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.
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.
Carballido
J M
JM
Department of Human Immunology, DNAX Research Institute, Palo Alto, CA 94304, USA.
Schols
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D
Namikawa
R
R
Zurawski
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S
Zurawski
G
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Roncarolo
M G
MG
de Vries
J E
JE
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000187:drug effects; D007136:Immunoglobulins / Q000097:blood; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D013950:Thymus Gland / Q000637:transplantation; D018183:Transplantation Chimera
D015703:Antigens, CD; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D007073:Immunoglobulin E