Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Feb;93(2):711–717. doi: 10.1172/JCI117024

Role of interleukin-4 in human immunoglobulin E formation in hu-PBL-SCID mice.

H L Spiegelberg 1, L Beck 1, H P Kocher 1, W C Fanslow 1, A H Lucas 1
PMCID: PMC293907  PMID: 8113405

Abstract

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.

Full text

PDF
714

Images in this article

714Image
on p.714

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aaberge I. S., Michaelsen T. E., Rolstad A. K., Groeng E. C., Solberg P., Løvik M. SCID-Hu mice immunized with a pneumococcal vaccine produce specific human antibodies and show increased resistance to infection. Infect Immun. 1992 Oct;60(10):4146–4153. doi: 10.1128/iai.60.10.4146-4153.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Abedi M. R., Christensson B., Islam K. B., Hammarström L., Smith C. I. Immunoglobulin production in severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood mononuclear cells. Eur J Immunol. 1992 Mar;22(3):823–828. doi: 10.1002/eji.1830220329. [DOI] [PubMed] [Google Scholar]
  3. Boguniewicz M., Jaffe H. S., Izu A., Sullivan M. J., York D., Geha R. S., Leung D. Y. Recombinant gamma interferon in treatment of patients with atopic dermatitis and elevated IgE levels. Am J Med. 1990 Apr;88(4):365–370. doi: 10.1016/0002-9343(90)90490-5. [DOI] [PubMed] [Google Scholar]
  4. Bosma G. C., Custer R. P., Bosma M. J. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. doi: 10.1038/301527a0. [DOI] [PubMed] [Google Scholar]
  5. Bosma G. C., Fried M., Custer R. P., Carroll A., Gibson D. M., Bosma M. J. Evidence of functional lymphocytes in some (leaky) scid mice. J Exp Med. 1988 Mar 1;167(3):1016–1033. doi: 10.1084/jem.167.3.1016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carlsson R., Mårtensson C., Kalliomäki S., Ohlin M., Borrebaeck C. A. Human peripheral blood lymphocytes transplanted into SCID mice constitute an in vivo culture system exhibiting several parameters found in a normal humoral immune response and are a source of immunocytes for the production of human monoclonal antibodies. J Immunol. 1992 Feb 15;148(4):1065–1071. [PubMed] [Google Scholar]
  7. Coffman R. L., Carty J. A T cell activity that enhances polyclonal IgE production and its inhibition by interferon-gamma. J Immunol. 1986 Feb 1;136(3):949–954. [PubMed] [Google Scholar]
  8. Davies T. F., Kimura H., Fong P., Kendler D., Shultz L. D., Thung S., Martin A. The SCID-hu mouse and thyroid autoimmunity: characterization of human thyroid autoantibody secretion. Clin Immunol Immunopathol. 1991 Aug;60(2):319–330. doi: 10.1016/0090-1229(91)90075-l. [DOI] [PubMed] [Google Scholar]
  9. Duchosal M. A., Eming S. A., Fischer P., Leturcq D., Barbas C. F., 3rd, McConahey P. J., Caothien R. H., Thornton G. B., Dixon F. J., Burton D. R. Immunization of hu-PBL-SCID mice and the rescue of human monoclonal Fab fragments through combinatorial libraries. Nature. 1992 Jan 16;355(6357):258–262. doi: 10.1038/355258a0. [DOI] [PubMed] [Google Scholar]
  10. Duchosal M. A., Eming S. A., McConahey P. J., Dixon F. J. Characterization of hu-PBL-SCID mice with high human immunoglobulin serum levels and graft-versus-host disease. Am J Pathol. 1992 Nov;141(5):1097–1113. [PMC free article] [PubMed] [Google Scholar]
  11. Duchosal M. A., Eming S. A., McConahey P. J., Dixon F. J. The hu-PBL-SCID mouse model. Long-term human serologic evolution associated with the xenogeneic transfer of human peripheral blood leukocytes into SCID mice. Cell Immunol. 1992 Feb;139(2):468–477. doi: 10.1016/0008-8749(92)90086-5. [DOI] [PubMed] [Google Scholar]
  12. Duchosal M. A., McConahey P. J., Robinson C. A., Dixon F. J. Transfer of human systemic lupus erythematosus in severe combined immunodeficient (SCID) mice. J Exp Med. 1990 Sep 1;172(3):985–988. doi: 10.1084/jem.172.3.985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fanslow W. C., Spriggs M. K., Rauch C. T., Clifford K. N., Macduff B. M., Ziegler S. F., Schooley K. A., Mohler K. M., March C. J., Armitage R. J. Identification of a distinct low-affinity receptor for human interleukin-4 on pre-B cells. Blood. 1993 Jun 1;81(11):2998–3005. [PubMed] [Google Scholar]
  14. Fishkin B. G., Glassy F. J., Hattersley P. G., Hirose F. M., Spiegelberg H. L. IgD multiple myeloma: a report of five cases. Am J Clin Pathol. 1970 Feb;53(2):209–214. doi: 10.1093/ajcp/53.2.209. [DOI] [PubMed] [Google Scholar]
  15. Gascan H., Gauchat J. F., Roncarolo M. G., Yssel H., Spits H., de Vries J. E. Human B cell clones can be induced to proliferate and to switch to IgE and IgG4 synthesis by interleukin 4 and a signal provided by activated CD4+ T cell clones. J Exp Med. 1991 Mar 1;173(3):747–750. doi: 10.1084/jem.173.3.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ishizaka A., Sakiyama Y., Nakanishi M., Tomizawa K., Oshika E., Kojima K., Taguchi Y., Kandil E., Matsumoto S. The inductive effect of interleukin-4 on IgG4 and IgE synthesis in human peripheral blood lymphocytes. Clin Exp Immunol. 1990 Mar;79(3):392–396. doi: 10.1111/j.1365-2249.1990.tb08101.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Li J. T., Yunginger J. W., Reed C. E., Jaffe H. S., Nelson D. R., Gleich G. J. Lack of suppression of IgE production by recombinant interferon gamma: a controlled trial in patients with allergic rhinitis. J Allergy Clin Immunol. 1990 May;85(5):934–940. doi: 10.1016/0091-6749(90)90080-n. [DOI] [PubMed] [Google Scholar]
  18. Lucas A. H., Siff T. E., Trujillo K. H., Kitamura M. Y. Vaccine-induced human antibody responses to the Haemophilus influenzae b polysaccharide in severe combined immunodeficient mice engrafted with human leukocytes. Pediatr Res. 1992 Jul;32(1):132–135. doi: 10.1203/00006450-199207000-00026. [DOI] [PubMed] [Google Scholar]
  19. Lundgren M., Persson U., Larsson P., Magnusson C., Smith C. I., Hammarström L., Severinson E. Interleukin 4 induces synthesis of IgE and IgG4 in human B cells. Eur J Immunol. 1989 Jul;19(7):1311–1315. doi: 10.1002/eji.1830190724. [DOI] [PubMed] [Google Scholar]
  20. Mazingue C., Cottrez F., Auriault C., Cesbron J. Y., Capron A. Obtention of a human primary humoral response against schistosome protective antigens in severe combined immunodeficiency mice after the transfer of human peripheral blood mononuclear cells. Eur J Immunol. 1991 Jul;21(7):1763–1766. doi: 10.1002/eji.1830210728. [DOI] [PubMed] [Google Scholar]
  21. Mosier D. E., Gulizia R. J., Baird S. M., Wilson D. B. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988 Sep 15;335(6187):256–259. doi: 10.1038/335256a0. [DOI] [PubMed] [Google Scholar]
  22. Mosier D. E. Immunodeficient mice xenografted with human lymphoid cells: new models for in vivo studies of human immunobiology and infectious diseases. J Clin Immunol. 1990 Jul;10(4):185–191. doi: 10.1007/BF00918650. [DOI] [PubMed] [Google Scholar]
  23. Nüsslein H. G., Spiegelberg H. L. Interleukin-4 induces both IgG4 and IgE secretion by peripheral blood B cells. J Clin Lab Anal. 1990;4(6):414–419. doi: 10.1002/jcla.1860040605. [DOI] [PubMed] [Google Scholar]
  24. Pène J., Rousset F., Brière F., Chrétien I., Bonnefoy J. Y., Spits H., Yokota T., Arai N., Arai K., Banchereau J. IgE production by normal human lymphocytes is induced by interleukin 4 and suppressed by interferons gamma and alpha and prostaglandin E2. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6880–6884. doi: 10.1073/pnas.85.18.6880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Saxon A., Macy E., Denis K., Tary-Lehmann M., Witte O., Braun J. Limited B cell repertoire in severe combined immunodeficient mice engrafted with peripheral blood mononuclear cells derived from immunodeficient or normal humans. J Clin Invest. 1991 Feb;87(2):658–665. doi: 10.1172/JCI115043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Spiegelberg H. L., Grey H. M. Catabolism of human gamma-G immunoglobulins of different heavy chain subclasses. II. Catabolism of gamma-G myeloma proteins in heterologous species. J Immunol. 1968 Oct;101(4):711–716. [PubMed] [Google Scholar]
  27. Torbett B. E., Picchio G., Mosier D. E. hu-PBL-SCID mice: a model for human immune function, AIDS, and lymphomagenesis. Immunol Rev. 1991 Dec;124:139–164. doi: 10.1111/j.1600-065x.1991.tb00620.x. [DOI] [PubMed] [Google Scholar]
  28. Vercelli D., Geha R. S. Regulation of IgE synthesis in humans: a tale of two signals. J Allergy Clin Immunol. 1991 Sep;88(3 Pt 1):285–295. doi: 10.1016/0091-6749(91)90087-5. [DOI] [PubMed] [Google Scholar]
  29. Williams S. S., Umemoto T., Kida H., Repasky E. A., Bankert R. B. Engraftment of human peripheral blood leukocytes into severe combined immunodeficient mice results in the long term and dynamic production of human xenoreactive antibodies. J Immunol. 1992 Oct 15;149(8):2830–2836. [PubMed] [Google Scholar]
  30. Yount W. J., Fuller C. R., Simmons J. G. Distribution of IgG subclasses in human B lymphocytes: evidence for dual expression of subclasses in surface and cytoplasmic IgG in minor B lymphocyte subpopulations. J Immunol. 1980 Jan;124(1):431–436. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES