Modulation of susceptibility and resistance to an autoimmune model of multiple sclerosis in prototypically susceptible and resistant strains by neutralization of interleukin-12 and interleukin-4, respectively.
Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, is mediated by Th1 cells. The major Th1 inducer, IL-12, enhances EAE, while its blockade suppresses it. IL-4 suppresses EAE. Here, we determined IFN-gamma and IL-4 production by myelin basic protein-stimulated lymphocytes from prototypically EAE-susceptible SJL/J and EAE-resistant BALB/c mice, 9 days after immunization with spinal cord homogenate. While lymphocytes from SJL/J mice produce IFN-gamma and no IL-4, lymphocytes from BALB/c mice produce IL-4 and no IFN-gamma. Since early endogenous production of IL-12/IFN-gamma or IL-4 is linked to Th1 or Th2 responses, respectively, we determined whether neutralization of IL-12 or IL-4 at immunization modifies susceptibility or resistance to EAE. SJL/J mice given neutralizing anti-IL-12 mAb are protected from EAE. BALB/c mice given neutralizing anti-IL-4 mAb develop EAE, while those treated with control antibody remain resistant. These studies confirm the pivotal role of IL-12 in EAE development and show that endogenous IL-4 is important for determining the genetic resistance to EAE.
Constantinescu
C S
CS
Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.cc50@le.ac.uk
Hilliard
B
B
Ventura
E
E
Wysocka
M
M
Showe
L
L
Lavi
E
E
Fujioka
T
T
Scott
P
P
Trinchieri
G
G
Rostami
A
A
D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D023421:Models, Animal; D009103:Multiple Sclerosis / Q000276:immunology*; D009500:Neutralization Tests
D018664:Interleukin-12; D015847:Interleukin-4