Abstract
To test the hypothesis that deficient interleukin 2 (IL-2) secretion may underlie the impaired capacity of T cells from patients with Acquired Immunodeficiency Syndrome (AIDS) and the AIDS-related complex (ARC) to generate the macrophage-activating lymphokine, gamma interferon (IFN-gamma), we used five specific microbial antigens to examine IL-2 production. Mononuclear cells from only one of 32 (3%) AIDS patients secreted normal levels of IL-2, and 21 (66%) failed to produce any detectable IL-2. For 36 ARC patients, IL-2 generation was normal in nine (25%) and absent in 11 (31%). Given these results, recombinant (r) IL-2 was tested for its capacity to stimulate or enhance IFN-gamma production. rIL-2 (10 U/ml) alone stimulated cells from controls, ARC, and AIDS patients to secrete 93 +/- 25, 99 +/- 33, and 7 +/- 3 U/ml of IFN-gamma, respectively. rIL 2 (10 U/ml) plus antigen induced no change in mean IFN-gamma levels for controls, a 4.4-fold increase for 17 AIDS patients (16 +/- 16 vs. 71 +/- 21 U/ml), and a 7.2-fold increase (18 +/- 5 vs. 130 +/- 27 U/ml) for 19 ARC patients with abnormal IFN-gamma generation to antigen alone. Individual responses indicated that six of the 17 (35%) AIDS patients with opportunistic infections and 12 of the 19 (63%) with ARC were apparent responders to 10-100 U/ml of rIL-2. These results (a) document profound impairment in antigen-induced IL-2 secretion by AIDS and ARC T cells, (b) indicate that, in vitro, mononuclear cells from certain patients can respond to rIL-2 with enhanced IFN-gamma production, and thus (c) suggest that in selected patients rIL-2 might have a potentially beneficial therapeutic (AIDS) or prophylactic (ARC) effect against opportunistic infections.
Full text
PDF





Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bindon C., Czerniecki M., Ruell P., Edwards A., McCarthy W. H., Harris R., Hersey P. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer. 1983 Jan;47(1):123–133. doi: 10.1038/bjc.1983.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chang T. W., McKinney S., Liu V., Kung P. C., Vilcek J., Le J. Use of monoclonal antibodies as sensitive and specific probes for biologically active human gamma-interferon. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5219–5222. doi: 10.1073/pnas.81.16.5219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Farrar W. L., Johnson H. M., Farrar J. J. Regulation of the production of immune interferon and cytotoxic T lymphocytes by interleukin 2. J Immunol. 1981 Mar;126(3):1120–1125. [PubMed] [Google Scholar]
- Flomenberg N., Welte K., Mertelsmann R., Kernan N., Ciobanu N., Venuta S., Feldman S., Kruger G., Kirkpatrick D., Dupont B. Immunologic effects of interleukin 2 in primary immunodeficiency diseases. J Immunol. 1983 Jun;130(6):2644–2650. [PubMed] [Google Scholar]
- Gallo R. C., Salahuddin S. Z., Popovic M., Shearer G. M., Kaplan M., Haynes B. F., Palker T. J., Redfield R., Oleske J., Safai B. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science. 1984 May 4;224(4648):500–503. doi: 10.1126/science.6200936. [DOI] [PubMed] [Google Scholar]
- Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
- Gillis S., Mochizuki D. Y., Conlon P. J., Hefeneider S. H., Ramthun C. A., Gillis A. E., Frank M. B., Henney C. S., Watson J. D. Molecular characterization of interleukin 2. Immunol Rev. 1982;63:167–209. doi: 10.1111/j.1600-065x.1982.tb00415.x. [DOI] [PubMed] [Google Scholar]
- Gillis S., Mochizuki D. Y., Conlon P. J., Hefeneider S. H., Ramthun C. A., Gillis A. E., Frank M. B., Henney C. S., Watson J. D. Molecular characterization of interleukin 2. Immunol Rev. 1982;63:167–209. doi: 10.1111/j.1600-065x.1982.tb00415.x. [DOI] [PubMed] [Google Scholar]
- Handa K., Suzuki R., Matsui H., Shimizu Y., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). II. IL 2-induced interferon gamma production. J Immunol. 1983 Feb;130(2):988–992. [PubMed] [Google Scholar]
- Heagy W., Kelley V. E., Strom T. B., Mayer K., Shapiro H. M., Mandel R., Finberg R. Decreased expression of human class II antigens on monocytes from patients with acquired immune deficiency syndrome. Increased expression with interferon-gamma. J Clin Invest. 1984 Dec;74(6):2089–2096. doi: 10.1172/JCI111633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- James S. L., Natovitz P. C., Farrar W. L., Leonard E. J. Macrophages as effector cells of protective immunity in murine schistosomiasis: macrophage activation in mice vaccinated with radiation-attenuated cercariae. Infect Immun. 1984 Jun;44(3):569–575. doi: 10.1128/iai.44.3.569-575.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kasahara T., Djeu J. Y., Dougherty S. F., Oppenheim J. J. Capacity of human large granular lymphocytes (LGL) to produce multiple lymphokines: interleukin 2, interferon, and colony stimulating factor. J Immunol. 1983 Nov;131(5):2379–2385. [PubMed] [Google Scholar]
- Kasahara T., Hooks J. J., Dougherty S. F., Oppenheim J. J. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 1983 Apr;130(4):1784–1789. [PubMed] [Google Scholar]
- Kiderlen A. F., Kaufmann S. H., Lohmann-Matthes M. L. Protection of mice against the intracellular bacterium Listeria monocytogenes by recombinant immune interferon. Eur J Immunol. 1984 Oct;14(10):964–967. doi: 10.1002/eji.1830141019. [DOI] [PubMed] [Google Scholar]
- Lifson J. D., Benike C. J., Mark D. F., Koths K., Engleman E. G. Human recombinant interleukin-2 partly reconstitutes deficient in-vitro immune responses of lymphocytes from patients with AIDS. Lancet. 1984 Mar 31;1(8379):698–702. doi: 10.1016/s0140-6736(84)92220-7. [DOI] [PubMed] [Google Scholar]
- Lotze M. T., Frana L. W., Sharrow S. O., Robb R. J., Rosenberg S. A. In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J Immunol. 1985 Jan;134(1):157–166. [PubMed] [Google Scholar]
- Luger T. A., Smolen J. S., Chused T. M., Steinberg A. D., Oppenheim J. J. Human lymphocytes with either the OKT4 or OKT8 phenotype produce interleukin 2 in culture. J Clin Invest. 1982 Aug;70(2):470–473. doi: 10.1172/JCI110637. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCabe R. E., Luft B. J., Remington J. S. Effect of murine interferon gamma on murine toxoplasmosis. J Infect Dis. 1984 Dec;150(6):961–962. doi: 10.1093/infdis/150.6.961. [DOI] [PubMed] [Google Scholar]
- Meuer S. C., Hussey R. E., Penta A. C., Fitzgerald K. A., Stadler B. M., Schlossman S. F., Reinherz E. L. Cellular origin of interleukin 2 (IL 2) in man: evidence for stimulus-restricted IL 2 production by T4+ and T8+ T lymphocytes. J Immunol. 1982 Sep;129(3):1076–1079. [PubMed] [Google Scholar]
- Moretta A., Pantaleo G., Maggi E., Mingari M. C. Recent advances in the phenotypic and functional analysis of human T lymphocytes. Semin Hematol. 1984 Oct;21(4):257–269. [PubMed] [Google Scholar]
- Murray H. W., Rubin B. Y., Masur H., Roberts R. B. Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med. 1984 Apr 5;310(14):883–889. doi: 10.1056/NEJM198404053101404. [DOI] [PubMed] [Google Scholar]
- Murray H. W., Rubin B. Y., Rothermel C. D. Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-gamma is the activating lymphokine. J Clin Invest. 1983 Oct;72(4):1506–1510. doi: 10.1172/JCI111107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nacy C. A., James S. L., Benjamin W. R., Farrar J. J., Hockmeyer W. T., Meltzer M. S. Activation of macrophages for microbicidal and tumoricidal effector functions by soluble factors from EL-4, a continuous T cell line. Infect Immun. 1983 May;40(2):820–824. doi: 10.1128/iai.40.2.820-824.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C. F., Murray H. W., Wiebe M. E., Rubin B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. doi: 10.1084/jem.158.3.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C. F., Prendergast T. J., Wiebe M. E., Stanley E. R., Platzer E., Remold H. G., Welte K., Rubin B. Y., Murray H. W. Activation of human macrophages. Comparison of other cytokines with interferon-gamma. J Exp Med. 1984 Aug 1;160(2):600–605. doi: 10.1084/jem.160.2.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ockenhouse C. F., Schulman S., Shear H. L. Induction of crisis forms in the human malaria parasite Plasmodium falciparum by gamma-interferon-activated, monocyte-derived macrophages. J Immunol. 1984 Sep;133(3):1601–1608. [PubMed] [Google Scholar]
- Ortaldo J. R., Mason A. T., Gerard J. P., Henderson L. E., Farrar W., Hopkins R. F., 3rd, Herberman R. B., Rabin H. Effects of natural and recombinant IL 2 on regulation of IFN gamma production and natural killer activity: lack of involvement of the Tac antigen for these immunoregulatory effects. J Immunol. 1984 Aug;133(2):779–783. [PubMed] [Google Scholar]
- Palacios R. Cloned lines on interleukin 2 producer human T lymphocytes. J Immunol. 1982 Dec;129(6):2586–2593. [PubMed] [Google Scholar]
- Pearlstein K. T., Palladino M. A., Welte K., Vilcek J. Purified human interleukin-2 enhances induction of immune interferon. Cell Immunol. 1983 Aug;80(1):1–9. doi: 10.1016/0008-8749(83)90088-6. [DOI] [PubMed] [Google Scholar]
- Prince H. E., Kermani-Arab V., Fahey J. L. Depressed interleukin 2 receptor expression in acquired immune deficiency and lymphadenopathy syndromes. J Immunol. 1984 Sep;133(3):1313–1317. [PubMed] [Google Scholar]
- Reem G. H., Yeh N. H. Interleukin 2 regulates expression of its receptor and synthesis of gamma interferon by human T lymphocytes. Science. 1984 Jul 27;225(4660):429–430. doi: 10.1126/science.6429853. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Rothermel C. D., Rubin B. Y., Murray H. W. Gamma-interferon is the factor in lymphokine that activates human macrophages to inhibit intracellular Chlamydia psittaci replication. J Immunol. 1983 Nov;131(5):2542–2544. [PubMed] [Google Scholar]
- Rubin B. Y., Bartal A. H., Anderson S. L., Millet S. K., Hirshaut Y., Feit C. The anticellular and protein-inducing activities of human gamma interferon preparations are mediated by the interferon. J Immunol. 1983 Mar;130(3):1019–1020. [PubMed] [Google Scholar]
- Ruscetti F. W., Gallo R. C. Human T-lymphocyte growth factor: regulation of growth and function of T lymphocytes. Blood. 1981 Mar;57(3):379–394. [PubMed] [Google Scholar]
- Seligmann M., Chess L., Fahey J. L., Fauci A. S., Lachmann P. J., L'Age-Stehr J., Ngu J., Pinching A. J., Rosen F. S., Spira T. J. AIDS--an immunologic reevaluation. N Engl J Med. 1984 Nov 15;311(20):1286–1292. doi: 10.1056/NEJM198411153112005. [DOI] [PubMed] [Google Scholar]
- Sheridan J. F., Aurelian L., Donnenberg A. D., Quinn T. C. Cell-mediated immunity to cytomegalovirus (CMV) and herpes simplex virus (HSV) antigens in the acquired immune deficiency syndrome: interleukin-1 and interleukin-2 modify in vitro responses. J Clin Immunol. 1984 Jul;4(4):304–311. doi: 10.1007/BF00915298. [DOI] [PubMed] [Google Scholar]
- Smith K. A. T-cell growth factor. Immunol Rev. 1980;51:337–357. doi: 10.1111/j.1600-065x.1980.tb00327.x. [DOI] [PubMed] [Google Scholar]
- Stiehm E. R., Kronenberg L. H., Rosenblatt H. M., Bryson Y., Merigan T. C. UCLA conference. Interferon: immunobiology and clinical significance. Ann Intern Med. 1982 Jan;96(1):80–93. doi: 10.7326/0003-4819-96-1-80. [DOI] [PubMed] [Google Scholar]
- Svedersky L. P., Shepard H. M., Spencer S. A., Shalaby M. R., Palladino M. A. Augmentation of human natural cell-mediated cytotoxicity by recombinant human interleukin 2. J Immunol. 1984 Aug;133(2):714–718. [PubMed] [Google Scholar]
- Torres B. A., Farrar W. L., Johnson H. M. Interleukin 2 regulates immune interferon (IFN gamma) production by normal and suppressor cell cultures. J Immunol. 1982 May;128(5):2217–2219. [PubMed] [Google Scholar]
- Trinchieri G., Matsumoto-Kobayashi M., Clark S. C., Seehra J., London L., Perussia B. Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med. 1984 Oct 1;160(4):1147–1169. doi: 10.1084/jem.160.4.1147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Welte K., Platzer E., Wang C. Y., Rinnooy Kan E. A., Moore M. A., Mertelsmann R. OKT8 antibody inhibits OKT3-induced IL 2 production and proliferation in OKT8+ cells. J Immunol. 1983 Nov;131(5):2356–2361. [PubMed] [Google Scholar]
- Welte K., Wang C. Y., Mertelsmann R., Venuta S., Feldman S. P., Moore M. A. Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity. J Exp Med. 1982 Aug 1;156(2):454–464. doi: 10.1084/jem.156.2.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Winkelstein A., Klein R. S., Evans T. L., Dixon B. W., Holder W. L., Weaver L. D. Defective in vitro T cell colony formation in the acquired immunodeficiency syndrome. J Immunol. 1985 Jan;134(1):151–156. [PubMed] [Google Scholar]
- Wisseman C. L., Jr, Waddell A. Interferonlike factors from antigen- and mitogen-stimulated human leukocytes with antirickettsial and cytolytic actions on Rickettsia prowazekii. Infected human endothelial cells, fibroblasts, and macrophages. J Exp Med. 1983 Jun 1;157(6):1780–1793. doi: 10.1084/jem.157.6.1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamamoto J. K., Farrar W. L., Johnson H. M. Interleukin 2 regulation of mitogen induction of immune interferon (IFN gamma) in spleen cells and thymocytes. Cell Immunol. 1982 Jan 15;66(2):333–341. doi: 10.1016/0008-8749(82)90183-6. [DOI] [PubMed] [Google Scholar]