Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue.
The therapeutic effects of ABR-215062, which is a new immunoregulator derived from Linomide, have been evaluated in experimental autoimmune neuritis (EAN), a CD4(+) T cell-mediated animal model of Guillain-Barré syndrome in man. In previous studies, we reported that Linomide suppressed the clinical EAN and myelin antigen-reactive T and B cell responses. Here EAN induced in Lewis rats by inoculation with peripheral nerve myelin P0 protein peptide 180-199 and Freund's complete adjuvant was strongly suppressed by ABR-215062 administered daily subcutaneously from the day of inoculation. ABR-215062 dose-dependently reduced the incidence of EAN, ameliorated clinical signs and inhibited P0 peptide 180-199-specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves. The suppression of clinical EAN was associated with inhibition of the inflammatory cytokines IFN-gamma and TNF-alpha, as well as the enhancement of anti-inflammatory cytokine IL-4 in lymph node cells and periphery nerve tissues, respectively, in a dose-dependent manner. These effects indicate that ABR-215062 may mediate its effects by regulation of Th1/Th2 cytokine balance and suggest that ABR-215062 is potentially a new chemical entity for effective treatment of autoimmune diseases.
Zou
L-P
LP
Division of Geriatric Medicine, Department of Clinical Neuroscience, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Abbas
N
N
Volkmann
I
I
Nennesmo
I
I
Levi
M
M
Wahren
B
B
Winblad
B
B
Hedlund
G
G
Zhu
J
J
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010525:Peripheral Nerves / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015363:Quinolones; D051381:Rats; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D006912:Hydroxyquinolines; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; C045282:roquinimex; D007371:Interferon-gamma; C476223:laquinimod