Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch.
Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-A(s)/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 x SJL)F(1) mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 x SJL/J)F(1) mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-beta3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.
Huan
Jianya
J
Department of Neurology, Oregon Health and Science University, Portland, OR 97207, USA.
Subramanian
Sandhya
S
Jones
Richard
R
Rich
Cathleen
C
Link
Jason
J
Mooney
Jeff
J
Bourdette
Dennis N
DN
Vandenbark
Arthur A
AA
Burrows
Gregory G
GG
Offner
Halina
H
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000037:antagonists & inhibitors / Q000633:toxicity; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D012008:Recurrence; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C432412:RTL303 protein, human; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C435023:myelin proteolipid protein (139-151)