Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis.
Increasing evidence suggests that schistosome egg granulomas are primarily Th2 cellular reactions. Mice infected with Schistosoma mansoni were treated with a neutralizing mAb against IL-4 to evaluate the role of this cytokine in the generation of parasite egg-induced cell-mediated responses and hepatic pathology. Animals treated with anti-IL-4 before egg deposition showed decreased IL-4, IL-5, and IL-10 production in response to in vitro antigenic stimulations and decreased IL-5 and IL-13 mRNA levels in the liver. As observed previously, non-B, non-T cells were a major source of IL-4 in infected mice treated with control mAb, and the diminished IL-4 response in anti-IL-4-treated animals was shown to be caused at least in part by a reduction in the number of these cells, as well as by decreased secretion of IL-4 per cell. In contrast, production of the Th1 cytokines IL-2 and IFN-gamma was elevated in anti-IL-4-treated infected mice in vitro, and the corresponding mRNAs in the liver were increased. Anti-IL-4 treatment did not consistently reduce the size of hepatic granulomas around S. mansoni eggs, but markedly inhibited granuloma formation in the lungs of the same animals after i.v. egg injection. Nevertheless, anti-IL-4-treated infected mice showed consistent and marked reductions in hepatic collagen deposition. These findings indicate that IL-4 plays a major role in the development of the Th2 response in S. mansoni-infected mice and contributes to the pathogenesis of hepatic fibrosis.
Laboratory of Parasitic Diseases, National Institutes of Health, Bethesda, MD 20892.
A W
AW
Cheever
M E
ME
Williams
T A
TA
Wynn
F D
FD
Finkelman
R A
RA
Seder
T M
TM
Cox
S
S
Hieny
P
P
Caspar
A
A
Sher
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006099:Granuloma / Q000209:etiology / Q000517:prevention & control; D015847:Interleukin-4 / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010063:Ovum / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D012555:Schistosomiasis mansoni / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012333:RNA, Messenger; D015847:Interleukin-4