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 leuko cytes (hu-PBL-SCID). PBL from four nonatopic donors produced only smal l (< 20 ng/ml) or undetectable amounts of IgE in SCID mice whereas eng rafted 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 peak ed 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 le vels 5-7 wk after PBL transfer and declined little thereafter. Injecti on of a neutralizing monoclonal antibody to the human IL-4 receptor (I L-4R) on day 0 inhibited completely the IgE formation and caused an ap proximate twofold reduction of IgG production of all subclasses. The a nti-IL-4 R antibody had no effect on IgE secretion when administered 4 wk after PBL engraftment. Incubation of PBL with IL-4 before engraftm ent resulted in a 10-fold increase in IgE production and could be furt her enhanced by 100 fold if, in addition to preincubation with IL-4, I L-4 was injected daily for 5 d after PBL transfer. This treatment with IL-4 also induced two- to threefold increase in Ige levels. IFN-gamma had no effect on either IgE or IgG subclass production. In similar to 50% of the mice, one or more IgG subclasses increased disproportional ly 5 wk after PBL injection as a result of monoclonal IgG formation. T hese data demonstrate that PBL from atopic donors secrete IgE in SCID mice in an IL-4-dependent manner, and that IgE production can be enhan ced 10- to 100-fold with exogenous human IL-4 in these mice. This mous e model is amenable for the in vivo study of immunomodulators on human IgE formation.