Abstract
We investigated the mechanisms by which interleukin-10 (IL-10) regulates antigen-specific hyporesponsiveness in asymptomatic microfilaremic (MF) individuals. Peripheral blood mononuclear cells from MF individuals (n = 11) were stimulated in vitro with Brugia malayi antigen (BMA) or mycobacterial purified protein derivative (PPD) in the presence of neutralizing anti-IL-10 or isotype control monoclonal antibodies. As expected, BMA stimulated little or no gamma interferon (IFN-gamma) secretion in MF individuals, whereas PPD stimulated IFN-gamma in all but one. Neutralization of endogenous BMA-driven IL-10 secretion led to augmentation of IFN-gamma in seven of nine MF individuals (1.5- to 10-fold) and did so in a BMA-specific manner (PPD-driven IFN-gamma was augmented in only two of eight MF individuals and only 1.5- to 2-fold), indicating that IL-10 downregulates type 1 responses in these individuals. Type 2 responses (IL-5 secretion) were unaffected by the IL-10 blockade. To assess whether IL-12 could reverse the type 1 downregulation observed, the effect of recombinant human IL-12 (rhIL-12) on BMA-driven IL-5 and IFN-gamma production was also evaluated. rhIL-12 augmented both BMA- and PPD-driven IFN-gamma production 5- to 10-fold in six of nine MF individuals. These data demonstrate that IL-10 downregulates BMA-driven type 1 responses and that IL-12 can overcome downregulation of Th1 responses associated with MF but does so in a non-antigen-specific manner.
Full Text
The Full Text of this article is available as a PDF (182.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abrams J. S., Roncarolo M. G., Yssel H., Andersson U., Gleich G. J., Silver J. E. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992 Jun;127:5–24. doi: 10.1111/j.1600-065x.1992.tb01406.x. [DOI] [PubMed] [Google Scholar]
- Bendelac A., Lantz O., Quimby M. E., Yewdell J. W., Bennink J. R., Brutkiewicz R. R. CD1 recognition by mouse NK1+ T lymphocytes. Science. 1995 May 12;268(5212):863–865. doi: 10.1126/science.7538697. [DOI] [PubMed] [Google Scholar]
- Biron C. A., Gazzinelli R. T. Effects of IL-12 on immune responses to microbial infections: a key mediator in regulating disease outcome. Curr Opin Immunol. 1995 Aug;7(4):485–496. doi: 10.1016/0952-7915(95)80093-x. [DOI] [PubMed] [Google Scholar]
- Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cesano A., Visonneau S., Clark S. C., Santoli D. Cellular and molecular mechanisms of activation of MHC nonrestricted cytotoxic cells by IL-12. J Immunol. 1993 Sep 15;151(6):2943–2957. [PubMed] [Google Scholar]
- Cunha F. Q., Moncada S., Liew F. Y. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1155–1159. doi: 10.1016/0006-291x(92)91852-h. [DOI] [PubMed] [Google Scholar]
- D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dasgupta A., Bala S., Dutta S. N. Cellular unresponsiveness in patients with soluble circulating antigens in bancroftian filariasis. Indian J Med Res. 1987 Feb;85:136–139. [PubMed] [Google Scholar]
- Del Prete G., De Carli M., Almerigogna F., Giudizi M. G., Biagiotti R., Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993 Jan 15;150(2):353–360. [PubMed] [Google Scholar]
- Dimock K. A., Addiss D. G., Eberhard M. L., Lammie P. J. Differential proliferative and interleukin-10 responses to fractionated filarial antigens: preferential recognition by patients with chronic lymphatic dysfunction. J Infect Dis. 1994 Aug;170(2):403–412. doi: 10.1093/infdis/170.2.403. [DOI] [PubMed] [Google Scholar]
- Ding L., Linsley P. S., Huang L. Y., Germain R. N., Shevach E. M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993 Aug 1;151(3):1224–1234. [PubMed] [Google Scholar]
- Ding L., Shevach E. M. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J Immunol. 1992 May 15;148(10):3133–3139. [PubMed] [Google Scholar]
- Finkelman F. D., Pearce E. J., Urban J. F., Jr, Sher A. Regulation and biological function of helminth-induced cytokine responses. Immunol Today. 1991 Mar;12(3):A62–A66. doi: 10.1016/S0167-5699(05)80018-0. [DOI] [PubMed] [Google Scholar]
- Flores Villanueva P. O., Chikunguwo S. M., Harris T. S., Stadecker M. J. Role of IL-10 on antigen-presenting cell function for schistosomal egg-specific monoclonal T helper cell responses in vitro and in vivo. J Immunol. 1993 Sep 15;151(6):3192–3198. [PubMed] [Google Scholar]
- Flores Villanueva P. O., Harris T. S., Ricklan D. E., Stadecker M. J. Macrophages from schistosomal egg granulomas induce unresponsiveness in specific cloned Th-1 lymphocytes in vitro and down-regulate schistosomal granulomatous disease in vivo. J Immunol. 1994 Feb 15;152(4):1847–1855. [PubMed] [Google Scholar]
- Flores Villanueva P. O., Reiser H., Stadecker M. J. Regulation of T helper cell responses in experimental murine schistosomiasis by IL-10. Effect on expression of B7 and B7-2 costimulatory molecules by macrophages. J Immunol. 1994 Dec 1;153(11):5190–5199. [PubMed] [Google Scholar]
- Gazzinelli R. T., Oswald I. P., James S. L., Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol. 1992 Mar 15;148(6):1792–1796. [PubMed] [Google Scholar]
- Groux H., Bigler M., de Vries J. E., Roncarolo M. G. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med. 1996 Jul 1;184(1):19–29. doi: 10.1084/jem.184.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
- Hsu D. H., Moore K. W., Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol. 1992 May;4(5):563–569. doi: 10.1093/intimm/4.5.563. [DOI] [PubMed] [Google Scholar]
- King C. L., Mahanty S., Kumaraswami V., Abrams J. S., Regunathan J., Jayaraman K., Ottesen E. A., Nutman T. B. Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset. J Clin Invest. 1993 Oct;92(4):1667–1673. doi: 10.1172/JCI116752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- King C. L., Nutman T. B. Biological role of helper T-cell subsets in helminth infections. Chem Immunol. 1992;54:136–165. [PubMed] [Google Scholar]
- King C. L., Nutman T. B. Regulation of the immune response in lymphatic filariasis and onchocerciasis. Immunol Today. 1991 Mar;12(3):A54–A58. doi: 10.1016/S0167-5699(05)80016-7. [DOI] [PubMed] [Google Scholar]
- Lammie P. J., Addiss D. G., Leonard G., Hightower A. W., Eberhard M. L. Heterogeneity in filarial-specific immune responsiveness among patients with lymphatic obstruction. J Infect Dis. 1993 May;167(5):1178–1183. doi: 10.1093/infdis/167.5.1178. [DOI] [PubMed] [Google Scholar]
- Mahanty S., Abrams J. S., King C. L., Limaye A. P., Nutman T. B. Parallel regulation of IL-4 and IL-5 in human helminth infections. J Immunol. 1992 Jun 1;148(11):3567–3571. [PubMed] [Google Scholar]
- Mahanty S., King C. L., Kumaraswami V., Regunathan J., Maya A., Jayaraman K., Abrams J. S., Ottesen E. A., Nutman T. B. IL-4- and IL-5-secreting lymphocyte populations are preferentially stimulated by parasite-derived antigens in human tissue invasive nematode infections. J Immunol. 1993 Oct 1;151(7):3704–3711. [PubMed] [Google Scholar]
- Mahanty S., Mollis S. N., Ravichandran M., Abrams J. S., Kumaraswami V., Jayaraman K., Ottesen E. A., Nutman T. B. High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis. J Infect Dis. 1996 Mar;173(3):769–773. doi: 10.1093/infdis/173.3.769. [DOI] [PubMed] [Google Scholar]
- Maizels R. M., Blaxter M. L., Selkirk M. E. Forms and functions of nematode surfaces. Exp Parasitol. 1993 Nov;77(3):380–384. doi: 10.1006/expr.1993.1096. [DOI] [PubMed] [Google Scholar]
- Maizels R. M., Bundy D. A., Selkirk M. E., Smith D. F., Anderson R. M. Immunological modulation and evasion by helminth parasites in human populations. Nature. 1993 Oct 28;365(6449):797–805. doi: 10.1038/365797a0. [DOI] [PubMed] [Google Scholar]
- Maizels R. M., Lawrence R. A. Immunological tolerance: The key feature in human filariasis? Parasitol Today. 1991 Oct;7(10):271–276. doi: 10.1016/0169-4758(91)90093-4. [DOI] [PubMed] [Google Scholar]
- Maizels R. M., Sartono E., Kurniawan A., Partono F., Selkirk M. E., Yazdanbakhsh M. T-cell activation and the balance of antibody isotypes in human lymphatic filariasis. Parasitol Today. 1995 Feb;11(2):50–56. doi: 10.1016/0169-4758(95)80116-2. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Moore K. W. The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunol Today. 1991 Mar;12(3):A49–A53. doi: 10.1016/S0167-5699(05)80015-5. [DOI] [PubMed] [Google Scholar]
- Nutman T. B., Kumaraswami V., Ottesen E. A. Parasite-specific anergy in human filariasis. Insights after analysis of parasite antigen-driven lymphokine production. J Clin Invest. 1987 May;79(5):1516–1523. doi: 10.1172/JCI112982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ottesen E. A., Weller P. F., Heck L. Specific cellular immune unresponsiveness in human filariasis. Immunology. 1977 Sep;33(3):413–421. [PMC free article] [PubMed] [Google Scholar]
- Pearce E. J., Caspar P., Grzych J. M., Lewis F. A., Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. doi: 10.1084/jem.173.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Piessens W. F., McGreevy P. B., Piessens P. W., McGreevy M., Koiman I., Saroso J. S., Dennis D. T. Immune responses in human infections with Brugia malayi: specific cellular unresponsiveness to filarial antigens. J Clin Invest. 1980 Jan;65(1):172–179. doi: 10.1172/JCI109648. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Piessens W. F., Partono F., Hoffman S. L., Ratiwayanto S., Piessens P. W., Palmieri J. R., Koiman I., Dennis D. T., Carney W. P. Antigen-specific suppressor T lymphocytes in human lymphatic filariasis. N Engl J Med. 1982 Jul 15;307(3):144–148. doi: 10.1056/NEJM198207153070302. [DOI] [PubMed] [Google Scholar]
- Piessens W. F., Ratiwayanto S., Tuti S., Palmieri J. H., Piessens P. W., Koiman I., Dennis D. T. Antigen-specific suppressor cells and suppressor factors in human filariasis with Brugia malayi. N Engl J Med. 1980 Apr 10;302(15):833–837. doi: 10.1056/NEJM198004103021503. [DOI] [PubMed] [Google Scholar]
- Secrist H., DeKruyff R. H., Umetsu D. T. Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type. J Exp Med. 1995 Mar 1;181(3):1081–1089. doi: 10.1084/jem.181.3.1081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sher A., Fiorentino D., Caspar P., Pearce E., Mosmann T. Production of IL-10 by CD4+ T lymphocytes correlates with down-regulation of Th1 cytokine synthesis in helminth infection. J Immunol. 1991 Oct 15;147(8):2713–2716. [PubMed] [Google Scholar]
- Stadecker M. J., Flores Villanueva P. O. Accessory cell signals regulate Th-cell responses: from basic immunology to a model of helminthic disease. Immunol Today. 1994 Dec;15(12):571–574. doi: 10.1016/0167-5699(94)90219-4. [DOI] [PubMed] [Google Scholar]
- Steel C., Guinea A., McCarthy J. S., Ottesen E. A. Long-term effect of prenatal exposure to maternal microfilaraemia on immune responsiveness to filarial parasite antigens. Lancet. 1994 Apr 9;343(8902):890–893. doi: 10.1016/s0140-6736(94)90009-4. [DOI] [PubMed] [Google Scholar]
- Taga K., Tosato G. IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol. 1992 Feb 15;148(4):1143–1148. [PubMed] [Google Scholar]
- Turner P., Copeman B., Gerisi D., Speare R. A comparison of the Og4C3 antigen capture ELISA, the Knott test, an IgG4 assay and clinical signs, in the diagnosis of Bancroftian filariasis. Trop Med Parasitol. 1993 Mar;44(1):45–48. [PubMed] [Google Scholar]
- Velupillai P., Harn D. A. Oligosaccharide-specific induction of interleukin 10 production by B220+ cells from schistosome-infected mice: a mechanism for regulation of CD4+ T-cell subsets. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):18–22. doi: 10.1073/pnas.91.1.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson R. A. Immunity and immunoregulation in helminth infections. Curr Opin Immunol. 1993 Aug;5(4):538–547. doi: 10.1016/0952-7915(93)90035-q. [DOI] [PubMed] [Google Scholar]
- Wynn T. A., Eltoum I., Oswald I. P., Cheever A. W., Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. doi: 10.1084/jem.179.5.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wynn T. A., Jankovic D., Hieny S., Cheever A. W., Sher A. IL-12 enhances vaccine-induced immunity to Schistosoma mansoni in mice and decreases T helper 2 cytokine expression, IgE production, and tissue eosinophilia. J Immunol. 1995 May 1;154(9):4701–4709. [PubMed] [Google Scholar]
- de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Waal Malefyt R., Yssel H., de Vries J. E. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [PubMed] [Google Scholar]