The critical role of IL-12p40 in initiating, enhancing, and perpetuating pathogenic events in murine experimental autoimmune neuritis.
Interleukin 12 (IL-12) is a proinflammatory cytokine with important immunoregulatory activities and is critical in determining the differentiation and generation of Th1 cells. For the present study, we investigated the role of endogenous IL-12 in the pathogenesis of experimental autoimmune neuritis (EAN), which is a CD4+ T-cell mediated autoimmune inflammatory disease of the peripheral nervous system. EAN is used as an animal model for Guillain-Barré syndrome of humans. Here, EAN was established in IL-12 p40 deficient mutant (IL-12-/-) C57BL/6 mice by immunization with P0 peptide 180-199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. In these IL-12-/- mice the onset of clinical disease was delayed, and the incidence and severity of EAN were significantly reduced compared to that in wild-type mice.The former group's clinical manifestations were associated with less P0-peptide 180-199 induced secretion of interferon-gamma (IFN-gamma) by splenocytes in vitro and low production of anti-P0-peptide 180-199 IgG2b antibodies in serum. Fewer IFN-gamma and TNF-alpha producing cells, but more cells secreting IL-4, were found in sciatic nerve sections from IL-12-/- mice, consistent with impaired Th1 functions and response. However, the IL-12 deficiency appeared not to affect P0 peptide 180-199-specific T-cell proliferation. These results indicate that IL-12 has a major role in the initiation, enhancement and perpetuation of pathogenic events in EAN by promoting a Th1 cell-mediated immune response and suppressing the Th2 response. This information augments consideration of IL-12 as a therapeutic target in Guillain-Barré syndrome and other T-cell-mediated autoimmune diseases.
Bao
Lei
L
Department of NEUROTEC, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Lindgren
J Urban
JU
van der Meide
Peter
P
Zhu
Shun wei
Sw
Ljunggren
Hans-Gustaf
HG
Zhu
Jie
J
D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D020275:Guillain-Barre Syndrome / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40; D051379:Mice; D018345:Mice, Knockout; D018993:Myelin P0 Protein / Q000276:immunology / Q000494:pharmacology; D009186:Myelin Sheath / Q000235:genetics / Q000276:immunology; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D010525:Peripheral Nerves / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D016207:Cytokines; D018836:Inflammation Mediators; D053762:Interleukin-12 Subunit p40; D018993:Myelin P0 Protein; D021122:Protein Subunits; D018664:Interleukin-12