Role of interleukin-4 in human immunoglobulin E formation in hu-PBL-SCID mice.
We studied the role of IL-4 in human IgE formation in severe combined immunodeficient mice engrafted with peripheral blood mononuclear leukocytes (hu-PBL-SCID). PBL from four nonatopic donors produced only small (< 20 ng/ml) or undetectable amounts of IgE in SCID mice whereas engrafted PBL from seven atopic donors secreted IgE with IgE serum levels reaching a mean +/- SE of 184 +/- 37 ng/ml (n = 20). Serum IgE levels peaked 2-3 wk after PBL transfer and declined thereafter with a half-life of 1-2 wk. In contrast, IgG of all subclasses reached maximum serum levels 5-7 wk after PBL transfer and declined little thereafter. Injection of a neutralizing monoclonal antibody to the human IL-4 receptor (IL-4R) on day 0 inhibited completely the IgE formation and caused an approximate twofold reduction of IgG production of all subclasses. The anti-IL-4 R antibody had no effect on IgE secretion when administered 4 wk after PBL engraftment. Incubation of PBL with IL-4 before engraftment resulted in a 10-fold increase in IgE production and could be further enhanced by 100 fold if, in addition to preincubation with IL-4, IL-4 was injected daily for 5 d after PBL transfer. This treatment with IL-4 also induced two- to threefold increase in IgG levels. IFN-gamma had no effect on either IgE or IgG subclass production. In approximately 50% of the mice, one or more IgG subclasses increased disproportionally 5 wk after PBL injection as a result of monoclonal IgG formation. These data demonstrate that PBL from atopic donors secrete IgE in SCID mice in an IL-4-dependent manner, and that IgE production can be enhanced 10- to 100-fold with exogenous human IL-4 in these mice. This mouse model is amenable for the in vivo study of immunomodulators on human IgE formation.
Spiegelberg
H L
HL
Department of Pediatrics, University of California at San Diego 92093.
Beck
L
L
Kocher
H P
HP
Fanslow
W C
WC
Lucas
A H
AH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects; D003876:Dermatitis, Atopic / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000097:blood / Q000145:classification; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000145:classification; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000276:immunology / Q000502:physiology*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D015847:Interleukin-4; D007073:Immunoglobulin E