Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Feb 1;177(2):483–492. doi: 10.1084/jem.177.2.483

Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection

PMCID: PMC2190894  PMID: 8093894

Abstract

13 patients with human immunodeficiency virus type 1 infection class II- IV, but without opportunistic infection or neoplasm, received 6 micrograms (3.6 x 10(4) IU) of polyethylene glycol recombinant human interleukin 2 (PEG IL-2) intradermally twice a week for 4 mo were then followed for an additional 6 mo. Clinical, immunological, and viral parameters were monitored in the patients, all of whom were taking zidovudine. The cutaneous administration of PEG IL-2 resulted in an indurated zone resembling a delayed-type hypersensitivity response of 26 +/- 1 mm diameter (676 mm2) at 72-96 h after injection throughout the 4 mo of administration. This dose, which was appreciably lower than in most previous trials, was not associated with local or systemic toxicity. No increase in the viral burden of circulating leukocytes or plasma occurred. A number of immunological functions were stimulated by this course of therapy. All patients demonstrated high levels of lymphokine-activated killer cell activity by cells freshly removed from the circulation and in the absence of in vitro exposure to IL-2. Natural killer cell activity was also enhanced. Limiting dilution analysis revealed an increase in the frequency of IL-2-responsive cells from abnormally low to levels above normal during the course of injections. In a subgroup of four patients with > or = 400 CD4+ T cells/microliter at entry, there was a trend to sustained increases in CD4+ T cell numbers. However, this increase did not reach statistical significance. This subset of patients also exhibited higher proliferative responses to phytohemagglutinin as mitogen. Several of these effects persisted for 3-6 mo after cessation of therapy. In conclusion, low-dose IL-2 regimens lead to sustained immune enhancement in the absence of toxicity. We suggest pursuit of this approach for further clinical trials both as prophylaxis and therapy.

Full Text

The Full Text of this article is available as a PDF (874.4 KB).

Selected References

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

  1. Bonavida B., Katz J., Gottlieb M. Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. I. Defective trigger on NK cells for NKCF production by target cells, and partial restoration by IL 2. J Immunol. 1986 Aug 15;137(4):1157–1163. [PubMed] [Google Scholar]
  2. Ciobanu N., Welte K., Kruger G., Venuta S., Gold J., Feldman S. P., Wang C. Y., Koziner B., Moore M. A., Safai B. Defective T-cell response to PHA and mitogenic monoclonal antibodies in male homosexuals with acquired immunodeficiency syndrome and its in vitro correction by interleukin 2. J Clin Immunol. 1983 Oct;3(4):332–340. doi: 10.1007/BF00915794. [DOI] [PubMed] [Google Scholar]
  3. Clark A. G., Holodniy M., Schwartz D. H., Katzenstein D. A., Merigan T. C. Decrease in HIV provirus in peripheral blood mononuclear cells during zidovudine and human rIL-2 administration. J Acquir Immune Defic Syndr. 1992;5(1):52–59. [PubMed] [Google Scholar]
  4. Coombs R. W., Collier A. C., Allain J. P., Nikora B., Leuther M., Gjerset G. F., Corey L. Plasma viremia in human immunodeficiency virus infection. N Engl J Med. 1989 Dec 14;321(24):1626–1631. doi: 10.1056/NEJM198912143212402. [DOI] [PubMed] [Google Scholar]
  5. Ernst M., Kern P., Flad H. D., Ulmer A. J. Effects of systemic in vivo interleukin-2 (IL-2) reconstitution in patients with acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC) on phenotypes and functions of peripheral blood mononuclear cells (PBMC). J Clin Immunol. 1986 Mar;6(2):170–181. doi: 10.1007/BF00918750. [DOI] [PubMed] [Google Scholar]
  6. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  7. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kaplan G., Britton W. J., Hancock G. E., Theuvenet W. J., Smith K. A., Job C. K., Roche P. W., Molloy A., Burkhardt R., Barker J. The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy. J Exp Med. 1991 Apr 1;173(4):993–1006. doi: 10.1084/jem.173.4.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kaplan G., Kiessling R., Teklemariam S., Hancock G., Sheftel G., Job C. K., Converse P., Ottenhoff T. H., Becx-Bleumink M., Dietz M. The reconstitution of cell-mediated immunity in the cutaneous lesions of lepromatous leprosy by recombinant interleukin 2. J Exp Med. 1989 Mar 1;169(3):893–907. doi: 10.1084/jem.169.3.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kern P., Toy J., Dietrich M. Preliminary clinical observations with recombinant interleukin-2 in patients with AIDS or LAS. Blut. 1985 Jan;50(1):1–6. doi: 10.1007/BF00319762. [DOI] [PubMed] [Google Scholar]
  11. Lane H. C., Depper J. M., Greene W. C., Whalen G., Waldmann T. A., Fauci A. S. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985 Jul 11;313(2):79–84. doi: 10.1056/NEJM198507113130204. [DOI] [PubMed] [Google Scholar]
  12. Lane H. C., Siegel J. P., Rook A. H., Masur H., Gelmann E. P., Quinnan G. V., Fauci A. S. Use of interleukin-2 in patients with acquired immunodeficiency syndrome. J Biol Response Mod. 1984 Oct;3(5):512–516. [PubMed] [Google Scholar]
  13. Lemp G. F., Payne S. F., Rutherford G. W., Hessol N. A., Winkelstein W., Jr, Wiley J. A., Moss A. R., Chaisson R. E., Chen R. T., Feigal D. W., Jr Projections of AIDS morbidity and mortality in San Francisco. JAMA. 1990 Mar 16;263(11):1497–1501. [PubMed] [Google Scholar]
  14. Leoung G. S., Feigal D. W., Jr, Montgomery A. B., Corkery K., Wardlaw L., Adams M., Busch D., Gordon S., Jacobson M. A., Volberding P. A. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia. The San Francisco community prophylaxis trial. N Engl J Med. 1990 Sep 20;323(12):769–775. doi: 10.1056/NEJM199009203231201. [DOI] [PubMed] [Google Scholar]
  15. Lotze M. T., Robb R. J., Sharrow S. O., Frana L. W., Rosenberg S. A. Systemic administration of interleukin-2 in humans. J Biol Response Mod. 1984 Oct;3(5):475–482. [PubMed] [Google Scholar]
  16. McElrath M. J., Kaplan G., Burkhardt R. A., Cohn Z. A. Cutaneous response to recombinant interleukin 2 in human immunodeficiency virus 1-seropositive individuals. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5783–5787. doi: 10.1073/pnas.87.15.5783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. McElrath M. J., Pruett J. E., Cohn Z. A. Mononuclear phagocytes of blood and bone marrow: comparative roles as viral reservoirs in human immunodeficiency virus type 1 infections. Proc Natl Acad Sci U S A. 1989 Jan;86(2):675–679. doi: 10.1073/pnas.86.2.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mertelsmann R., Welte K., Sternberg C., O'Reilly R., Moore M. A., Clarkson B. D., Oettgen H. F. Treatment of immunodeficiency with interleukin-2: initial exploration. J Biol Response Mod. 1984 Oct;3(5):483–490. [PubMed] [Google Scholar]
  19. Moss A. R., Bacchetti P., Osmond D., Krampf W., Chaisson R. E., Stites D., Wilber J., Allain J. P., Carlson J. Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort. Br Med J (Clin Res Ed) 1988 Mar 12;296(6624):745–750. doi: 10.1136/bmj.296.6624.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Murray H. W., Welte K., Jacobs J. L., Rubin B. Y., Mertelsmann R., Roberts R. B. Production of and in vitro response to interleukin 2 in the acquired immunodeficiency syndrome. J Clin Invest. 1985 Nov;76(5):1959–1964. doi: 10.1172/JCI112194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Quinnan G. V., Jr, Siegel J. P., Epstein J. S., Manischewitz J. F., Barnes S., Wells M. A. Mechanisms of T-cell functional deficiency in the acquired immunodeficiency syndrome. Ann Intern Med. 1985 Nov;103(5):710–714. doi: 10.7326/0003-4819-103-5-710. [DOI] [PubMed] [Google Scholar]
  22. Rook A. H., Hooks J. J., Quinnan G. V., Lane H. C., Manischewitz J. F., Macher A. M., Masur H., Fauci A. S., Djeu J. Y. Interleukin 2 enhances the natural killer cell activity of acquired immunodeficiency syndrome patients through a gamma-interferon-independent mechanism. J Immunol. 1985 Mar;134(3):1503–1507. [PubMed] [Google Scholar]
  23. Rook A. H., Masur H., Lane H. C., Frederick W., Kasahara T., Macher A. M., Djeu J. Y., Manischewitz J. F., Jackson L., Fauci A. S. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. J Clin Invest. 1983 Jul;72(1):398–403. doi: 10.1172/JCI110981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schwartz D. H., Skowron G., Merigan T. C. Safety and effects of interleukin-2 plus zidovudine in asymptomatic individuals infected with human immunodeficiency virus. J Acquir Immune Defic Syndr. 1991;4(1):11–23. [PubMed] [Google Scholar]
  25. Siegel J. P., Puri R. K. Interleukin-2 toxicity. J Clin Oncol. 1991 Apr;9(4):694–704. doi: 10.1200/JCO.1991.9.4.694. [DOI] [PubMed] [Google Scholar]
  26. Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
  27. Soiffer R. J., Murray C., Cochran K., Cameron C., Wang E., Schow P. W., Daley J. F., Ritz J. Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood. 1992 Jan 15;79(2):517–526. [PubMed] [Google Scholar]
  28. Stein R. C., Malkovska V., Morgan S., Galazka A., Aniszewski C., Roy S. E., Shearer R. J., Marsden R. A., Bevan D., Gordon-Smith E. C. The clinical effects of prolonged treatment of patients with advanced cancer with low-dose subcutaneous interleukin-2 [corrected]. Br J Cancer. 1991 Feb;63(2):275–278. doi: 10.1038/bjc.1991.64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Taniguchi T., Matsui H., Fujita T., Takaoka C., Kashima N., Yoshimoto R., Hamuro J. Structure and expression of a cloned cDNA for human interleukin-2. Nature. 1983 Mar 24;302(5906):305–310. doi: 10.1038/302305a0. [DOI] [PubMed] [Google Scholar]
  30. Teppler H., Kaplan G., Smith K., Cameron P., Montana A., Meyn P., Cohn Z. Efficacy of low doses of the polyethylene glycol derivative of interleukin-2 in modulating the immune response of patients with human immunodeficiency virus type 1 infection. J Infect Dis. 1993 Feb;167(2):291–298. doi: 10.1093/infdis/167.2.291. [DOI] [PubMed] [Google Scholar]
  31. Volberding P., Moody D. J., Beardslee D., Bradley E. C., Wofsy C. B. Therapy of acquired immune deficiency syndrome with recombinant interleukin-2. AIDS Res Hum Retroviruses. 1987 Summer;3(2):115–124. doi: 10.1089/aid.1987.3.115. [DOI] [PubMed] [Google Scholar]
  32. Weinberg A., Konrad M., Merigan T. C. Regulation by recombinant interleukin-2 of protective immunity against recurrent herpes simplex virus type 2 genital infection in guinea pigs. J Virol. 1987 Jul;61(7):2120–2127. doi: 10.1128/jvi.61.7.2120-2127.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES