title: Tolerogenic forms of auto-antigens and cytokines in the induction of resistance to experimental allergic encephalomyelitis.
abstract: Resistance to experimental allergic encephalomyelitis (EAE) induction by homogenized myelin (MSCH) in complete Freund's adjuvant (CFA) and pertussigen (P) in SJL mice was seen 1 week after intravenous injection of PLP 139-151 coupled to spleen cells (PLP-ECDI-SP). Although this resistance could be transferred by spleen cells enriched for CD8+ T cells and thus had a component of immunoregulatory T cells, it was primarily due to anergy, as it was reversible by four daily injections of interleukin (II)-2 starting 3 days after the PLP-ECDI-SP. Earlier treatment with IL-2 did not reverse the tolerance. In view of the known higher sensitivity to anergy induction of Th1 than of Th2 cells, a change in the cytokine balance in the response to MSCH+CFA after anergy induction might be responsible for the resistance to EAE induction. The effect of treatment with cytokines alone on induction of EAE was therefore also determined. Short-term (1-2 weeks) daily pretreatment with IL-2 (4000 U) or TGF-beta 2 (1 micrograms) somewhat decreased the susceptibility to subsequent EAE induction, but IL-4 (5 ng), IL-10 (5 micrograms) or IL-12 (50-200 ng) had no effect under those conditions, even if low doses of PLP were injected simultaneously. Daily injections of IL-4 over an 8-week period prior to immunization, however, significantly lowered the incidence of EAE. Simultaneous injections of IFN-gamma (2000 U/day) completely abolished this effect of IL-4. The effect of these cytokines administered immediately after the immunization with MSCH + CFA + P was also examined. As shown earlier, TGF-beta 2 (100-1000 ng/day) caused a marked protection when it was given intraperitoneally on days 5-9 after injection of MSCH + CFA. IL-4 (5 ng/day), in contrast, was very protective when administered on days 0-4 and less so when given on days 5-9 or even on days 0-12. IL-10 (1 microgram/day) was not protective under these conditions and IL-12 (50 ng/day) significantly increased the severity and mortality of EAE when given on days 0-4 after MSCH + CFA.
authors.affiliation: Department of Pathology, New York University Medical Center, NY 10016, USA.
authors.forename: L
authors.initials: L
authors.lastname: Santambrogio
authors.forename: G M
authors.initials: GM
authors.lastname: Crisi
authors.forename: J
authors.initials: J
authors.lastname: Leu
authors.forename: G M
authors.initials: GM
authors.lastname: Hochwald
authors.forename: T
authors.initials: T
authors.lastname: Ryan
authors.forename: G J
authors.initials: GJ
authors.lastname: Thorbecke
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects; D007376:Interleukin-2 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D009185:Myelin Proteins / Q000276:immunology / Q000494:pharmacology; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments / Q000494:pharmacology
chemical_list: D001324:Autoantigens; D007376:Interleukin-2; D007378:Interleukins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D005620:Freund's Adjuvant