title: RTL551 treatment of EAE reduces CD226 and T-bet+ CD4 T cells in periphery and prevents infiltration of T-bet+ IL-17, IFN-γ producing T cells into CNS.
abstract: Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1-5 daily injections of RTL551 (two-domain I-A(b) covalently linked to MOG-35-55 peptide), but not the control RTL550 ("empty" two-domain I-A(b) without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen. Concomitantly, RTL551 selectively reduced CNS inflammatory lesions, absolute numbers of CNS infiltrating T-bet expressing CD4+ T-cells and IL-17 and IFN-γ secretion by CNS derived MOG-35-55 reactive cells cultured ex vivo. These novel results demonstrate that a major effect of RTL therapy is to attenuate Th1 specific changes in CD4+ T-cells during EAE and prevent expansion of effector T-cells that mediate clinical signs and CNS inflammation in EAE.
authors.affiliation: Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon, United States of America.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Sinha
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Miller
authors.forename: Sandhya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D000098815:T-bet Transcription Factor
chemical_list: D015704:CD4 Antigens; D020381:Interleukin-17; C542327:RTL551 protein; D011993:Recombinant Fusion Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma