Meeting of the American Neurological Association, October 1996. 14. Genain CP, Belmar N, Diaz-Villoslada P, Abel K, Hauser SL. Immune responses against myelin/oligodendrocyte glycoprotein in the common marmoset. Neurology 48: A115. 1997.
  • 15. Diaz-Villoslada P, Bartke, I, Unger J, Fischer S, Rosenberg D, Genain CP, Hauser SL. Recombinant human nerve growth factor prevents autoimmune demyelination in marmosets. Neurology 48; A 142-143. 1997. 16. Koehler NKU, Shao L, Genain CP, Hauser SL. Frequency and fine specificity of T cell clones reactive to myelin oligodendrocyte glycoprotein in a multiplex family with multiple sclerosis. Ann. Neurol. 42: 458. 1997. 17. Diaz-Villoslada P, Koehler NKU, Shih AC, Genain CP, Hauser SL. T cell responses to myelin oligodendrocyte glycoprotein and other myelin antigens in multiple sclerosis. Ann. Neurol. 43: 459A. 1997. 18. Diaz-Villoslada P, Koehler NKU, Shih AC, Genain CP, Hauser SL. T cell responses to myelin oligodendrocyte glycoprotein and other myelin antigens in multiple sclerosis. Ann. Neurol. 43: 459A. 1997. 19. Merrill JE, Genain CP, Parkinson JF, Medberry P, Halks-Miller M, DelVecchio V, Kardos S, Murphy SP. Inducible nitric oxide synthase and nitration of protein tyrosines in macrophages, glia and endothelial cells in MS and EAE. Society for Neuroscience. 1998. 20. Genain, CP, Cannella, B, Belmar, N, Hauser, SL, Raine, CS. Molecular mechanisms of autoimmune demyelination in marmosets. Neurology 50 (Suppl. 4): A424. 1998. 21. Genain, CP. The molecular basis for autoimmune demyelination: In situ detection of autoantibodies associated with myelin damage in multiple sclerosis. J. Neuroimmunol. 90: 5. 1998. 22. Genain, CP, Belmar, N, Diaz-Villoslada, P, Hauser, SL. Fine Specificities of T cell and B cell responses to myelin/oligodendrocyte glycoprotein in common marmosets. J. Neuroimmunol. 90: 34. 1998. 23. Raine, CS, Cannella, B, Belmar, N, Hauser, SL, Genain, CP. Antigen-specific antibody- mediated demyelination in experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). J. Neuropathol. Exp. Neurol. 57: 489. 1998. 24. Mohr, DC, Goodkin, DE, Marietta, P, Mayfield, SA, Boudewyn, AC, Waubant, E, Andersson, PB, Hauser, SL, Genain, CP. Relationship between treatment of depression and interferon-gamma in patients with multiple sclerosis. Neurology 50: A35. 1998. 25. Ouallet, J-C, Heald, N, Islar, J, Hauser, SL, Genain, CP. Detection of B-cells specific for the autoantigen myelin/oligodendrocyte glycoprotein using a sensitive immunogold- labeling assay. Neurology 52 (Suppl. 2): A337. 1999. 26. Ohler, B, Graf, K, Lemons, T, Coe, R, Jahangir, S, See, W, Genain, C, Husted, C. Alterations in membrane forming properties of myelin lipids may explain demyelinating process in multiple sclerosis. J. Neurochem. 72 (Suppl.): S15D.1999. 27. Genain, CP, Thornton, KH, Krishnan, VV, Mesleh, MF, Monique Cosman, M. Structural plasticity of a protein antigen implicated in the immunopathogenesis of multiple sclerosis. Ann. Neurol. 46(6): 936. 2000. 28. Ouallet, JC, Baumann, N, Hauser, SL, Genain, CP. Efficacy of intravenous soluble peptide therapies in non human primate experimental allergic encephalomyelitis. Neurology 54 (Suppl 3): A126. 2000. 29. von Büdingen, H-C, Hauser, SL, Genain, CP. Characterization of the B cell response to myelin/oligodendrocyte glycoprotein (MOG) in primate EAE. Immunology 2000 (The American Association of Immunologists). Seattle, WA May 12-16, 2000. 30. von Büdingen, H-C, Hauser, SL, Genain, CP. Molecular analysis of the antibody response against myelin oligodendrocyte glycoprotein in primate experimental autoimmune encephalomyelitis. Ann. Neurol. 48(3):A416. 2000. 31. von Budingen, H-C, Nabavi, C, Hauser, SL, Genain, CP. Diversity of the humoral immune response against myelin/oligodendrocyte glycoprotein in marmoset experimental allergic encephalomyelitis. Neurology 56 (Suppl 3) A466, 2001.
  • 32. Grenier, D, Pelletier, D, Lu, Y, Genain, C, Nelson, SJ, Goodkin, DE. 3-Dimensional Echo Planar Spectrocopy Imaging (3D-EPSI) in Multiple Sclerosis; a regional comparison of supratentorial brain versus corpus callosum area. Neurology 56 (Suppl 3) A237, 2001. 33. Henry, R, Pelletier, D, Grenier, D, Nelson, S, Majumdar, S, Genain, C, and Donald Goodkin. Diffusion Tensor Imaging and Lesion Load in MS. Diffusion Tensor Imaging and Lesion Load in MS. Neurology 56 (Suppl 3) A256, 2001. 34. Cox, DS, Pelletier, D, Genain, CP, Evangelista, A, Nelson, S, Majumdar, S, Goodkin, DE, Mohr, DC. Relationships between T1 and T2 Lesion Load, Magnetization Transfer Imaging, and 3[H]-Spectroscopy and Cognitive Functioning in Secondary Progressive Multiple Sclerosis. Neurology 56 (Suppl 3) A380, 2001. 35. Wendland, M, Martinez, S, Nelson, S, Majumdar, S, Dillon, WP, Hauser, SL, Genain, CP. Magnetic Imaging Resonance Characteristics of Antibody-Mediated Demyelination. Ann. Neurol. (Suppl 1) S37, 2001. 36. von Büdingen, H-C, Genain, CP, Villoslada, P, Hauser, SL. Epitope Recognition Influences Pathogencity of Autoantibodies Against the Myelin/oligodendrocyte Glycoprotein. Ann. Neurol. (Suppl 1) S26, 2001. 37. B. Della Gaspera, C. Delarasse, C. Lu, D. Rodriguez, F. Lachapelle, C. Genain, A. Dautigny, and D. Pham-Dinh. Alternative Splicing of the MOG Gene Across Species. J. Neuroimmunol. 118:88, 2001. 38. Villoslada, P, Abel, K, Goersches, R, Hauser, SL, Genain, CP. Repertoire Heterogeneity of MOG-reactive T cells in Naive Outbred Primates. J. Neuroimmunol. 118:48, 2001. 39. Ouallet, J-C, Tanuma, N, Hauser, SL, and Genain, CP. Effects Of Intravenous Soluble Peptide Therapies In Non Human Primate EAE. J. Neuroimmunol. 118:58, 2001. 40. Tanuma, N, Ouallet, J-C, von Büdingen,H-C, Hauser, SL, and Genain, CP. A Trial of Oral MOG and MOG-Derived Peptides in Marmoset EAE. J. Neuroimmunol. 118:60, 2001. 41. Ouallet, J-C, Hauser, SL, Genain, CP. Selective Expansion of Circulating B-Cells Specific for the Myelin/Oligodendrocyte Glycoprotein in Multiple Sclerosis. VIth International Congress of Neuroimmunology, Edinburg, Scotland, September 2001. Call for late abstract. 42. Genain CP, Fuhrmann A, Menge T, von Budingen H-C, Bae S, Swerdlin A, Evangelista A, Woo C, Pelletier D, Waubant E, Goodin D, Kita M, Zamvil S, Cree B, Goodkin D, Hauser S. Autoantibody Reactivity To Myelin/Oligodendrocyte Glycoprotein (MOG) Correlates With Progressive Forms Of Multiple Sclerosis. American Neurological Association (Work In Progress), New York, October 2002. 43. von Budingen H-C, Hauser SL, Fuhrmann A, Nabavi C, Genain CP. Functional diversity of antibodies against myelin oligodendrocyte glycoprotein in experimental autoimmune demyelination. Multiple Sclerosis, 8 (Suppl 1): S2. 44. von Budingen, H-C, Fuhrmann A, Ouallet, J-C, Tanuma N, Hauser SL, Genain, CP. Humoral autoimmunity against myelin/oligodendrocyte glycoprotein is a determining factor for phenotypic expression of inflammatory central nervous system demyelination. Neurology, 60:A218, 2003. 45. Menge T, von Buedingen HC, Bae SJ, Hauser SL, Genain CP. Time course of antibody responses to myelin proteins and galactocerebroside in marmoset experimental allergic encephalomyelitis and multiple sclerosis. Ann Neurol 2003;54:S38 included in MS poster walking tour. 46. von Buedingen HC, Hauser SL, Quallet JC, Tanuma N, Menge T, Genain CP. Epitope recognition differentially controls effector functions of myelin/oligo-dendrocyte
  • glycoprotein-specific autoantibodies and phenotypic expression of autoimmune demyelination. Ann Neurol 2003;54:S37 47. Tanuma N, Menge T, von Buedingen HC, Islar J, Martinez S, Weiner LP, Genain CP. A novel model to study the viral pathogenesis of multiple sclerosis after infection with human herpesvirus-6. Ann Neurol 2003;54:S47. 48. Genain CP, Buedingen HC, Menge T, Hauser SL. Restriction of humoral responses to conformational epitopes after exposure to the native myelin/oligodendrocyte glycoprotein polypeptide. Ann Neurol 2003;54:S60. 49. von Buedingen HC, Fuhrmann A, Quallet JC, Tanuma N, Menge T, Hauser SL, Genain CP. Humoral autoimmunity against myelin/oligodendrocyte glycoprotein is a determining factor for phenotypic expression of inflammatory central nervous system demyelination. Neurology 2003;60:A218. 50. Cree B, Lamb S, Chin A, Bonovich A, Islar J, Genain C. Tolerability and effects of rituximab (anti-CD20 antibody) in neuromyelitis optica (NMO) and rapidly worsening multiple sclerosis (MS). Neurology, 62 (Suppl 5), A492, 2004. 51. Swanson RA, Kauppinen TM, Genain CP. Poly (ADP-ribose) polymerase-1 is activated in plaques in the marmoset model of multiple sclerosis. Neurology, 62 (Suppl. 5), A439, 2004. 52. Menge T, von Budingen H-C, Hauser SL, Genain CP. Detection of anti- galactocerebroside antibodies by a new assay that is specific for patients with multiple sclerosis. Neurology, 62 (Suppl 5), A482, 2004. 53. Menge T, Lalive PH, von Budingen H-C, Cree B, Hauser SL, Genain CP. The anti- galactocerebroside antibody response as a novel biomarker for staging multiple sclerosis. Neurology 2005, 64 (Suppl 6), A270. 54. Lalive P, Menge T, Hauser S, Genain CP. Serum Neuronal Toxicity in Multiple Sclerosis. Neurology 2005, 64 (Suppl 6), A270. 55. Genain CP, Menge T, Lalive P, Morgan K, Islar J, Cree B, Pelletier D. Natalizumab Induced Immunosuppression in a Case of Progressive Multifocal Leukoencephalopathy. Abstract #228, American Neurological Association, 2005. 56. Menge T, von Buedingen H-C, Lalive P, Genain CP. Marmoset derived anti-myelin Fab fragments that uniquely stain within multiple sclerosis lesions. Abstract #234, American Neurological Association, 2005. 57. Menge T, Lalive P, Genain CP. Lack of reactivity against liquid-phase myelin/oligodendrocyte glycoprotein in multiple sclerosis sera. Abstract #236, American Neurological Association, 2005. 58. Lalive P, Menge T, Genain CP. Serum reactivity against native myelin/oligodendrocyte glycoprotein in multiple sclerosis. Accepted, American Neurological Association, 2005. 59. Lalive PH, Menge T, Hauser S, Genain CP. Serum IgG Reactivity Against MOG- Transfected Cells Is Selectively Increased In Specific Clinical Subtypes Of Multiple Sclerosis. American Society of Neurochemistry, Madison, WI, June 2005.
  • CURRENT RESEARCH PROGRAM AND INTERESTS 1. Neuroimmunology Laboratory (USCF) My research program focuses on understanding the pathological processes involved in human multiple sclerosis (MS), and on the development of novel therapeutic approaches to this disease. My laboratory has developed a sophisticated model of experimental allergic encephalomyelitis (EAE) in a small outbred New World primate, the common marmoset Callithrix jacchus (C. jacchus), which is highly reminiscent of human MS. The MS-like, primary demyelinating lesion in C. jacchus results from a complex immune response directed against several myelin antigens. While myelin- reactive T-cells are capable of mediating the inflammatory component, the presence of pathogenic antibody responses is required for demyelination. An important target for these antibodies is myelin oligodendrocyte glycoprotein (MOG), a surface-expressed protein of myelin. Autoantibodies specific for MOG have been directly identified in situ in contact with disintegrating myelin sheaths within areas of ongoing demyelination, not only in marmoset EAE, but also in lesions in human MS. We are investigating the mechanisms by which these autoantibodies promote demyelination. Preliminary experiments indicate that intact antibody is required, as opposed to F(ab)2 fragments, suggesting that pathogenicity is dependent upon functions supported by Fc fragments, for example complement or macrophage activation. It is possible to prevent demyelination in C. jacchus by administration of MOG-specific F(ab)2 fragments that competitively block the effect of the intact antibodies. The laboratory has employed a combinatorial approach to generate monoclonal Fab species specific for MOG that are being analyzed in terms of their immunoglobulin gene usage and their potential to competitively block the effects of demyelinating antibodies, both in vitro in MOG-expressing cell systems and in vivo in C. jacchus EAE. An attractive aspect of these marmoset studies is that the epitope specificities captured by our combinatorial libraries in MOG-immunized animals appear to be the ones represented within human anti-MOG repertoires, as demonstrated by competition between the human antibodies and the C. jacchus Fabs. If inhibition of antibody binding proves to be a valid paradigm for prevention of CNS damage in EAE, this approach could be rapidly translated into MS therapeutics. Having developed reliable assay systems to measure human antibody responses against myelin, I have recently began to extend these experimental concepts to studies of clinical immunology in MS. Being fortunate to belong to the MS Center Clinical and Research groups at UCSF, I have with colleagues secured funding to undertake the screening of the large family-based database and serum bank that are used for MS genetics studies. A separate study will sequentially assess the incidence of autoantibodies against MOG and other myelin constituents in serum and cerebrospinal fluid of patients presenting with a first, isolated demyelinating event (clinically isolated syndrome). The purpose of these studies is to investigate the genetic basis and potential prognostic significance of myelin-directed humoral responses in MS. A second important concept will be tested practically, namely the value of antibody measures as biomarkers of disease in MS: for example, can antibodies be used to predict disability, subtypes, response to treatment, etc., similar to the use made of certain autoantibodies in diabetes. Longer term, an extensive screening for other antibody targets than MOG and other biomarkers will be undertaken using combinatorial and microarray approaches.
  • In addition to antibodies, these clinical immunology studies are now being expanded to B cells, in particular characterization of the surface receptors and B cell subtypes, and to the effects of B cell ablation in MS on T cell function (see below). We also are developing cellular assays to study the functional, effector properties of antibodies present in human serum and cerebrospinal fluid and have recently successfully established a promising system to detect neuronal toxicity that appears to be specific for certain MS subtypes. Ultimately, I can envision that studies of humoral immunity and B cells will gain further importance and extend far beyond disorders traditionally thought to be antibody-mediated in the fields of Neurology and Neurosciences. As a transitional researcher and physician scientist, I am committed to bringing the product and experience of what is learned at the bench to the patient bedside. I am fortunate to have acquired a broad background in science and medicine, which allows me to interact well with multiple disciplines and integrate their advances in complex and comprehensive research projects that still, focus on benefiting MS. It is hoped that the above research will yield useful information for both clinicians and researchers, at an appropriate and exciting time: specific anti-B cell therapy (Rituximab) is available for hematologic malignancies, and trials in several autoimmune diseases including one in MS have started. I was just approved to conduct an Investigator initiated trial of Rituximab in Neuromyelitis Optica, sponsored by Genentech and BiogenIdec. We continue to exploit the resemblance between marmoset EAE and MS, and conduct pre-clinical studies, which could be rapidly applied to MS clinical trials. My program was recently enriched by the successful development of an experimental system in the marmoset to test susceptibility to human herpesvirus-6 infection and how infestation with this virus may lead to central nervous system demyelination. This is a unique system since it involves an outbred primate that is naïve to the virus but is highly susceptible to infection as it shares receptor for the virus that is highly homologous to humans. This work favorable consideration from the DANA Foundation for seed funding over the next 2 years, and is rapidly moving towards the discoveries of mechanistic links between viral infection and MS, and of biomarkers to diagnose this problem in patients and the risk of developing MS in children depending on when they had the exposure. I have personally designed, performed and interpreted all experiments establishing the role of autoantibodies in C. jacchus EAE. I am currently supervising all aspects of the complex and integrated research projects in my laboratory. I am responsible for the training of 2 funded post-doctorate, and one part-time student. I plan to add additional personnel to expand the herpesvirus project. The various facets of my research activities are fully integrated, from pre-clinical (marmoset models) to clinical (MS patients and clinically isolated syndromes), and vice- versa. I view the future of biomarkers for example, not as a single marker for MS but an array of parameters combining imaging, antibody, and other serologic marker to increase specificity and classify disease subtypes. Although the concept is still in development and relatively early, I envision that in the future we will be able to categorize and stratify the multiple disease currently combined under the term “MS” into “disease subtypes” defined by the markers of immunopathology, clinical presentation and prognosis. This
  • approach is highly innovative, and I expect that when this information will become available, it will afford the design of better and less toxic treatments for MS. 2. Summary of collaborative efforts Extensive efforts of collaborations, both intramural and extramural have occurred, are ongoing or are being initiated that tremendously enhance the scope of my research program. Highlighting just a few of these, I work/have worked with the following investigators and institutions: Extramural: - Drs. Henry McFarland, Michael Lenardo and Hugh McFarland (National Institutes of Health, Bethesda.MD). I have helped these investigators establish the marmoset EAE model in their institution, and procured them with advice and reagents to conduct studies of efficacy of a tolerogenic protein (MP4). My laboratory has performed the antibody reactivity assays that allowed the discovery of epitope spreading of antibody responses to MOG in that system. - Dr. Francois Villinger (Emory University, Atlanta, GA) continues to collaborate with my laboratory in order to study the immunology of the marmoset system, and develop primer and antibody reagents useful for primate studies. - Dr. Cedric Raine (Bronx, NY) performs detailed ultrastructural analyses of demyelination and its relationship with autoantibodies. It is with his expertise in morphology that we have discovered the deposition of anti-MOG antibody in MS lesions. - The Lawrence Livermore National Laboratories (Drs. Cosman, Balborn and Rupp), and the Biochemical Engineering laboratory (Neuroscience Research Institute, University of California, Santa Barbara -Dr. Cynthia Husted), currently study the molecular interactions between antibody, MOG, and whole myelin membranes. Whereas published crystallographic studies have so far involved only rodent MOG (rat and mouse), I believe that there is more relevance to studies of the human protein. Our recombinant marmoset Fab fragments show high affinity for human MOG (108 or greater), and further, do not compete for binding with several murine monoclonal anti-MOG IgGs unlike natural human anti-MOG IgGs. There are several interspecies substitutions in the MOG sequence that appear to define antibody binding sites that are unique to the higher primate species including man. The laboratory has just recently, been successful in generating human recombinant MOG proteins that are highly soluble in aqueous buffers at neutral pH, and crystallization experiments are underway. Information derived from these studies will allow rational design of second and third generations of antibody inhibitors. - Drs. Isobel Scarisbrick, Moses Rodriguez and the MS group at the Mayo Clinic, Rochester, MN, are investigating the roles of a newly discovered, CNS specific protease that appears up-regulated in MS and EAE and is capable of directly injuring myelin by degradation of myelin such as MOG and myelin basic protein.
  • - Drs. William Robinson and Lawrence Steinman (Stanford University) have developed a novel system for high throughput studies of antibody reactivity in EAE. I have provided Dr. Robinson with reagents and peptides to construct his antibody arrays, and have an ongoing collaboration with his laboratory and that of Dr. Steinman to extend these studies to human MS. This effort is NIH and NMSS funded. - Dr. Lisa Barcellos was part of the UCSF MS Genetics study group and has recently relocated at the University of Berkeley, CA. In coordination with my collaborations with Drs. Hauser and Oksenberg, I continue an open collaboration with Lisa for statistical analyses of our antibody profile screen in the UCSF genetics serum repository. - Drs. Jean Merrill and Karen Chandross (Aventis Pharmaceuticals) have a very strong collaboration with my team. We have completed acquisition of tissue samples from a large study of marmoset EAE, which will be analyzed for CNS gene expression using gene chips microarrays. We are now further developing these studies to focus on genes involved in CNS remyelination and repair, as well as to find useful non-invasive biomarkers of CNS damage and repair. - Drs. Jacob Israelashvili and Joseph Zazadzinski (University of Santa Barbara, CA) are top notch specialists of biomembrane physics, and are studying the effect of changes in myelin composition that occur in MS and marmoset EAE on myelin membrane distortion. Two manuscripts that describe a basis to physically explain myelin disintegration actually observed in the lesions of marmoset EAE have resulted from this collaboration. The study of forces that lead to myelin fragilization and distorsion as seen in MS (Dr. Raine’s work), is unique in the MS field, intriguing and promising because chemical agents that are not toxic and modify these forces in a way that could restore the intact myelin structure are already available for treatment of human disorders (to replace surfactant in premature infants, for example). If the concept is valid, these agents which do not carry the risks associated with medications that manipulate the immune system could be useful for CNS repair, not only in MS but other demyelinating, and dysmyelinating disorders such as neonatal ischemia, and inborn errors of metabolism. Studies of myelin lipid composition and their changes in disease or induced by treatment, can now be beautifully and accurately studied in vivo and non-invasively by high resolution MRI and proton, phosphorus or carbon spectroscopy. - Dr. Danielle Pham-Dinh is a Faculty member and molecular biologist in the Department of developmental Neurosciences at the Pitie-Salpetriere, Paris, France. We have several ongoing two-way collaborations with studies of the encephalitogenic properties of myelin from MOG- and PLP-knock-out mice, expression of MOG in thymus and peripheral nervous system, and alternative splicing of the MOG gene in higher mammal species. - Dr. Jack Antel (Montreal neurological Institute, Quebec, Canada) has developed an in vitro system for cultures of adult human oligodendrocytes. We are collaborating on studies of antibody binding and their toxic properties in this system.
  • - Dr. Anne Cross (Washington University, St Louis, MI) is currently pursuing a small trial of anti-CD20 therapy funded by the National MS Society (NMSS). I am a collaborator in Dr. Cross’ trial for measuring the effects of B cell depletion on antibody responses. - Drs. Kathleen Hawker, Michael Racke, Nancy Monson, and Eliot Frohman (University of Texas, Southwestern Medical Center, Dallas, TX) are conducting and planning studies of the effects of rituximab on B cell in primary progressive MS. I am a collaborator of these studies to assess the effects on antibody levels in blood and CSF. - I have numerous other collaborations at other Academic and Industry sites. I have provided research reagents and advice to several dozens of other Investigators. UCSF campus collaborations Laboratory - Drs. Steinunn Baekkeskov and Juan-Carlos Jaume. I have provided these colleagues with advice and technical support in their attempts in producing an outbred model of T cell-mediated diabetes in marmosets. Dr. Jaume is also currently pursuing attempts to produce autoimmune thyroiditis in this species. - Similarly, I have very active and involved collaborations with Drs. Sarah Nelson, Sharmila Majumbdar, Roland Henry (UCSF-MRSC) Michael Wendland, William Dillon (UCSF-Radiology). We perform in vivo imaging studies in C. jacchus EAE, in order to establish pathological and immunopathological correlates of MRI findings in MS. This research will not only improve our understanding of this disease and accelerate the development of efficient and appropriately targeted therapies for autoimmune demyelination. The research is tied to the clinical side through my open collaboration with Dr. Daniel Pelletier (UCSF MS Center). I am also beginning to explore the feasibility of molecular imaging to track immune cells and antibodies in the marmoset model. - I have assisted Dr. Jay Levy and his laboratory in attempts to develop a model of Kaposi’s sarcoma induced by human herpesvirus (HHV)-8 in the marmoset. In fact, although the work with HHV-8 was not pursued due to lack of funding, it is through the advice and collaboration of Dr. Levy that the laboratory has now successfully produced the HHV-6 mediated MS model. His letters of support have greatly contributed to funding for this work at the current level. - I am pursuing a collaboration with Dr. Ray Swanson (UCSF-Neurology), who has recently discovered that the DNA-repairing enzyme poly-ADP-ribose polymerase I (PARP) is strikingly up-regulated in lesions of marmoset EAE. We are hoping to develop this research as a path to novel MS therapeutics. - I am assisting Dr. Scott Zamvil in his efforts to understand the effects of statins on the immune system and CNS, and to translate this principle into clinical applications and MS treatments. In fact, I am the one that suggested the best target
  • group for this application –the clinically isolated syndromes or first demyelinating event- at a research meeting with the MS center investigators in early 2001. I have advised fellows in his laboratory for experiments of EAE and writing manuscripts. We are also conducting comparative studies of class II transactivator and its promoters in several primate species. - I have recently initiated a planned collaborative project with Dr. Krys Bankievicz (UCSF Neurosurgery) for studies of remyelination using human embryonic stem cells and neurospheres, as well as viral vectors for the delivery of neural growth factors in the marmoset EAE system. Clinical studies and clinical trials - I am as outlined above engaged in an extensive collaborative effort with Drs. Oksenberg and Hauser to decipher the significance and genetic basis of anti- myelin antibody responses in MS. Both are co-Investigators on my NMSS and NIH grants. - Dr. Daniel Pelletier is co-Investigator for the imaging aspects on my funded research that investigates correlations between MRI and antibody measurements in MS patients. It is my hope that in combination with the results of the marmoset studies, we will quickly be able to validate non-invasive biomarkers of disease for human MS in addition to antibody profiling, that will be helpful to Neurologists for practical management of their patients. - Because I have a background and interest in neuroendocrinology and its ties to immune and CNS systems, I have collaborated with Dr. David Mohr in studies of MS that investigate the impact of stress and depression in this disease. We are hoping to move these studies to a larger scale and bring psycho- neuroimmunology to the clinical MS field. - In October 2002, I was approached by Clinical Scientists from Genentech regarding the possibility of launching a program of anti-CD20 therapy (rituximab) for MS. As a result of these discussions, the company is currently planning 2 large multicenter trials of monotherapy with rituximab (Rituxan) in relapsing remitting MS and primary progressive MS that it plans to fully fund, and has asked my laboratory to conduct immunological studies for these trials. - I have personally secured funding to begin 1 clinical trial, in collaboration with investigators at the UCSF MS Center. Dr. Bruce Cree and I will soon begin a phaseI/II trial in spino-optical MS (neuromyelitis optica, NMO) We have received final approval from FDA, our IRB and the GCRC at UCSF and are now enrolling for this trial, the largest one of the current UCSF MS Center trials (20 patients), although not placebo controlled. A muticenter, national and international trial of NMO is in the planning for 2006, including Japanese and European investigators and investigators as the Mayo Clinic (Drs. Weishenker and Wingerchuk). We are hoping to accomplish the establishment of the first and only word-wide repository of data and biological samples for this prototypal, antibody and humoral mediated form of MS. My group will be leading this effort.
  • On the next page, are a short paragraph, and a diagram that recapitulate the innovative aspects of my research program.
  • Summary of research interests, innovative efforts, and future milestones: 1. Discovery and validation of the ‘humoral” concept of MS or some of its subtypes, from experimental work in the marmoset to clinical trials that are currently enrolling (rituximab in relapsing remitting MS, primary progressive MS and Neuromyelitis Optica). 2. Extension to characterization of the very complex, antigen-specific antibody responses (MOG) that appear sharply dichotomized in terms of their pathological functions, depending on epitope recognition. A consequence of this will be the need, similar to T cell work, to specifically target certain antibody and B cell populations for refining B cell ablation or antibody neutralization treatments in the future. 3. Discovery and exploration of human herpesvirus 6 links to the etio-pathogenesis of MS, which will hopefully achieve the following: discovery of causal mechanisms, establishment of biomarkers to identify individuals at risk to develop this complication, and longer term, discovery of a vaccine to eradicate MS. 4. Discovery and pursuit of various means to promote neuroregeneration and neuroprotection. 5. Discovery of biomarkers (serum and imaging, eg., mostly non invasive and frequently obtainable) to diagnose, predict and prognose MS and its subtypes, which will lead to better and safer treatments for this disease.
  • RESEARCH SUPPORT PAST: 07/01/91-06/30/94. National Multiple Sclerosis Society. Advanced Fellowship 1027-A1. The T cell repertoire in primate experimental allergic encephalomyelitis. Stipend $ 124,480. 07/01/94-06/30/95. Radiology Research Foundation (UCSF). MR-Spectroscopy and magnetization transfer during experimental allergic encephalomyelitis in common marmosets. $ 14,600. 09/01/96-08/31/97. Nancy Davis Center Without Walls. Mechanisms of Autoimmune Demyelination in non Human Primates. Direct costs $ 50,000. 12/01/96-11/30/97. Boehringer-Mannheim, Inc. "Efficacy of Nerve Growth Factor in the Prevention and Treatment of Acute Experimental Allergic Encephalomyelitis". Direct costs $ 109,090. 05/18/98-05/18/99. Otsuka America Pharmaceuticals. "Therapeutic efficacy of OPC-8212 (Vesnarinone) in autoimmune demyelination. Direct costs $ 120,907. 07/01/99-06/30/00. Individual Investigator Research Grant Application, University of California Academic Senate. Award 430000-19900-502797. MRI
  • correlates of autoimmune demyelination in non human primates. $ 20,000. 07/01/96-06/30/01. National Multiple Sclerosis Society. Harry Weaver Junior Faculty Award JF 2087-A-2. "The Immune Pathogenesis of a Multiple Sclerosis-Like Lesion". Direct costs $ 515,241. 05/01/95-05/01/01. Principal Investigator, Industry (Biogen). ORA Project No. 95017489. "An open-label study of interferon beta 1-a (recombinant human interferon beta) in subjects with multiple sclerosis". Direct costs $332,630. 08/01/01-07/31/03. Principal Investigator, Industry (Aventis Pharmaceuticals). ORA project # 01029379. "CNS Gene expression during EAE in C. jacchus". Direct costs $254,885. 10/01/99-09/30/03. Principal Investigator, National Multiple Sclerosis Society. Regular Grant RG 2655B6/1. "monitoring MS lesions with serial MRI, H-MRSI and MTI. Predicting magnetic resonance activity and sustained progression of disability in early RRMS". Direct costs $440,883. 05/01/03-04/30/04. Principal Investigator, National Multiple Sclerosis Society. Pilot Grant PP 0916. “In vivo models for replication and pathogenesis of human herpes virus”. Direct costs $ 40,000. 04/01/03-03/31/05. Principal Investigator, National Multiple Sclerosis Society. RG 3438-A-7. “Pathophysiological significance of autoantibodies to myelin”. Direct costs $317,554. 04/01/04-03/31/05. Principal Investigator, Industry (Sanofi Aventis). “Biomarkers for tissue damage and repair in central nervous system autoimmune demyelination”. Direct costs $67,000. ACTIVE: 03/01/03-02/28/08. Co-investigator, National Institutes of Health (NIAID) RO1 AI43073-11. "Mechanisms of EAE in non human primates" (Stephen L. Hauser, Principal Investigator). Direct costs $ 1,164,868. 10/01/01-09/30/05. Principal Investigator, National Multiple Sclerosis Society. Regular grant RG 3320-A-3. "Molecular analysis of demyelinating antibody responses in EAE". Direct costs $459,756. 08/01/03-07/31/07. Principal Investigator, National Institutes of Health (NINDS) RO1 NS 46678-01. “Genetic and MRI correlates of humoral immunity to myelin”. Direct costs $ 948,123. 10/01/03-09/30/06. Principal Investigator, The DANA Foundation. Pathogenesis of Autoimmune Demyelination Mediated by Human herpesvirus-6 Infection. Direct costs $300,000. 01/01/05-12/31/07. Principal Investigator, Industry (Genentech-Biogenidec). “Open label study of safety and tolerability of Rituximab in neuromyelitis optica, recurrent transverse myelitis and recurrent bilateral simultaneous optic neuritis”. Direct costs $272,054. 12/01/04-11/30/05. Principal Investigator, Industry ( Serono, Inc). Effects of Mitoxantrone on Humoral Immunity in Primary Progressive Multiple Sclerosis (PPMS). Direct costs $100,000.
  • PENDING: 12/01/05-11/30/07. Principal Investigator, National Institutes of Health. R21.” Novel models for viral pathogenesis of multiple sclerosis”. Direct costs $275,000 requested. 12/01/05-11/30/10. Co-Investigator, National Institutes of Health (PI: Jacob Israelachvili, University of California, Santa Barbara). RO1. “Control of CNS membrane structure in demyelinating disorders”. Direct costs $1,000,000 requested. SUPPORT FOR FELLOWS AND TRAINEES PAST: 07/01/99-06/30/02: National Multiple Sclerosis Society. Advanced Fellowship Award to Hans-Christian von Büdingen, MD. FA 1342-A-1. "Diversity of the antibody repertoire in non human primates". Direct costs $31,281 (Year 01, terminated on 09/30/99). 07/01/00-06/30/02: National Multiple Sclerosis Society. Fellowship Award to Naoyuki Tanuma, MD, PhD. FG 1406-A-1. Immunologic tolerance and cytokine- based therapies in EAE. Direct costs $61,695 (terminated January 19, 2002 due to Dr. Tanuma’s family emergency). 10/01/99-09/30/02: National Institutes of Health. NRSA to Hans-Christian von Büdingen, MD. F32 NS109-96 "Antibody Responses Against MOG in Marmoset EAE". Direct costs $120,084. 07/01/01-06/30/04: National Multiple Sclerosis Society. Fellowship Award to Til Menge, MD. FG 1476-A-1. Structural Basis for Antibody responses to Myelin/oligodendrocyte Glycoprotein. Direct costs $132,701. 12/01/03-11/30/05: National Multiple Sclerosis Society. Fellowship Award to Patrice Lalive d’Epinay, MD. FG 1562-A-1. $111,984.