In this proposal, we will study the immune response responsible for a unique form of experimental allergic encephalomyelitis (EAE) in a nonhuman primate. Following immunization with whole white matter in adjuvant, Callithrix jacchus (C. jacchus) marmosets develop a relapsing-remitting disease and prominent acute and chronic demyelination closely resembling human multiple sclerosis (MS). In the initial funding period, we have found that the MS-like lesion appears to result from a complex immune response requiring both encephalitogenic T-cells and pathogenic antibody. T-cells reactive against myelin basic protein (MBP) are capable of mediating the inflammatory component of marmoset EAE. Demyelination, on the other hand, is antibody mediated. We have also found that the quantitatively minor myelin protein, myelin oligodendrocyte glycoprotein (MOG), is an important antigen in this system, as immunization against MOG or passive transfer of anti-MOG antibody reproduces the core features of the disease. We propose to utilize a number of state-of-the-art technologies to fully characterize the cellular and humoral immune response against MOG in C. jacchus, to study the role of determinant spreading in chronic disease, and to identify the antigen targets of demyelinating antibody and the mechanisms of antibody mediated demyelination. These studies will provide a foundation for immunotherapy based upon an understanding of the antigens and the immune mechanisms responsible for a complex autoimmune disease. ? ? MS affects approximately 350,000 Americans and is thus, excluding trauma, the most important acquired neurologic disease arising in early- to mid-adulthood. Because MS affects women more often than men, it is a particularly significant women's health problem. It is essential that useful model systems for this disabling disease be developed and studied. Advantages of the C. jacchus model for the study of MS include its clinical and pathologic similarity to MS, the natural chimerism of marmosets that permits adoptive transfer of T-cells, and the extensive conservation of immune and nervous system genes and proteins between human and nonhuman primate species. Equally important, work to date in C. jacchus has found that a diverse immune response to more than one antigen appears to be responsible for the MS-like lesion, a finding that parallels emerging concepts of the pathogenesis of human MS. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI043073-15
Application #
7201597
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Esch, Thomas R
Project Start
1992-06-01
Project End
2008-02-29
Budget Start
2006-03-03
Budget End
2007-02-28
Support Year
15
Fiscal Year
2006
Total Cost
$368,559
Indirect Cost
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
071882724
City
San Francisco
State
CA
Country
United States
Zip Code
94107
Menge, Til; von Budingen, Hans-Christian; Lalive, Patrice H et al. (2007) Relevant antibody subsets against MOG recognize conformational epitopes exclusively exposed in solid-phase ELISA. Eur J Immunol 37:3229-39
von Budingen, H-Christian; Menge, Til; Hauser, Stephen L et al. (2006) Restrictive and diversifying elements of the anti-myelin/oligodendrocyte glycoprotein antibody response in primate experimental allergic encephalomyelitis. Immunogenetics 58:122-8
Lalive, Patrice H; Menge, Til; Delarasse, Cecile et al. (2006) Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis. Proc Natl Acad Sci U S A 103:2280-5
Menge, Til; Lalive, Patrice H; von Budingen, Hans-Christian et al. (2005) Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis. J Allergy Clin Immunol 116:453-9
von Budingen, Hans-Christian; Hauser, Stephen L; Ouallet, Jean-Christophe et al. (2004) Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination. Eur J Immunol 34:2072-83
von Budingen, Hans-Christian; Hauser, Stephen L; Fuhrmann, Antje et al. (2002) Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination. Proc Natl Acad Sci U S A 99:8207-12
Villoslada, P; Abel, K; Heald, N et al. (2001) Frequency, heterogeneity and encephalitogenicity of T cells specific for myelin oligodendrocyte glycoprotein in naive outbred primates. Eur J Immunol 31:2942-50
von Budingen, H C; Hauser, S L; Nabavi, C B et al. (2001) Characterization of the expressed immunoglobulin IGHV repertoire in the New World marmoset Callithrix jacchus. Immunogenetics 53:557-63
Genain, C P; Hauser, S L (2001) Experimental allergic encephalomyelitis in the New World monkey Callithrix jacchus. Immunol Rev 183:159-72
von Budingen, H C; Tanuma, N; Villoslada, P et al. (2001) Immune responses against the myelin/oligodendrocyte glycoprotein in experimental autoimmune demyelination. J Clin Immunol 21:155-70

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