Recombinant soluble murine IL-4 receptor can inhibit or enhance IgE responses in vivo.
This study examines the effects of soluble IL-4R (sIL-4R) administration on IgE production in vivo by using an anti-IgD injection model. Anti-IgD-treated mice were given various doses of sIL-4R or anti-IL-4 mAb over a 3-day period and serum IgE levels were determined by ELISA on day 9. The sIL-4R inhibited IgE production by up to 85%. Anti-IL-4 mAb administration resulted in comparable levels of inhibition at considerably lower doses. The disparity in efficacy between sIL-4R and anti-IL-4 mAb was likely the result of differences in the biodistribution and in vivo half-life of the two IL-4-binding proteins. The specificity of the sIL-4R inhibitory effect was assessed by mixing sIL-4R with various concentrations of IL-4 before injection. Exogenous IL-4 partially overcame the inhibitory effect of high-dose sIL-4R or anti-IL-4 mAb. Unexpectedly, coadministration of suboptimal concentrations of anti-IL-4 mAb or sIL-4R with IL-4 resulted in superinduction of the IgE response. This stimulatory effect was dose dependent for both IL-4 and the IL-4 cognates and was not seen in the absence of exogenous IL-4 over the entire concentration range tested for either sIL-4R or anti-IL mAb. The results indicate that sIL-4R can block IgE secretion by neutralizing endogenous IL-4. Furthermore, sIL-4R can enhance, in a dose-dependent manner, the biologic effects of exogenously administered IL-4, presumably by altering the biodistribution of the cytokine. These findings suggest two alternative applications for cytokine-binding proteins, i.e., 1) as antagonists of biologic activities of endogenously produced cytokines and, 2) as vehicles for cytokine delivery.
Sato
T A
TA
Department of Immunology, Immunex Research and Development Corp., Seattle, WA 98101.
Widmer
M B
MB
Finkelman
F D
FD
Madani
H
H
Jacobs
C A
CA
Grabstein
K H
KH
Maliszewski
C R
CR
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007072:Immunoglobulin D / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000502:physiology*; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D012995:Solubility
D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D007072:Immunoglobulin D; D007166:Immunosuppressive Agents; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011994:Recombinant Proteins; C039951:anti-IgD; D015847:Interleukin-4; D007073:Immunoglobulin E