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Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1997 Nov;110(2):167–173. doi: 10.1111/j.1365-2249.1997.tb08313.x

A double blind, placebo-controlled, crossover therapy study with natural human IL-2 (nhuIL-2) in combination with regular intravenous gammaglobulin (IVIG) infusions in 10 patients with common variable immunodeficiency (CVID)

J A RUMP 1, A JAHREIS 1, M SCHLESIER 1, S STECHER 1, H H PETER 1
PMCID: PMC2265503  PMID: 9367398

Abstract

Ten CVID patients with defective IL-2 synthesis in vitro were treated with nhuIL-2 in a placebo-controlled, double blind, crossover therapy study during a period of 12 months. No severe side-effects of nhuIL-2 were recorded. Marginal serum nhuIL-2 levels were measurable in individual patients only during the therapy phase. Serum levels of soluble IL-2 receptors were unaffected by the therapy. nhuIL-2 and placebo groups did not differ significantly with respect to requirement of IVIG substitutions which were performed whenever serum IgG levels dropped below 5 g/l: a total of 53 IVIG infusions (corresponding to 17.6 g IgG/month per patient) was necessary during the placebo phase, and 48 infusions (16-4 g IgG/month per patient) during the nhuIL-2 treatment phase. Thus, nhuIL-2 therapy was ineffective in improving spontaneous IgG synthesis in vivo. Nevertheless, the group of patients receiving nhuIL-2 during the first 6 months of the study exhibited a significant reduction of severe infections (n = 25) during the following 6 months of placebo treatment (n = 7) (P < 0–045). The infection score dropped in this group from 181 to 23 (P < 0015). Patients of the second group receiving first placebo and then nhuIL-2 did not experience a significant difference in number and score of infectious episodes: 25 infections were recorded during the first 6 months and 24 during the following 6 months. We suppose that nhuIL-2 therapy of CVID patients reduces susceptibility to severe infections, possibly via the induction of a specific antibody response, which is effective at the earliest 6 months after initiating nhuIL-2 therapy.

Keywords: common variable immunodeficiency, IL-2, nhuIL-2 therapy

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References

  • 1.WHO Scientific Group. Primary immunodeficiency diseases: report of a WHO Scientific Group. Immunodefic Rev. 1992;3:195–236. [PubMed] [Google Scholar]
  • 2.WHO Scientific Group. Primary immunodeficiency diseases. Clin Exp Immunol. 1995;99(Suppl. 1):10–19. [PMC free article] [PubMed] [Google Scholar]
  • 3.Webster ADB, Farrant J, Hany M, North M, Toubi E, Beattie R. Clinical and cellular features of ‘common variable’ hypogammaglobulinemia. J Immunol Immunopharmacol. 1990;10:14–16. [Google Scholar]
  • 4.Saiki O, Ralph P, Cunningham-Rundles C, Good RA. Three distinct B cell defects in common variable immunodeficiency. Proc Natl Acad Sci USA. 1982;79:6008–12. doi: 10.1073/pnas.79.19.6008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Saxon A, Giorgi JV, Sherr EH, Kagan JM. The failure of B cells in common variable immunodeficiency to transit from proliferation to differentiation is associated with altered B cell surface display. J Allergy Clin Immunol. 1989;841:44–55. doi: 10.1016/0091-6749(89)90177-2. [DOI] [PubMed] [Google Scholar]
  • 6.Farrant J, Bryant A, Almandoz F, Spickett G, Evans SW, Webster ADB. B cell function in acquired common variable hypogammaglobulinemia: proliverative responses to lymphokines. Clin Immunol Immunopathol. 1989;51:196–204. doi: 10.1016/0090-1229(89)90019-6. [DOI] [PubMed] [Google Scholar]
  • 7.Spickett GP, Webster ADB, Farrant J. Cellular abnormalities in common variable immunodeficiency. Immunodef Rev. 1990;2:199–219. [PubMed] [Google Scholar]
  • 8.North ME, Spickett GP, Allsop J. Defects in proliferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C. Clin Exp Immunol. 1991;85:198–201. doi: 10.1111/j.1365-2249.1991.tb05704.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Baumert E, Wolff-Vorbeck G, Schlesier M, Peter HH. Immunophenotypical alterations in a subset of patients with common variable immunodeficiency (CVID) Clin Exp Immunol. 1992;90:25–30. doi: 10.1111/j.1365-2249.1992.tb05826.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Stagg AJ, Funauchi M, Knight SC, Webster ADB, Farrant J. Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID) Clin Exp Immunol. 1994;96:48–53. doi: 10.1111/j.1365-2249.1994.tb06228.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Fischer MB, Hauber I, Eggenbauer H, et al. A defect in early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency. Blood. 1994;84:4234–41. [PubMed] [Google Scholar]
  • 12.Funauchi M, Farrant J, Moreno C, Webster ADB. Defects in antigen-driven lymphocyte responses in common variable immunodeficiency (CVID) are due to a reduction in the number of antigen-specific CD4+ T cells. Clin Exp Immunol. 1995;101:82–88. doi: 10.1111/j.1365-2249.1995.tb02281.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Spickett GP, Farrant J. The role of lymphokines in common variable hypogammaglobulinemia. Immunol Today. 1989;6:192–4. doi: 10.1016/0167-5699(89)90323-X. [DOI] [PubMed] [Google Scholar]
  • 14.Pastorelli G, Roncarlo MG, Touraine JL, Peronne G, Tovo PA, De Vries JE. Peripheral blood lymphocytes of patients with common variable immunodeficiency (CVID) produce reduced levels of interleukin 4, interleukin 2 and interferon-gamma, but proliferate normally upon activation by mitogens. Clin Exp Immunol. 1989;78:334–40. [PMC free article] [PubMed] [Google Scholar]
  • 15.Fischer MB, Hauber I, Vogel E, Wolf HM, Mannhalter JW, Eibl MM. Defective interleukin-2 and interferon-γ gene expression in response to antigen in a subgroup of patients with common variable immunodeficiency. J Allergy Clin Immunol. 1993;92:340–52. doi: 10.1016/0091-6749(93)90178-i. [DOI] [PubMed] [Google Scholar]
  • 16.Eisenstein EM, Laffe JS, Strober W. Reduced interleukin-2 (IL-2) production in common variable immunodeficiency is due to a primary abnormality of CD4+ T cell differentiation. J Clin Immunol. 1993;13:247–58. doi: 10.1007/BF00919383. [DOI] [PubMed] [Google Scholar]
  • 17.Ferrer IM, Iglesias J, Hernandez M, Matamoros N. Alterations in interleukin secretion (IL-2 and IL-4) by CD4 and CD4 CD45RO cells from common variable immunodeficiency (CVI) patients. Clin Exp Immunol. 1995;102:286–9. doi: 10.1111/j.1365-2249.1995.tb03779.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Hauber I, Fischer MB, Maris M, Eibl MM. Reduced IL-2 expression upon antigen stimulation is accompanied by deficient IL9 gene expression in T cells of patients with CVID. Scand J Immunol. 1995;41:215–9. doi: 10.1111/j.1365-3083.1995.tb03556.x. [DOI] [PubMed] [Google Scholar]
  • 19.Rump JA, Lahreis A, Schlesier M, Dräger R, Melchers I, Peter HH. Possible role of IL2 deficiency for hypogammaglobulinemia in patients with common variable immunodeficiency. Clin Exp Immunol. 1992;89:204–10. doi: 10.1111/j.1365-2249.1992.tb06933.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Zielen S, Bauscher P, Hofmann D, Meuer SC. Interleukin 10 and immune restoration in common variable immunodeficiency. Lancet. 1993;342:750–1. [PubMed] [Google Scholar]
  • 21.Punnonen J, Kainulainen L, Ruuskanen O, Nikoskelainen J, Arvilommi H. IL-4 synergizes with IL-10 and anti-CD40 MoAbs to induce B-cell differentiation in patients with common variable immunodeficiency. Scand J Immunol. 1997;45:203–12. doi: 10.1046/j.1365-3083.1997.d01-381.x. [DOI] [PubMed] [Google Scholar]
  • 22.North ME, Akbar A, Borthwick N, Webster ADB. Anti-CD28 enhances defective mitogen responses by mononuclear cells from patients with common variable immunodeficiency. Immunodeficiency. 1993;4:17–18. [PubMed] [Google Scholar]
  • 23.North ME, Akbar AN, Borthwick N, Sagawa K, Funauchi M, Webster ADB. Co-stimulation with anti-CD28 (Kolt-2) enhance DNA synthesis by defective T-cells in common variable immunodeficiency. Clin Exp Immunol. 1994;95:204–8. doi: 10.1111/j.1365-2249.1994.tb06511.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Fischer MB, Wolf HM, Eggenbauer H, et al. The costimulatory signal CD28 is fully functional but cannot correct the impaired antigen response in T cells of patients with common variable immunodeficiency. Clin Exp Immunol. 1994;95:209–14. doi: 10.1111/j.1365-2249.1994.tb06512.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Moser C, Schlesier M, Dräger R, Eibel H, Peter HH. Transient CD80 expression defect in a patient with variable immunodeficiency and cyclic neutropenia. Int Arch Allergy Immunol. 1997;112:96–99. doi: 10.1159/000237438. [DOI] [PubMed] [Google Scholar]
  • 26.Farrington M, Grosmaire LS, Nonoyama S, et al. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci USA. 1994;91:1099–103. doi: 10.1073/pnas.91.3.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Nonoyama S, Farrington ML, Ochs HD. Effect on immunoglobulin production by anti-CD40-activated human B cells: synergistic effect with IL-10 and antagonistic effect with IL-4. Clin Immunol Immunopathol. 1994;72:373–9. doi: 10.1006/clin.1994.1155. [DOI] [PubMed] [Google Scholar]
  • 28.Thon V, Eggenbauer H, Wolf HM, Fischer MB, Litzmann J, Lokaj J, Eibl MM. Antigen presentation by common variable immunodeficiency (CVID) B cells and monocytes is unimpaired. Clin Exp Immunol. 1997;108:1–8. doi: 10.1046/j.1365-2249.1997.d01-989.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Bryant A, Calver NC, Toubi E, Webster ADB, Farrant J. Classification of patients with common variable immuno-deficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2. Clin Immunol Immunopathol. 1990;56:239–48. doi: 10.1016/0090-1229(90)90145-g. [DOI] [PubMed] [Google Scholar]
  • 30.Smith KA. Interleukin-2: inception impact and implications. Science. 1988;240:1169–76. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  • 31.Paul WE. Pleiotropy and redundancy: T cell-derived lymphokines in the immune response. Cell. 1989;57:521–4. doi: 10.1016/0092-8674(89)90121-9. [DOI] [PubMed] [Google Scholar]
  • 32.Riegel JS, Corthesy B, Flanagan WM, Crabtree GR. Regulation of the interleukin-2 gene. In: Kichimoto T, editor. Interleukins: molecular biology and immunology. Vol. 51. Basel: Karger-Verlag. Chem Immunol; 1992. pp. 266–98. [PubMed] [Google Scholar]
  • 33.Nonoyama S, Farrington M, Ishida H, Howard M, Ochs HD. Activated B cells from patients with common variable immunodeficiency proliferate and synthesize immunoglobulin. J Clin Invest. 1993;92:1282–7. doi: 10.1172/JCI116701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Meuer SC, Dumann H, Meyer zum Büschelfelde KH, Kohler H. Low dose interleukin 2 induces systemic immune responses against HbsAg in immunodeficient non responders to hepatitis B vaccination. Lancet. 1989;1:15–17. doi: 10.1016/s0140-6736(89)91674-7. [DOI] [PubMed] [Google Scholar]
  • 35.Cunningham-Rundles C, Mayer L, Sapira E, Mendelsohn L. Restoration of immunoglobulin secretion in vitro in common variable immunodeficiency by in vivo treatment with polyethylene glycol-conjugated human recombinant interleukin-2. Clin Immunol Immunopathol. 1992;64:46–56. doi: 10.1016/0090-1229(92)90058-v. [DOI] [PubMed] [Google Scholar]
  • 36.Cunningham-Rundles C, Kasbay K, Mayer L. Potential use of polyethyleneglycol conjugated recombinant IL-2 in common variable immunodeficiency. Immunodeficiency. 1993;4:31–36. [PubMed] [Google Scholar]
  • 37.Cunningham-Rundles C, Kazbay K, Hassett J, Zhou Z, Mayer L. Brief report: enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethyleneglycol conjugated interleukin-2. N Engl J Med. 1994;331:918–21. doi: 10.1056/NEJM199410063311405. [DOI] [PubMed] [Google Scholar]
  • 38.Wallays G, Ceuppens JL. Ligation of leucocyte function-associated (LFA) molecule-1 provides an accessory signal for T-cell activation with pokeweed mitogen. Scand J Immunol. 1994;39:137–43. doi: 10.1111/j.1365-3083.1994.tb03352.x. [DOI] [PubMed] [Google Scholar]
  • 39.Cunningham-Rundles C. Clinical and immunologic analyses of 103 patients with common variable immunodeficiency. J Clin Immunol. 1989;9:22–33. doi: 10.1007/BF00917124. [DOI] [PubMed] [Google Scholar]

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