Exogenous type-1 cytokines modulate mercury-induced hyper-IgE in the rat.
Suppression of IgE responses is a major goal for immunotherapy, especially in the field of allergy. The Th2 subset of helper T cells plays a vital role in class switching of B cells to IgE production by releasing IL-4. In susceptible rat strains, mercuric chloride (HgCl2) induces activation of Th2 cells, with enhanced expression of IL-4, polyclonal B cell activation and very high levels of circulating IgE. We have previously shown that spontaneous regulation of this response coincides with enhanced expression of Th1/type-1 cytokines, including interferon-gamma (IFN-gamma) and IL-12. We now report the effects of administration of exogenous type-1 cytokines on HgCl2-induced Th2 responses. At high doses, recombinant rat IFN-gamma markedly reduced serum IgE levels. Recombinant mouse IL-12 was less effective at suppressing the IgE response following HgCl2, although it caused marked up-regulation of IFN-gamma gene expression in the spleen. In Lewis rats, which are resistant to HgCl2-induced autoimmunity, a rise in serum IFN-gamma was observed after HgCl2, but administration of polyclonal anti-IFN-gamma antibodies did not render them susceptible to induction of a Th2 response by HgCl2. Our data show that individual type-1 cytokines are capable of suppressing the dramatic Th2 response induced by HgCl2 in the rat, even when they are not given until after starting HgCl2 administration. IFN-gamma is a pivotal cytokine in ameliorating the Th2 response and measures aimed at selective up-regulation of this cytokine may be of therapeutic value in suppression of unwanted IgE responses.
Gorrie
M J
MJ
Department of Renal Medicine, Western Infirmary, Glasgow, Department of Medicine, University of Cambridge, Cambridge and Academic Renal Unit, University of Bristol, Bristol, UK.
Qasim
F J
FJ
Whittle
C J
CJ
Gillespie
K M
KM
Szeto
C C
CC
Nicoletti
F
F
Bolton
E M
EM
Bradley
J A
JA
Mathieson
P W
PW
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D015870:Gene Expression; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000097:blood; D007371:Interferon-gamma / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics; D008627:Mercuric Chloride / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007073:Immunoglobulin E; D008627:Mercuric Chloride; D007371:Interferon-gamma