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. 1993 Aug;92(2):644–651. doi: 10.1172/JCI116633

Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.

V A Varney 1, Q A Hamid 1, M Gaga 1, S Ying 1, M Jacobson 1, A J Frew 1, A B Kay 1, S R Durham 1
PMCID: PMC294897  PMID: 8349803

Abstract

We have studied the influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. In a double-blind, placebo-controlled trial of immunotherapy in 40 adult hay fever sufferers, clinical improvement was accompanied by a decrease in the size of the late-phase skin response. When the immunotherapy-treated group was compared with the placebo group, analysis of skin biopsies obtained 24 h after intradermal allergen revealed a significant reduction in the number of infiltrating CD3+ (P = 0.04) and CD4+ (P = 0.009) cells and a trend for a decrease in EG2+ eosinophils (P = 0.08). Treatment did not influence allergen-induced recruitment of CD8+ cells, neutrophils, or macrophages. Unexpected increases in expression of CD25 (P = 0.006) and HLA-DR (P = 0.007) were observed in the actively treated group. In situ hybridization using a panel of riboprobes demonstrated "TH2-type" (IL-4, IL-5) cytokine mRNA responses in both groups of patients. In contrast, significant hybridization for IL-2 (8/16 patients, P = 0.02) and for interferon-gamma (6/16 patients, P = 0.04) was observed only in the actively treated group. These findings indicate that immunotherapy is associated with suppression of allergen-induced CD4+ T lymphocyte infiltration, but among the cells that are recruited, there is upregulation of CD25 and HLA-DR. At least in this model, immunotherapy does not appear to affect expression of TH2-pattern cytokines in response to allergen exposure, but expression of mRNA for Th1-type cytokines was enhanced in half of the patients. The results support the view that immunotherapy may possibly be working through induction of T cell tolerance.

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Selected References

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  1. Bousquet J., Calvayrac P., Guérin B., Hejjaoui A., Dhivert H., Hewitt B., Michel F. B. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment. J Allergy Clin Immunol. 1985 Nov;76(5):734–744. doi: 10.1016/0091-6749(85)90680-3. [DOI] [PubMed] [Google Scholar]
  2. Brunet C., Bédard P. M., Lavoie A., Jobin M., Hébert J. Allergic rhinitis to ragweed pollen. I. Reassessment of the effects of immunotherapy on cellular and humoral responses. J Allergy Clin Immunol. 1992 Jan;89(1 Pt 1):76–86. doi: 10.1016/s0091-6749(05)80043-0. [DOI] [PubMed] [Google Scholar]
  3. Chand N., Harrison J. E., Rooney S., Pillar J., Jakubicki R., Nolan K., Diamantis W., Sofia R. D. Anti-IL-5 monoclonal antibody inhibits allergic late phase bronchial eosinophilia in guinea pigs: a therapeutic approach. Eur J Pharmacol. 1992 Jan 28;211(1):121–123. doi: 10.1016/0014-2999(92)90273-7. [DOI] [PubMed] [Google Scholar]
  4. Desreumaux P., Janin A., Colombel J. F., Prin L., Plumas J., Emilie D., Torpier G., Capron A., Capron M. Interleukin 5 messenger RNA expression by eosinophils in the intestinal mucosa of patients with coeliac disease. J Exp Med. 1992 Jan 1;175(1):293–296. doi: 10.1084/jem.175.1.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Djurup R. The subclass nature and clinical significance of the IgG antibody response in patients undergoing allergen-specific immunotherapy. Allergy. 1985 Oct;40(7):469–486. doi: 10.1111/j.1398-9995.1985.tb00253.x. [DOI] [PubMed] [Google Scholar]
  6. Fanslow W. C., Clifford K. N., Park L. S., Rubin A. S., Voice R. F., Beckmann M. P., Widmer M. B. Regulation of alloreactivity in vivo by IL-4 and the soluble IL-4 receptor. J Immunol. 1991 Jul 15;147(2):535–540. [PubMed] [Google Scholar]
  7. Fling J. A., Ruff M. E., Parker W. A., Whisman B. A., Martin M. E., Moss R. B., Reid M. J. Suppression of the late cutaneous response by immunotherapy. J Allergy Clin Immunol. 1989 Jan;83(1):101–109. doi: 10.1016/0091-6749(89)90483-1. [DOI] [PubMed] [Google Scholar]
  8. Frew A. J., Kay A. B. The pattern of human late-phase skin reactions to extracts of aeroallergens. J Allergy Clin Immunol. 1988 Jun;81(6):1117–1121. doi: 10.1016/0091-6749(88)90878-0. [DOI] [PubMed] [Google Scholar]
  9. Frew A. J., Kay A. B. The relationship between infiltrating CD4+ lymphocytes, activated eosinophils, and the magnitude of the allergen-induced late phase cutaneous reaction in man. J Immunol. 1988 Dec 15;141(12):4158–4164. [PubMed] [Google Scholar]
  10. Frew A. J., Kay A. B. UCHL1+ (CD45RO+) 'memory' T cells predominate in the CD4+ cellular infiltrate associated with allergen-induced late-phase skin reactions in atopic subjects. Clin Exp Immunol. 1991 May;84(2):270–274. doi: 10.1111/j.1365-2249.1991.tb08160.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frew A. J., O'Hehir R. E. What can we learn from studies of lymphocytes present in allergic-reaction sites? J Allergy Clin Immunol. 1992 Apr;89(4):783–788. doi: 10.1016/0091-6749(92)90431-z. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. Hamid Q., Barkans J., Robinson D. S., Durham S. R., Kay A. B. Co-expression of CD25 and CD3 in atopic allergy and asthma. Immunology. 1992 Apr;75(4):659–663. [PMC free article] [PubMed] [Google Scholar]
  15. Herzog C., Walker C., Müller W., Rieber P., Reiter C., Riethmüller G., Wassmer P., Stockinger H., Madic O., Pichler W. J. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J Autoimmun. 1989 Oct;2(5):627–642. doi: 10.1016/s0896-8411(89)80002-2. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Kemeny D. M., Tomioka H., Tsutsumi A., Koike T., Lessof M. H., Lee T. H. The relationship between anti-IgE auto-antibodies and the IgE response to wasp venom during immunotherapy. Clin Exp Allergy. 1990 Jan;20(1):67–69. doi: 10.1111/j.1365-2222.1990.tb02777.x. [DOI] [PubMed] [Google Scholar]
  18. Kita H., Ohnishi T., Okubo Y., Weiler D., Abrams J. S., Gleich G. J. Granulocyte/macrophage colony-stimulating factor and interleukin 3 release from human peripheral blood eosinophils and neutrophils. J Exp Med. 1991 Sep 1;174(3):745–748. doi: 10.1084/jem.174.3.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lichtenstein L. M., Ishizaka K., Norman P. S., Sobotka A. K., Hill B. M. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J Clin Invest. 1973 Feb;52(2):472–482. doi: 10.1172/JCI107204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lichtenstein L. M., Norman P. S., Winkenwerder W. L. A single year of immunotherapy for ragweed hay fever. Immunologic and clinical studies. Ann Intern Med. 1971 Nov;75(5):663–671. doi: 10.7326/0003-4819-75-5-663. [DOI] [PubMed] [Google Scholar]
  21. McHugh S. M., Ewan P. W. Reduction of increased serum neutrophil chemotactic activity following effective hyposensitization in house dust mite allergy. Clin Exp Allergy. 1989 May;19(3):327–334. doi: 10.1111/j.1365-2222.1989.tb02391.x. [DOI] [PubMed] [Google Scholar]
  22. Moqbel R., Hamid Q., Ying S., Barkans J., Hartnell A., Tsicopoulos A., Wardlaw A. J., Kay A. B. Expression of mRNA and immunoreactivity for the granulocyte/macrophage colony-stimulating factor in activated human eosinophils. J Exp Med. 1991 Sep 1;174(3):749–752. doi: 10.1084/jem.174.3.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mosbech H., Osterballe O. Does the effect of immunotherapy last after termination of treatment? Follow-up study in patients with grass pollen rhinitis. Allergy. 1988 Oct;43(7):523–529. doi: 10.1111/j.1398-9995.1988.tb01631.x. [DOI] [PubMed] [Google Scholar]
  24. Nagaya H. Induction of antigen-specific suppressor cells in patients with hay fever receiving immunotherapy. J Allergy Clin Immunol. 1985 Mar;75(3):388–394. doi: 10.1016/0091-6749(85)90077-6. [DOI] [PubMed] [Google Scholar]
  25. Norman P. S. Immunotherapy. Prog Allergy. 1982;32:318–346. doi: 10.1159/000318291. [DOI] [PubMed] [Google Scholar]
  26. O'Hehir R. E., Aguilar B. A., Schmidt T. J., Gollnick S. O., Lamb J. R. Functional inactivation of Dermatophagoides spp. (house dust mite) reactive human T-cell clones. Clin Exp Allergy. 1991 Mar;21(2):209–215. doi: 10.1111/j.1365-2222.1991.tb00832.x. [DOI] [PubMed] [Google Scholar]
  27. O'Hehir R. E., Yssel H., Verma S., de Vries J. E., Spits H., Lamb J. R. Clonal analysis of differential lymphokine production in peptide and superantigen induced T cell anergy. Int Immunol. 1991 Aug;3(8):819–826. doi: 10.1093/intimm/3.8.819. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Plaut M., Pierce J. H., Watson C. J., Hanley-Hyde J., Nordan R. P., Paul W. E. Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores. Nature. 1989 May 4;339(6219):64–67. doi: 10.1038/339064a0. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Rocklin R. E. Immune mechanisms in allergen-specific immunotherapy. Clin Immunol Immunopathol. 1989 Nov;53(2 Pt 2):S119–S131. doi: 10.1016/0090-1229(89)90077-9. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Van Bever H. P., Stevens W. J. Suppression of the late asthmatic reaction by hyposensitization in asthmatic children allergic to house dust mite (Dermatophagoides pteronyssinus). Clin Exp Allergy. 1989 Jul;19(4):399–404. doi: 10.1111/j.1365-2222.1989.tb02405.x. [DOI] [PubMed] [Google Scholar]
  34. Varney V. A., Gaga M., Frew A. J., Aber V. R., Kay A. B., Durham S. R. Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. BMJ. 1991 Feb 2;302(6771):265–269. doi: 10.1136/bmj.302.6771.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Varney V. A., Jacobson M. R., Sudderick R. M., Robinson D. S., Irani A. M., Schwartz L. B., Mackay I. S., Kay A. B., Durham S. R. Immunohistology of the nasal mucosa following allergen-induced rhinitis. Identification of activated T lymphocytes, eosinophils, and neutrophils. Am Rev Respir Dis. 1992 Jul;146(1):170–176. doi: 10.1164/ajrccm/146.1.170. [DOI] [PubMed] [Google Scholar]
  36. Varney V., Gaga M., Frew A. J., De Vos C., Kay A. B. The effect of a single oral dose of prednisolone or cetirizine on inflammatory cells infiltrating allergen-induced cutaneous late-phase reactions in atopic subjects. Clin Exp Allergy. 1992 Jan;22(1):43–49. doi: 10.1111/j.1365-2222.1992.tb00113.x. [DOI] [PubMed] [Google Scholar]
  37. Warner J. O., Price J. F., Soothill J. F., Hey E. N. Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma. Lancet. 1978 Oct 28;2(8096):912–915. doi: 10.1016/s0140-6736(78)91630-6. [DOI] [PubMed] [Google Scholar]
  38. Wodnar-Filipowicz A., Heusser C. H., Moroni C. Production of the haemopoietic growth factors GM-CSF and interleukin-3 by mast cells in response to IgE receptor-mediated activation. Nature. 1989 May 11;339(6220):150–152. doi: 10.1038/339150a0. [DOI] [PubMed] [Google Scholar]

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