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. 1998 Mar 15;101(6):1373–1378. doi: 10.1172/JCI2038

Ultra low dose interleukin-2 therapy promotes a type 1 cytokine profile in vivo in patients with AIDS and AIDS-associated malignancies.

V P Khatri 1, T A Fehniger 1, R A Baiocchi 1, F Yu 1, M H Shah 1, D S Schiller 1, M Gould 1, R T Gazzinelli 1, Z P Bernstein 1, M A Caligiuri 1
PMCID: PMC508692  PMID: 9502779

Abstract

This study was undertaken to determine if prolonged daily subcutaneous administration of ultra low dose IL-2 could influence the constitutive endogenous production of a type 1 (IFN-gamma) cytokine in patients with AIDS or AIDS-associated malignancies. Using a quantitative reverse transcription PCR assay, we demonstrate that daily administration of one type 1 cytokine, IL-2, for 3 mo increases significantly the constitutive endogenous gene expression of another type 1 cytokine, IFN-gamma, in vivo. The predominant source of IFN-gamma appears to be IL-2-expanded natural killer cells and CD8(+) T cells. Moreover, PBMC obtained from these patients during IL-2 therapy showed normalization of a profound deficit in IFN-gamma protein production after stimulation with extracts from infectious agents in vitro. Our data suggest that prolonged exogenous administration of a type 1 cytokine in a nontoxic fashion to patients with AIDS and AIDS-associated malignancies can enhance significantly the endogenous type 1 cytokine profile in vivo. Consequently, ultra low dose IL-2 therapy has the potential to improve the immunodeficient hosts' immune response to infectious pathogens that require IFN-gamma for clearance.

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Selected References

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

  1. Bancroft G. J. The role of natural killer cells in innate resistance to infection. Curr Opin Immunol. 1993 Aug;5(4):503–510. doi: 10.1016/0952-7915(93)90030-v. [DOI] [PubMed] [Google Scholar]
  2. Bernstein Z. P., Porter M. M., Gould M., Lipman B., Bluman E. M., Stewart C. C., Hewitt R. G., Fyfe G., Poiesz B., Caligiuri M. A. Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood. 1995 Nov 1;86(9):3287–3294. [PubMed] [Google Scholar]
  3. Caligiuri M. A. Low-dose recombinant interleukin-2 therapy: rationale and potential clinical applications. Semin Oncol. 1993 Dec;20(6 Suppl 9):3–10. [PubMed] [Google Scholar]
  4. Carson W. E., Fehniger T. A., Caligiuri M. A. CD56bright natural killer cell subsets: characterization of distinct functional responses to interleukin-2 and the c-kit ligand. Eur J Immunol. 1997 Feb;27(2):354–360. doi: 10.1002/eji.1830270203. [DOI] [PubMed] [Google Scholar]
  5. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chomarat P., Rissoan M. C., Banchereau J., Miossec P. Interferon gamma inhibits interleukin 10 production by monocytes. J Exp Med. 1993 Feb 1;177(2):523–527. doi: 10.1084/jem.177.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
  8. Connors M., Kovacs J. A., Krevat S., Gea-Banacloche J. C., Sneller M. C., Flanigan M., Metcalf J. A., Walker R. E., Falloon J., Baseler M. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med. 1997 May;3(5):533–540. doi: 10.1038/nm0597-533. [DOI] [PubMed] [Google Scholar]
  9. Denkers E. Y., Gazzinelli R. T., Martin D., Sher A. Emergence of NK1.1+ cells as effectors of IFN-gamma dependent immunity to Toxoplasma gondii in MHC class I-deficient mice. J Exp Med. 1993 Nov 1;178(5):1465–1472. doi: 10.1084/jem.178.5.1465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fauci A. S. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993 Nov 12;262(5136):1011–1018. doi: 10.1126/science.8235617. [DOI] [PubMed] [Google Scholar]
  11. Gazzinelli R. T., Bala S., Stevens R., Baseler M., Wahl L., Kovacs J., Sher A. HIV infection suppresses type 1 lymphokine and IL-12 responses to Toxoplasma gondii but fails to inhibit the synthesis of other parasite-induced monokines. J Immunol. 1995 Aug 1;155(3):1565–1574. [PubMed] [Google Scholar]
  12. Gazzinelli R. T., Hieny S., Wynn T. A., Wolf S., Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. doi: 10.1073/pnas.90.13.6115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gong J. H., Maki G., Klingemann H. G. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia. 1994 Apr;8(4):652–658. [PubMed] [Google Scholar]
  14. Graziosi C., Pantaleo G., Gantt K. R., Fortin J. P., Demarest J. F., Cohen O. J., Sékaly R. P., Fauci A. S. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994 Jul 8;265(5169):248–252. doi: 10.1126/science.8023143. [DOI] [PubMed] [Google Scholar]
  15. Jacobson E. L., Pilaro F., Smith K. A. Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10405–10410. doi: 10.1073/pnas.93.19.10405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jouanguy E., Altare F., Lamhamedi S., Revy P., Emile J. F., Newport M., Levin M., Blanche S., Seboun E., Fischer A. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection. N Engl J Med. 1996 Dec 26;335(26):1956–1961. doi: 10.1056/NEJM199612263352604. [DOI] [PubMed] [Google Scholar]
  17. Kinter A., Fauci A. S. Interleukin-2 and human immunodeficiency virus infection: pathogenic mechanisms and potential for immunologic enhancement. Immunol Res. 1996;15(1):1–15. doi: 10.1007/BF02918280. [DOI] [PubMed] [Google Scholar]
  18. Kubin M., Chow J. M., Trinchieri G. Differential regulation of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-1 beta production in human myeloid leukemia cell lines and peripheral blood mononuclear cells. Blood. 1994 Apr 1;83(7):1847–1855. [PubMed] [Google Scholar]
  19. Ma X., Chow J. M., Gri G., Carra G., Gerosa F., Wolf S. F., Dzialo R., Trinchieri G. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med. 1996 Jan 1;183(1):147–157. doi: 10.1084/jem.183.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Maggi E., Mazzetti M., Ravina A., Annunziato F., de Carli M., Piccinni M. P., Manetti R., Carbonari M., Pesce A. M., del Prete G. Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells. Science. 1994 Jul 8;265(5169):244–248. doi: 10.1126/science.8023142. [DOI] [PubMed] [Google Scholar]
  21. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  22. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  23. Murray H. W. Interferon-gamma and host antimicrobial defense: current and future clinical applications. Am J Med. 1994 Nov;97(5):459–467. doi: 10.1016/0002-9343(94)90326-3. [DOI] [PubMed] [Google Scholar]
  24. Newport M. J., Huxley C. M., Huston S., Hawrylowicz C. M., Oostra B. A., Williamson R., Levin M. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996 Dec 26;335(26):1941–1949. doi: 10.1056/NEJM199612263352602. [DOI] [PubMed] [Google Scholar]
  25. Reiner S. L., Zheng S., Corry D. B., Locksley R. M. Constructing polycompetitor cDNAs for quantitative PCR. J Immunol Methods. 1993 Sep 27;165(1):37–46. doi: 10.1016/0022-1759(93)90104-f. [DOI] [PubMed] [Google Scholar]
  26. Romagnani S. Biology of human TH1 and TH2 cells. J Clin Immunol. 1995 May;15(3):121–129. doi: 10.1007/BF01543103. [DOI] [PubMed] [Google Scholar]
  27. Ross M. E., Caligiuri M. A. Cytokine-induced apoptosis of human natural killer cells identifies a novel mechanism to regulate the innate immune response. Blood. 1997 Feb 1;89(3):910–918. [PubMed] [Google Scholar]
  28. Schnittman S. M., Fauci A. S. Human immunodeficiency virus and acquired immunodeficiency syndrome: an update. Adv Intern Med. 1994;39:305–355. [PubMed] [Google Scholar]
  29. Soudeyns H., Rebai N., Pantaleo G. P., Ciurli C., Boghossian T., Sékaly R. P., Fauci A. S. The T cell receptor V beta repertoire in HIV-1 infection and disease. Semin Immunol. 1993 Jun;5(3):175–185. doi: 10.1006/smim.1993.1021. [DOI] [PubMed] [Google Scholar]
  30. Stewart C. C., Stewart S. J. Cell preparation for the identification of leukocytes. Methods Cell Biol. 1994;41:39–60. doi: 10.1016/s0091-679x(08)61708-2. [DOI] [PubMed] [Google Scholar]
  31. Tripp C. S., Wolf S. F., Unanue E. R. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. doi: 10.1073/pnas.90.8.3725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wu C., Warrier R. R., Wang X., Presky D. H., Gately M. K. Regulation of interleukin-12 receptor beta1 chain expression and interleukin-12 binding by human peripheral blood mononuclear cells. Eur J Immunol. 1997 Jan;27(1):147–154. doi: 10.1002/eji.1830270122. [DOI] [PubMed] [Google Scholar]

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