Experimental allergic encephalomyelitis (EAE), an inflammatory disease of the central nervous system (CNS), is used as an animal model for human multiple sclerosis (MS). Demyelination and cell infiltration within the CNS are characteristic features associated with both EAE and MS. The involvement of the immune system in these diseases is beyond doubt and both EAE and MS are viewed as autoimmune diseases. Myelin-specific T lymphocytes display an increased frequency in MS patients and their animal counterparts transfer EAE into naive mice or rats. The implication of T lymphocytes in this form of CNS disease is well accepted and approaches targeting modulation of these aggressive cells are being considered as strategies to suppress the disease. Administration of antigen into animals without adjuvant induces inactivation rather than priming of immune responses. The absence of adjuvant leads to a lack of the inflammatory stimuli required for up-regulation of costimulatory molecules on antigen presenting cells (APCs). Under these circumstances, presentation will be carried out by APCs expressing minimal costimulatory molecules leading rather to tolerization of T cells. Self-peptides free of adjuvant have been used for modulation of autoreactive T cells and success has been met in animals. However, in humans repetitive injections were required leading to allergic reactions and in some cases premature termination of clinical trials. Genetic insertion of self-peptides into the variable region of immunoglobulins (Igs) generates Ig-self-peptide chimeras that would be more resistant to degradation and vehicle the peptides into APCs via Fcgamma receptors (Fc(Rs). Within the APC, the self-peptide is cleaved from the chimera, and access newly synthesized major histocompatibility complex (MHC) molecules. Consequently, peptide delivery on Igs magnifies presentation compared to free peptide. Aggregation of Igs cross-links FcgammaRs on APCs and triggers the production of IL-10. Since Igs are autologous proteins they do not up-regulate the expression of costimulatory molecules on APCs when injected into animals in saline. Consequently, delivery of self-peptides by aggregated Igs will lead to effective presentation of self-peptides by APCs that would be producing IL-10 and lacking costimulatory molecules. We hypothesize that broad and effective suppression of diverse T cell specificities will be the outcome of this presentation. To test this hypothesis, we propose to engineer myelin peptides into Igs, and evaluate the resulting Ig-myelin chimeras for bystander suppression of diverse autoreactive T cells and therapy of forms of EAE resembling circumstances of human MS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037406-07
Application #
7022200
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2000-01-01
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
7
Fiscal Year
2006
Total Cost
$295,705
Indirect Cost
Name
University of Missouri-Columbia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Olanow, C Warren; Kieburtz, Karl; Odin, Per et al. (2014) Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 13:141-9
Amara, Amy W; Standaert, David G (2013) Metabolomics and the search for biomarkers in Parkinson's disease. Mov Disord 28:1620-1
Yokoi, Fumiaki; Dang, Mai T; Zhou, Tong et al. (2012) Abnormal nuclear envelopes in the striatum and motor deficits in DYT11 myoclonus-dystonia mouse models. Hum Mol Genet 21:916-25
Divekar, Rohit D; Haymaker, Cara L; Cascio, Jason A et al. (2011) T cell dynamics during induction of tolerance and suppression of experimental allergic encephalomyelitis. J Immunol 187:3979-86
Zhang, Jinping; Lee, Sang-Myeong; Shannon, Stephen et al. (2009) The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119:3048-58
Yu, Ping; Haymaker, Cara L; Divekar, Rohit D et al. (2008) Fetal exposure to high-avidity TCR ligand enhances expansion of peripheral T regulatory cells. J Immunol 181:73-80
Bell, J Jeremiah; Ellis, Jason S; Guloglu, F Betul et al. (2008) Early effector T cells producing significant IFN-gamma develop into memory. J Immunol 180:179-87
Bell, J Jeremiah; Divekar, Rohit D; Ellis, Jason S et al. (2008) In trans T cell tolerance diminishes autoantibody responses and exacerbates experimental allergic encephalomyelitis. J Immunol 180:1508-16
Yu, Ping; Gregg, Randal K; Bell, J Jeremiah et al. (2005) Specific T regulatory cells display broad suppressive functions against experimental allergic encephalomyelitis upon activation with cognate antigen. J Immunol 174:6772-80
Bell, J Jeremiah; Min, Booki; Gregg, Randal K et al. (2003) Break of neonatal Th1 tolerance and exacerbation of experimental allergic encephalomyelitis by interference with B7 costimulation. J Immunol 171:1801-8

Showing the most recent 10 out of 13 publications