Intrinsic and induced regulation of the age-associated onset of spontaneous experimental autoimmune encephalomyelitis.
Multiple sclerosis is characterized by perivascular CNS infiltration of myelin-specific CD4(+) T cells and activated mononuclear cells. TCR transgenic mice on the SJL background specific for proteolipid protein (PLP)(139-151) develop a high incidence of spontaneous experimental autoimmune encephalomyelitis (sEAE). We examined the intrinsic mechanisms regulating onset and severity of sEAE. CD4(+) T cells isolated from the cervical lymph nodes, but not spleens, of diseased 5B6 transgenic mice are hyperactivated when compared with age-matched healthy mice and produce both IFN-gamma and IL-17, indicating that the cervical lymph node is the initial peripheral activation site. The age-associated development of sEAE correlates with a decline in both the functional capacity of natural regulatory T cells (nTregs) and in PLP(139-151)-induced IL-10 production and a concomitant increase in IL-17 production. Anti-CD25-induced inactivation of nTregs increased the incidence and severity of sEAE. Conversely, induction of peripheral tolerance via the i.v. injection of PLP(139-151)-pulsed, ethylcarbodiimide-fixed APCs (PLP(139-151)-SP) inhibited the development of clinical disease concomitant with increased production of IL-10 and conversion of Foxp3(+) Tregs from CD4(+)CD25(-) progenitors. These data indicate that heterogeneous populations of Tregs regulate onset of sEAE, and that induction of peripheral tolerance can be exploited to prevent/treat spontaneous autoimmune disease.
Zhang
Hong
H
Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University, Chicago, IL 60611, USA.
Podojil
Joseph R
JR
Luo
Xunrong
X
Miller
Stephen D
SD
D000375:Aging / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology* / Q000517:prevention & control; D005260:Female; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D012720:Severity of Illness Index; D013997:Time Factors
D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)
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