Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Dec 1;178(6):2123–2130. doi: 10.1084/jem.178.6.2123

Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals

PMCID: PMC2191292  PMID: 7902409

Abstract

Allergen specific CD4+ T cell clones generated from allergic individuals have been shown to produce increased levels of the cytokine interleukin 4 (IL-4), compared to allergen specific clones generated from nonallergic individuals. This difference between CD4+ T cells from allergic and nonallergic individuals with regard to cytokine production in response to allergen is thought to be responsible for the development of allergic disease with increased IgE synthesis in atopic individuals. We examined the production of IL-4 in subjects with allergic rhinitis and in allergic individuals treated with allergen immunotherapy, a treatment which involves the subcutaneous administration of increasing doses of allergen and which is highly effective and beneficial for individuals with severe allergic rhinitis. We demonstrated that the quantity of IL-4 produced by allergen specific memory CD4+ T cells from allergic individuals could be considerably reduced by in vivo treatment with allergen (allergen immunotherapy). Immunotherapy reduced IL-4 production by allergen specific CD4+ T cells to levels observed with T cells from nonallergic subjects, or to levels induced with nonallergic antigens such as tetanus toxoid. In most cases the levels of IL-4 produced were inversely related to the length of time on immunotherapy. These observations indicate that immunotherapy accomplishes its clinical effects by reducing IL-4 synthesis in allergen specific CD4+ T cells. In addition, these observations indicate that the cytokine profiles of memory CD4+ T cells can indeed be altered by in vivo therapies. Thus, the cytokine profiles of memory CD4+ T cells are mutable, and are not fixed as had been suggested by studies of murine CD4+ memory T cells. Finally, treatment of allergic diseases with allergen immunotherapy may be a model for other diseases which may require therapies that alter inappropriate cytokine profiles of memory CD4+ T cells.

Full Text

The Full Text of this article is available as a PDF (752.7 KB).

Selected References

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

  1. Coffman R. L., Seymour B. W., Hudak S., Jackson J., Rennick D. Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science. 1989 Jul 21;245(4915):308–310. doi: 10.1126/science.2787531. [DOI] [PubMed] [Google Scholar]
  2. Creticos P. S., Van Metre T. E., Mardiney M. R., Rosenberg G. L., Norman P. S., Adkinson N. F., Jr Dose response of IgE and IgG antibodies during ragweed immunotherapy. J Allergy Clin Immunol. 1984 Jan;73(1 Pt 1):94–104. doi: 10.1016/0091-6749(84)90490-1. [DOI] [PubMed] [Google Scholar]
  3. DeKruyff R. H., Fang Y., Umetsu D. T. IL-4 synthesis by in vivo primed keyhole limpet hemocyanin-specific CD4+ T cells. I. Influence of antigen concentration and antigen-presenting cell type. J Immunol. 1992 Dec 1;149(11):3468–3476. [PubMed] [Google Scholar]
  4. DeKruyff R. H., Ju S. T., Hunt A. J., Mosmann T. R., Umetsu D. T. Induction of antigen-specific antibody responses in primed and unprimed B cells. Functional heterogeneity among Th1 and Th2 T cell clones. J Immunol. 1989 Apr 15;142(8):2575–2582. [PubMed] [Google Scholar]
  5. DeKruyff R. H., Turner T., Abrams J. S., Palladino M. A., Jr, Umetsu D. T. Induction of human IgE synthesis by CD4+ T cell clones. Requirement for interleukin 4 and low molecular weight B cell growth factor. J Exp Med. 1989 Nov 1;170(5):1477–1493. doi: 10.1084/jem.170.5.1477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Del Prete G. F., De Carli M., Mastromauro C., Biagiotti R., Macchia D., Falagiani P., Ricci M., Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. doi: 10.1172/JCI115300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Durham S. R., Ying S., Varney V. A., Jacobson M. R., Sudderick R. M., Mackay I. S., Kay A. B., Hamid Q. A. Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia. J Immunol. 1992 Apr 15;148(8):2390–2394. [PubMed] [Google Scholar]
  8. Evans R., Pence H., Kaplan H., Rocklin R. E. The effect of immunotherapy on humoral and cellular responses in ragweed hayfever. J Clin Invest. 1976 May;57(5):1378–1385. doi: 10.1172/JCI108406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Finkelman F. D., Urban J. F., Jr, Beckmann M. P., Schooley K. A., Holmes J. M., Katona I. M. Regulation of murine in vivo IgG and IgE responses by a monoclonal anti-IL-4 receptor antibody. Int Immunol. 1991 Jun;3(6):599–607. doi: 10.1093/intimm/3.6.599. [DOI] [PubMed] [Google Scholar]
  10. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gaga M., Frew A. J., Varney V. A., Kay A. B. Eosinophil activation and T lymphocyte infiltration in allergen-induced late phase skin reactions and classical delayed-type hypersensitivity. J Immunol. 1991 Aug 1;147(3):816–822. [PubMed] [Google Scholar]
  12. Gross A., Ben-Sasson S. Z., Paul W. E. Anti-IL-4 diminishes in vivo priming for antigen-specific IL-4 production by T cells. J Immunol. 1993 Mar 15;150(6):2112–2120. [PubMed] [Google Scholar]
  13. HayGlass K. T., Stefura B. P. Anti-interferon gamma treatment blocks the ability of glutaraldehyde-polymerized allergens to inhibit specific IgE responses. J Exp Med. 1991 Feb 1;173(2):279–285. doi: 10.1084/jem.173.2.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  16. Kapsenberg M. L., Wierenga E. A., Bos J. D., Jansen H. M. Functional subsets of allergen-reactive human CD4+ T cells. Immunol Today. 1991 Nov;12(11):392–395. doi: 10.1016/0167-5699(91)90137-I. [DOI] [PubMed] [Google Scholar]
  17. Katona I. M., Urban J. F., Jr, Kang S. S., Paul W. E., Finkelman F. D. IL-4 requirements for the generation of secondary in vivo IgE responses. J Immunol. 1991 Jun 15;146(12):4215–4221. [PubMed] [Google Scholar]
  18. Kay A. B., Ying S., Varney V., Gaga M., Durham S. R., Moqbel R., Wardlaw A. J., Hamid Q. Messenger RNA expression of the cytokine gene cluster, interleukin 3 (IL-3), IL-4, IL-5, and granulocyte/macrophage colony-stimulating factor, in allergen-induced late-phase cutaneous reactions in atopic subjects. J Exp Med. 1991 Mar 1;173(3):775–778. doi: 10.1084/jem.173.3.775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Norman P. S. Immunotherapy for nasal allergy. J Allergy Clin Immunol. 1988 May;81(5 Pt 2):992–996. doi: 10.1016/0091-6749(88)90167-4. [DOI] [PubMed] [Google Scholar]
  21. Parish C. R., Liew F. Y. Immune response to chemically modified flagellin. 3. Enhanced cell-mediated immunity during high and low zone antibody tolerance to flagellin. J Exp Med. 1972 Feb 1;135(2):298–311. doi: 10.1084/jem.135.2.298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pearce E. J., Caspar P., Grzych J. M., Lewis F. A., Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. doi: 10.1084/jem.173.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pienkowski M. M., Norman P. S., Lichtenstein L. M. Suppression of late-phase skin reactions by immunotherapy with ragweed extract. J Allergy Clin Immunol. 1985 Nov;76(5):729–734. doi: 10.1016/0091-6749(85)90679-7. [DOI] [PubMed] [Google Scholar]
  24. Reid M. J., Moss R. B., Hsu Y. P., Kwasnicki J. M., Commerford T. M., Nelson B. L. Seasonal asthma in northern California: allergic causes and efficacy of immunotherapy. J Allergy Clin Immunol. 1986 Oct;78(4 Pt 1):590–600. doi: 10.1016/0091-6749(86)90076-x. [DOI] [PubMed] [Google Scholar]
  25. Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
  26. Rocklin R. E., Sheffer A. L., Greineder D. K., Melmon K. L. Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med. 1980 May 29;302(22):1213–1219. doi: 10.1056/NEJM198005293022201. [DOI] [PubMed] [Google Scholar]
  27. Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
  28. Saloga J., Renz H., Lack G., Bradley K. L., Greenstein J. L., Larsen G., Gelfand E. W. Development and transfer of immediate cutaneous hypersensitivity in mice exposed to aerosolized antigen. J Clin Invest. 1993 Jan;91(1):133–140. doi: 10.1172/JCI116162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Stern M., Meagher L., Savill J., Haslett C. Apoptosis in human eosinophils. Programmed cell death in the eosinophil leads to phagocytosis by macrophages and is modulated by IL-5. J Immunol. 1992 Jun 1;148(11):3543–3549. [PubMed] [Google Scholar]
  30. Stevens T. L., Bossie A., Sanders V. M., Fernandez-Botran R., Coffman R. L., Mosmann T. R., Vitetta E. S. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature. 1988 Jul 21;334(6179):255–258. doi: 10.1038/334255a0. [DOI] [PubMed] [Google Scholar]
  31. Swain S. L., Weinberg A. D., English M., Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed] [Google Scholar]
  32. Tepper R. I., Levinson D. A., Stanger B. Z., Campos-Torres J., Abbas A. K., Leder P. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell. 1990 Aug 10;62(3):457–467. doi: 10.1016/0092-8674(90)90011-3. [DOI] [PubMed] [Google Scholar]
  33. Urban J. F., Jr, Katona I. M., Paul W. E., Finkelman F. D. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5513–5517. doi: 10.1073/pnas.88.13.5513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Van Metre T. E., Jr, Adkinson N. F., Jr, Amodio F. J., Kagey-Sobotka A., Lichtenstein L. M., Mardiney M. R., Jr, Norman P. S., Rosenberg G. L. A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever. J Allergy Clin Immunol. 1982 Feb;69(2):181–193. doi: 10.1016/0091-6749(82)90098-7. [DOI] [PubMed] [Google Scholar]
  35. Van Metre T. E., Jr, Marsh D. G., Adkinson N. F., Jr, Kagey-Sobotka A., Khattignavong A., Norman P. S., Jr, Rosenberg G. L. Immunotherapy for cat asthma. J Allergy Clin Immunol. 1988 Dec;82(6):1055–1068. doi: 10.1016/0091-6749(88)90144-3. [DOI] [PubMed] [Google Scholar]
  36. Walker C., Virchow J. C., Jr, Bruijnzeel P. L., Blaser K. T cell subsets and their soluble products regulate eosinophilia in allergic and nonallergic asthma. J Immunol. 1991 Mar 15;146(6):1829–1835. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES