Regulation of human IgE response in hu-PBL-SCID mice

Abstract The human IgE response was investigated in hu-PBL-SCID mice created by ip injection of human PBL into C.B. 17 scid/scid (scid) mice. With 30-100 × 10 6 PBL/mouse, 80 to 90% of the animals responded with human IgE serum levels of 3-1000 ng/ml after 2 weeks. PBL from all donors analyzed (total number > 20) responded with IgE production. The half-lives of human IgE, IgM, and IgG in scid mice were determined to test the possibility of a passive transfer of the immunoglobulins in contrast to de novo synthesis. The values found were 88, 128, and 126 hr, respectively. In general, immunoglobulin production of all isotypes continuously increased over a period of 7-9 weeks after PBL injection, indicating de novo synthesis had taken place. The kinetics of the IgE response exhibited two phases: An initial burst of IgE production occurred between Days 12 and 22. This burst reached levels of 25-70 ng/ml IgE. After a rapid decline to about 50% of the peak value there was a sustained, slow, increase of IgE production for several weeks, excluding a passive transfer for IgE. About half of the donors lacked the initial burst of IgE production and only exhibited a slowly rising IgE production that is indistinguishable from the slow phase of the former donor population. The levels reached in this second phase of IgE production were 20-40 ng/ml after 6-7 weeks. This kinetics may reflect the presence of two different B cell populations, of which only one is present in all donors. The initial IgE burst was only partially dependent on the presence of human IL-4, reflected by a partial inhibition of this response by a neutralizing monoclonal anti-IL-4 antibody. The IgE response in scid mice seems to consist therefore of an IL-4-independent and an IL-4-dependent part, indicating the response to be partially driven by preswitched B cells. Injection of exogenous recombinant human IL-4 (rhIL-4) was not suitable due to the short half-life of rhIL-4 in scid mice of 12 min. Attempts to supply a constant source of rhIL-4 by injection of IL-4-producing Chinese hamster ovary cells failed because of toxic effects produced by these cells. The human IgE production in the scid mice was suppressed by interferon-α (BD) to 60-80% compared to that of untreated mice. The suppression was not isotype specific, however, because production of IgG and IgM was inhibited to similar extents. The suppression waned only after a period of several weeks, presumably due to clearance of intefferon-α. Thus a spontaneous human IgE production lasting over several weeks was induced in an immune-deficient foreign environment without additional stimulation requirements. The response is only partially dependent on IL-4 indicating that it may originate from B cells of different developmental states and the IgE induction is inhibited by interferon-α. Overall, the response is similar to the pattern of IgE production observed in atopic individuals. This model may therefore be of value for the investigation of a long-term human IgE response in an in vivo environment.