Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE).
BACKGROUND
Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis.


RESULTS
A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.


CONCLUSIONS
These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.
The Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
Derek J
DJ
Abbott
J Lori
JL
Blanchfield
David A
DA
Martinson
Sean C
SC
Russell
Najla
N
Taslim
Alan D
AD
Curtis
Mark D
MD
Mannie
D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D006023:Glycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D016056:Immunodominant Epitopes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009420:Nervous System / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology* / Q000627:therapeutic use
D001324:Autoantigens; D006023:Glycoproteins; D016056:Immunodominant Epitopes; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D022223:Vaccines, Subunit; C517781:myelin oligodendrocyte glycoprotein (34-56); D016178:Granulocyte-Macrophage Colony-Stimulating Factor