Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade enhances incidence and severity of experimental autoimmune neuritis in resistant mice.
Experimental autoimmune neuritis (EAN), an autoimmune inflammatory demyelinating disease of the peripheral nervous system, represents an animal model of the human Guillain-Barré syndrome. EAN can be induced by active immunization in several animals, including Lewis rats. In contrast, most strains of mice including the widely used C57BL/6 (B6) strain are reputedly resistant to the induction of EAN. In the present study, we demonstrate that in B6 mice, anti-CTLA-4 monoclonal antibody administration in conjunction with immunization with the P0 protein derived peptide 180-199 can induce clinical and pathological definite EAN. Upregulating effects of CTLA-4 blockade on initial and ongoing EAN are demonstrated. CTLA-4 blockade augmented cellular infiltration and enhanced demyelination in the target organ sciatic nerves as well as increased T cell proliferation in lymph node cells. Moreover, serum levels of IFN-gamma and IL-4 were increased. Thus, manipulation of CTLA-4/B7 costimulatory pathway by CTLA-4 blockade can promote autoreactivity and break the relative tolerance to peripheral autoantigen P0 in resistant B6 mice.
Division of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden. Jie.zhu@neurotec.ki.se
J
J
Zhu
L
L
Zou
S
S
Zhu
E
E
Mix
F
F
Shi
H
H
Wang
I
I
Volkmann
B
B
Winblad
M
M
Schalling
H
H
Ljunggren
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000097:blood; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015994:Incidence; D007371:Interferon-gamma / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018993:Myelin P0 Protein / Q000276:immunology; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D012720:Severity of Illness Index; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018993:Myelin P0 Protein; D010446:Peptide Fragments; D015847:Interleukin-4; D000069594:Abatacept; D007371:Interferon-gamma