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The Journal of Immunology, Vol 155, Issue 9 4162-4170, Copyright © 1995 by American Association of Immunologists

ARTICLES

IL-4 induces human B cell maturation and IgE synthesis in SCID-hu mice. Inhibition of ongoing IgE production by in vivo treatment with an IL- 4/IL-13 receptor antagonist

JM Carballido, D Schols, R Namikawa, S Zurawski, G Zurawski, MG Roncarolo and JE de Vries
Department of Human Immunology, DNAX Research Institute, Palo Alto, CA 94304, USA.

The effect of cytokine treatment on the in vivo maturation and Ig isotype switching of human B cells was studied in a modified SCID-hu mouse model. SCID mice, subcutaneously cotransplanted with small fragments of fetal human thymus and bone (SCID-hu BM/T mice) generated all human leukocyte lineages including T and B lymphocytes, macrophages, and granulocytes. All SCID-hu BM/T mice spontaneously produced human IgM and IgG, whereas IgE and IgA were detected in 37 and 80% of the mice, respectively, indicating that productive human T-B cell interactions resulting in Ig isotype switching occur in these mice. Administration of IL-4 to SCID-hu BM/T mice enhanced human B cell maturation, as judged by the increase in the percentages of CD45+, CD19+ bone marrow B cells expressing CD20, CD23, CD40, sIgM, and sIgD. Furthermore, these cells were also functionally more mature because they spontaneously produced human IgG/IgG4 in vitro and could be induced to secrete human IgE by addition of anti-CD40 mAb alone. In contrast, B cells isolated from PBS-treated mice only produced significant Ig levels after stimulation with anti-CD40 mAb in the presence of exogenous IL-4. IL-4 administration also induced human IgE synthesis in 44% of the mice, which had no serum IgE before treatment. More importantly, ongoing human IgE synthesis in SCID-hu BM/T mice was suppressed by > 90% following administration of an IL-4 mutant protein, which acts as an IL-4 and IL-13 receptor antagonist. These results suggest that IL-4/IL-13 receptor antagonists have potential clinical utility in treating human atopic diseases associated with enhanced IgE production.


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