title: IL-4, IL-10, IL-13, and TGF-beta from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is induced in the SJL/J mouse by adoptive transfer of activated proteolipid protein peptide (PLP) 139-151-specific Th1 cells. T cells responding to altered peptide ligands (APL) of PLP, previously shown to induce Th2 differentiation and regulate disease in PLP-immunized mice, do not transfer EAE. However, the exact mechanism of disease regulation by APL-specific T cells has not been elucidated. In this report, we show that 1F1, a Th2 clone specific for an APL of PLP139-151 can prevent adoptive transfer of EAE when cocultured with PLP-encephalitogenic spleen cells (PLP-spleen). Cytokines from activated 1F1 cells were detected by hybridization of mRNA to oligonucleotide arrays (DNA chip) and by ELISA. The Th2 cytokines found to be present at the highest protein and mRNA levels were evaluated for their role in suppression of adoptive transfer of EAE from PLP-activated spleen cell cultures. Abs to individual cytokines in 1F1 PLP-spleen cocultures suggested that IL-4, IL-13, and TGF-beta played a significant role in suppressing EAE. Abs to the combination of IL-4, IL-10, IL-13, and TGF-beta completely neutralized the protective effect of 1F1. Addition of Th2 cytokines to PLP-spleen cultures showed that IL-13 and TGF-beta were each individually effective and low levels of IL-4 synergized with IL-13 to inhibit disease transfer. IL-5, IL-9, and IL-10 had little or no effect whereas GM-CSF slightly enhanced EAE. Our results demonstrate that Th2 cytokines derived from APL-specific Th2 cells can effectively down-regulate the encephalitogenic potential of PLP-spleen cells if present during their reactivation in culture.
authors.affiliation: Genetics Institute, Cambridge, MA 02140, USA. dyoung@genetics.com
authors.forename: D A
authors.initials: DA
authors.lastname: Young
authors.forename: L D
authors.initials: LD
authors.lastname: Lowe
authors.forename: S S
authors.initials: SS
authors.lastname: Booth
authors.forename: M J
authors.initials: MJ
authors.lastname: Whitters
authors.forename: L
authors.initials: L
authors.lastname: Nicholson
authors.forename: V K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: M
authors.initials: M
authors.lastname: Collins
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004338:Drug Combinations; D004357:Drug Synergism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018793:Interleukin-13 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D008024:Ligands; D018991:Myelin Proteolipid Protein; D009842:Oligopeptides; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C435023:myelin proteolipid protein (139-151); D016753:Interleukin-10; D015847:Interleukin-4