Abstract
The induction of allergen-specific anergy in peripheral T cells represents a key step in specific immunotherapy (SIT). Here we demonstrate that the anergic state results from increased IL-10 production. In bee venom (BV)-SIT the specific proliferative and cytokine responses against the main allergen, the phospholipase A2 (PLA), and T cell epitope-containing PLA peptides were significantly suppressed after 7 d of treatment. Simultaneously, the production of IL-10 increased during BV-SIT. After 28 d of BV-SIT the anergic state was established. Intracytoplasmic cytokine staining of PBMC combined with surface marker detection revealed that IL-10 was produced initially by activated CD4(+)CD25(+), allergen-specific T cells, and followed by B cells and monocytes. Neutralization of IL-10 in PBMC fully reconstituted the specific proliferative and cytokine responses. A similar state of IL-10-associated T cell anergy, as induced in BV-SIT, was found in hyperimmune individuals who recently had received multiple bee stings. The addition of IL-10 to soluble CD40 ligand IL-4-stimulated PBMC or purified B cells inhibited the PLA-specific and total IgE and enhanced the IgG4 formation. Accordingly, increased IL-10 production by SIT causes specific anergy in peripheral T cells, and regulates specific IgE and IgG4 production toward normal IgG4-related immunity.
Full Text
The Full Text of this article is available as a PDF (1.6 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aalberse R. C., van der Gaag R., van Leeuwen J. Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4-restricted response. J Immunol. 1983 Feb;130(2):722–726. [PubMed] [Google Scholar]
- Akdis C. A., Akdis M., Blesken T., Wymann D., Alkan S. S., Müller U., Blaser K. Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. J Clin Invest. 1996 Oct 1;98(7):1676–1683. doi: 10.1172/JCI118963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Akdis C. A., Blesken T., Akdis M., Alkan S. S., Heusser C. H., Blaser K. Glucocorticoids inhibit human antigen-specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro. Eur J Immunol. 1997 Sep;27(9):2351–2357. doi: 10.1002/eji.1830270933. [DOI] [PubMed] [Google Scholar]
- Akdis C. A., Blesken T., Akdis M., Alkan S. S., Wüthrich B., Heusser C. H., Blaser K. Induction and differential regulation of bee venom phospholipase A2-specific human IgE and IgG4 antibodies in vitro requires allergen-specific and nonspecific activation of T and B cells. J Allergy Clin Immunol. 1997 Mar;99(3):345–353. doi: 10.1016/s0091-6749(97)70052-6. [DOI] [PubMed] [Google Scholar]
- Akdis M., Akdis C. A., Weigl L., Disch R., Blaser K. Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern: IgG4 counter-regulation by CLA- memory T cells. J Immunol. 1997 Nov 1;159(9):4611–4619. [PubMed] [Google Scholar]
- Arock M., Zuany-Amorim C., Singer M., Benhamou M., Pretolani M. Interleukin-10 inhibits cytokine generation from mast cells. Eur J Immunol. 1996 Jan;26(1):166–170. doi: 10.1002/eji.1830260126. [DOI] [PubMed] [Google Scholar]
- Bacchetta R., Bigler M., Touraine J. L., Parkman R., Tovo P. A., Abrams J., de Waal Malefyt R., de Vries J. E., Roncarolo M. G. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med. 1994 Feb 1;179(2):493–502. doi: 10.1084/jem.179.2.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Becker J. C., Czerny C., Bröcker E. B. Maintenance of clonal anergy by endogenously produced IL-10. Int Immunol. 1994 Oct;6(10):1605–1612. doi: 10.1093/intimm/6.10.1605. [DOI] [PubMed] [Google Scholar]
- Bellinghausen I., Metz G., Enk A. H., Christmann S., Knop J., Saloga J. Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur J Immunol. 1997 May;27(5):1131–1139. doi: 10.1002/eji.1830270513. [DOI] [PubMed] [Google Scholar]
- Birnbaum J., Charpin D., Vervloet D. Rapid Hymenoptera venom immunotherapy: comparative safety of three protocols. Clin Exp Allergy. 1993 Mar;23(3):226–230. doi: 10.1111/j.1365-2222.1993.tb00886.x. [DOI] [PubMed] [Google Scholar]
- Brunner T., Heusser C. H., Dahinden C. A. Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation. J Exp Med. 1993 Mar 1;177(3):605–611. doi: 10.1084/jem.177.3.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carballido J. M., Carballido-Perrig N., Kägi M. K., Meloen R. H., Wüthrich B., Heusser C. H., Blaser K. T cell epitope specificity in human allergic and nonallergic subjects to bee venom phospholipase A2. J Immunol. 1993 Apr 15;150(8 Pt 1):3582–3591. [PubMed] [Google Scholar]
- Carballido J. M., Carballido-Perrig N., Oberli-Schrämmli A., Heusser C. H., Blaser K. Regulation of IgE and IgG4 responses by allergen specific T-cell clones to bee venom phospholipase A2 in vitro. J Allergy Clin Immunol. 1994 Apr;93(4):758–767. doi: 10.1016/0091-6749(94)90256-9. [DOI] [PubMed] [Google Scholar]
- Carballido J. M., Faith A., Carballido-Perrig N., Blaser K. The intensity of T cell receptor engagement determines the cytokine pattern of human allergen-specific T helper cells. Eur J Immunol. 1997 Feb;27(2):515–521. doi: 10.1002/eji.1830270224. [DOI] [PubMed] [Google Scholar]
- Creticos P. S., Adkinson N. F., Jr, Kagey-Sobotka A., Proud D., Meier H. L., Naclerio R. M., Lichtenstein L. M., Norman P. S. Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. J Clin Invest. 1985 Dec;76(6):2247–2253. doi: 10.1172/JCI112233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Del Prete G., De Carli M., Almerigogna F., Giudizi M. G., Biagiotti R., Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993 Jan 15;150(2):353–360. [PubMed] [Google Scholar]
- Del Prete G., Maggi E., Parronchi P., Chrétien I., Tiri A., Macchia D., Ricci M., Banchereau J., De Vries J., Romagnani S. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol. 1988 Jun 15;140(12):4193–4198. [PubMed] [Google Scholar]
- Ding L., Shevach E. M. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol. 1992 May 15;148(10):3133–3139. [PubMed] [Google Scholar]
- Enk A. H., Saloga J., Becker D., Mohamadzadeh M., Knop J. Induction of hapten-specific tolerance by interleukin 10 in vivo. J Exp Med. 1994 Apr 1;179(4):1397–1402. doi: 10.1084/jem.179.4.1397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Faith A., Akdis C. A., Akdis M., Simon H. U., Blaser K. Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p56(lck) and ZAP-70 tyrosine kinase activities. J Immunol. 1997 Jul 1;159(1):53–60. [PubMed] [Google Scholar]
- 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]
- Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
- Furin M. J., Norman P. S., Creticos P. S., Proud D., Kagey-Sobotka A., Lichtenstein L. M., Naclerio R. M. Immunotherapy decreases antigen-induced eosinophil cell migration into the nasal cavity. J Allergy Clin Immunol. 1991 Jul;88(1):27–32. doi: 10.1016/0091-6749(91)90297-2. [DOI] [PubMed] [Google Scholar]
- Gascan H., Gauchat J. F., Aversa G., Van Vlasselaer P., de Vries J. E. Anti-CD40 monoclonal antibodies or CD4+ T cell clones and IL-4 induce IgG4 and IgE switching in purified human B cells via different signaling pathways. J Immunol. 1991 Jul 1;147(1):8–13. [PubMed] [Google Scholar]
- Groux H., O'Garra A., Bigler M., Rouleau M., Antonenko S., de Vries J. E., Roncarolo M. G. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997 Oct 16;389(6652):737–742. doi: 10.1038/39614. [DOI] [PubMed] [Google Scholar]
- Hoyne G. F., O'Hehir R. E., Wraith D. C., Thomas W. R., Lamb J. R. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice. J Exp Med. 1993 Nov 1;178(5):1783–1788. doi: 10.1084/jem.178.5.1783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsu D. H., Moore K. W., Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol. 1992 May;4(5):563–569. doi: 10.1093/intimm/4.5.563. [DOI] [PubMed] [Google Scholar]
- Hunt K. J., Valentine M. D., Sobotka A. K., Benton A. W., Amodio F. J., Lichtenstein L. M. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med. 1978 Jul 27;299(4):157–161. doi: 10.1056/NEJM197807272990401. [DOI] [PubMed] [Google Scholar]
- Hussain R., Poindexter R. W., Ottesen E. A. Control of allergic reactivity in human filariasis. Predominant localization of blocking antibody to the IgG4 subclass. J Immunol. 1992 May 1;148(9):2731–2737. [PubMed] [Google Scholar]
- Jutel M., Müller U. R., Fricker M., Rihs S., Pichler W. J., Dahinden C. Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils. Clin Exp Allergy. 1996 Oct;26(10):1112–1118. [PubMed] [Google Scholar]
- Jutel M., Pichler W. J., Skrbic D., Urwyler A., Dahinden C., Müller U. R. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. J Immunol. 1995 Apr 15;154(8):4187–4194. [PubMed] [Google Scholar]
- Lane P., Brocker T., Hubele S., Padovan E., Lanzavecchia A., McConnell F. Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation. J Exp Med. 1993 Apr 1;177(4):1209–1213. doi: 10.1084/jem.177.4.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lichtenstein L. M., Valentine M. D., Sobotka A. K. A case for venom treatment in anaphylactic sensitivity to hymenoptera sting. N Engl J Med. 1974 May 30;290(22):1223–1227. doi: 10.1056/NEJM197405302902204. [DOI] [PubMed] [Google Scholar]
- Lucas A. H. IgG subclass-restricted immune responses to allergens. Springer Semin Immunopathol. 1990;12(4):385–400. doi: 10.1007/BF00225325. [DOI] [PubMed] [Google Scholar]
- Marshall J. S., Leal-Berumen I., Nielsen L., Glibetic M., Jordana M. Interleukin (IL)-10 inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. J Clin Invest. 1996 Feb 15;97(4):1122–1128. doi: 10.1172/JCI118506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miltenyi S., Müller W., Weichel W., Radbruch A. High gradient magnetic cell separation with MACS. Cytometry. 1990;11(2):231–238. doi: 10.1002/cyto.990110203. [DOI] [PubMed] [Google Scholar]
- Mueller H. L. Diagnosis and treatment of insect sensitivity. J Asthma Res. 1966 Jun;3(4):331–333. doi: 10.3109/02770906609106941. [DOI] [PubMed] [Google Scholar]
- Müller U. R., Dudler T., Schneider T., Crameri R., Fischer H., Skrbic D., Maibach R., Blaser K., Suter M. Type I skin reactivity to native and recombinant phospholipase A2 from honeybee venom is similar. J Allergy Clin Immunol. 1995 Sep;96(3):395–402. doi: 10.1016/s0091-6749(95)70059-5. [DOI] [PubMed] [Google Scholar]
- Ohkawara Y., Lim K. G., Xing Z., Glibetic M., Nakano K., Dolovich J., Croitoru K., Weller P. F., Jordana M. CD40 expression by human peripheral blood eosinophils. J Clin Invest. 1996 Apr 1;97(7):1761–1766. doi: 10.1172/JCI118603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Otsuka H., Mezawa A., Ohnishi M., Okubo K., Seki H., Okuda M. Changes in nasal metachromatic cells during allergen immunotherapy. Clin Exp Allergy. 1991 Jan;21(1):115–119. doi: 10.1111/j.1365-2222.1991.tb00812.x. [DOI] [PubMed] [Google Scholar]
- Position paper: Immunotherapy with hymenoptera venoms. (EAACI) The European Academy of Allergology and Clinical Immunology. Allergy. 1993;48(14 Suppl):36–46. [PubMed] [Google Scholar]
- Prussin C., Metcalfe D. D. Detection of intracytoplasmic cytokine using flow cytometry and directly conjugated anti-cytokine antibodies. J Immunol Methods. 1995 Dec 15;188(1):117–128. doi: 10.1016/0022-1759(95)00209-x. [DOI] [PubMed] [Google Scholar]
- Punnonen J., Aversa G., Cocks B. G., McKenzie A. N., Menon S., Zurawski G., de Waal Malefyt R., de Vries J. E. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3730–3734. doi: 10.1073/pnas.90.8.3730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Punnonen J., de Waal Malefyt R., van Vlasselaer P., Gauchat J. F., de Vries J. E. IL-10 and viral IL-10 prevent IL-4-induced IgE synthesis by inhibiting the accessory cell function of monocytes. J Immunol. 1993 Aug 1;151(3):1280–1289. [PubMed] [Google Scholar]
- Rak S., Löwhagen O., Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J Allergy Clin Immunol. 1988 Sep;82(3 Pt 1):470–480. doi: 10.1016/0091-6749(88)90021-8. [DOI] [PubMed] [Google Scholar]
- Randolph C. C., Reisman R. E. Evaluation of decline in serum venom-specific IgE as a criterion for stopping venom immunotherapy. J Allergy Clin Immunol. 1986 Jun;77(6):823–827. doi: 10.1016/0091-6749(86)90379-9. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Schandené L., Alonso-Vega C., Willems F., Gérard C., Delvaux A., Velu T., Devos R., de Boer M., Goldman M. B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. J Immunol. 1994 May 1;152(9):4368–4374. [PubMed] [Google Scholar]
- Schleimer R. P., Derse C. P., Friedman B., Gillis S., Plaut M., Lichtenstein L. M., MacGlashan D. W., Jr Regulation of human basophil mediator release by cytokines. I. Interaction with antiinflammatory steroids. J Immunol. 1989 Aug 15;143(4):1310–1317. [PubMed] [Google Scholar]
- Secrist H., Chelen C. J., Wen Y., Marshall J. D., Umetsu D. T. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J Exp Med. 1993 Dec 1;178(6):2123–2130. doi: 10.1084/jem.178.6.2123. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Secrist H., DeKruyff R. H., Umetsu D. T. Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type. J Exp Med. 1995 Mar 1;181(3):1081–1089. doi: 10.1084/jem.181.3.1081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sobotka A. K., Franklin R. M., Adkinson N. F., Jr, Valentine M., Baer H., Lichtenstein L. M. Allergy to insect stings. II. Phospholipase A: the major allergen in honeybee venom. J Allergy Clin Immunol. 1976 Jan;57(1):29–40. doi: 10.1016/0091-6749(76)90076-2. [DOI] [PubMed] [Google Scholar]
- Takanaski S., Nonaka R., Xing Z., O'Byrne P., Dolovich J., Jordana M. Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils. J Exp Med. 1994 Aug 1;180(2):711–715. doi: 10.1084/jem.180.2.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Wyss M., Scheitlin T., Stadler B. M., Wüthrich B. Immunotherapy with aluminum hydroxide adsorbed insect venom extracts (Alutard SQ): immunologic and clinical results of a prospective study over 3 years. Allergy. 1993 Feb;48(2):81–86. doi: 10.1111/j.1398-9995.1993.tb00690.x. [DOI] [PubMed] [Google Scholar]
- Zuany-Amorim C., Créminon C., Nevers M. C., Nahori M. A., Vargaftig B. B., Pretolani M. Modulation by IL-10 of antigen-induced IL-5 generation, and CD4+ T lymphocyte and eosinophil infiltration into the mouse peritoneal cavity. J Immunol. 1996 Jul 1;157(1):377–384. [PubMed] [Google Scholar]
- Zuany-Amorim C., Hailé S., Leduc D., Dumarey C., Huerre M., Vargaftig B. B., Pretolani M. Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. J Clin Invest. 1995 Jun;95(6):2644–2651. doi: 10.1172/JCI117966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- von Grünigen R., Schneider C. H. Antigenic structure of the hexacosapeptide melittin: evidence for three determinants, one with a helical conformation. Immunology. 1989 Mar;66(3):339–342. [PMC free article] [PubMed] [Google Scholar]