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. 1996 Feb 15;97(4):1028–1034. doi: 10.1172/JCI118494

Effect of anti-interleukin 12 treatment on murine lyme borreliosis.

J Anguita 1, D H Persing 1, M Rincon 1, S W Barthold 1, E Fikrig 1
PMCID: PMC507149  PMID: 8613525

Abstract

The effect of anti-interleukin (IL-12 treatment on Lyme borreliosis in C3H/HeN (C3H) mice was assessed because other studies have implicated CD4+ T cell helper (Th) type 1 responses in the genesis of disease caused by Borrelia burgdorferi. Infection of inbred mice with B. burgdorferi results in varying degrees of arthritis: BALB/c mice develop mild disease and C3H mice develop severe arthritis that is most pronounced 2-4 wk after infection. Since IL-12 is a major inducer of Th1 responses, we blocked this cytokine in vivo in B. burgdorferi infected C3H mice, and evaluated the effects of treatment on the development of arthritis at the peak of acute joint inflammation (14 d) and in the resolution phase (60 d) of disease. As expected, intraperitoneal administration of an anti-IL-12 monoclonal antibody (mAb) to C3H mice resulted in a decrease in both IFN-gamma and B. burgdorferi-specific IgG2a in serum, indicative of diminished Th1 responses. No IL-4 production was detected in serum of anti-IL-12 mAb treated or control mice. IgG1 and IgG2b levels did not increase in B. burgdorferi infected mice treated with anti-IL-12 mAb compared with controls suggesting that Th2 responses were not affected. Nevertheless, CD4+ T cells from both control and anti-IL-12 mAb treated mice had similar in vitro responses to B. burgdorferi antigens. Treatment with anti-IL-12 mAb produced a significant reduction in peak arthritis severity, and an increase in the number of spirochetes in ear tissue. These data show that treatment of B. burgdorferi infected mice with anti-IL-12 mAb results in a reduction of the Th1 and/or innate immune responses in vivo and a reduction in the severity of acute murine Lyme arthritis.

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Selected References

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  1. Anderson J. F., Barthold S. W., Magnarelli L. A. Infectious but nonpathogenic isolate of Borrelia burgdorferi. J Clin Microbiol. 1990 Dec;28(12):2693–2699. doi: 10.1128/jcm.28.12.2693-2699.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbour A. G. Isolation and cultivation of Lyme disease spirochetes. Yale J Biol Med. 1984 Jul-Aug;57(4):521–525. [PMC free article] [PubMed] [Google Scholar]
  3. Barthold S. W., Beck D. S., Hansen G. M., Terwilliger G. A., Moody K. D. Lyme borreliosis in selected strains and ages of laboratory mice. J Infect Dis. 1990 Jul;162(1):133–138. doi: 10.1093/infdis/162.1.133. [DOI] [PubMed] [Google Scholar]
  4. Barthold S. W., Fikrig E., Bockenstedt L. K., Persing D. H. Circumvention of outer surface protein A immunity by host-adapted Borrelia burgdorferi. Infect Immun. 1995 Jun;63(6):2255–2261. doi: 10.1128/iai.63.6.2255-2261.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barthold S. W., Persing D. H., Armstrong A. L., Peeples R. A. Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice. Am J Pathol. 1991 Aug;139(2):263–273. [PMC free article] [PubMed] [Google Scholar]
  6. Barthold S. W., de Souza M. S., Janotka J. L., Smith A. L., Persing D. H. Chronic Lyme borreliosis in the laboratory mouse. Am J Pathol. 1993 Sep;143(3):959–971. [PMC free article] [PubMed] [Google Scholar]
  7. Brunda M. J. Interleukin-12. J Leukoc Biol. 1994 Feb;55(2):280–288. doi: 10.1002/jlb.55.2.280. [DOI] [PubMed] [Google Scholar]
  8. Chan S. H., Kobayashi M., Santoli D., Perussia B., Trinchieri G. Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J Immunol. 1992 Jan 1;148(1):92–98. [PubMed] [Google Scholar]
  9. D'Orazio J. A., Burke G. W., Stein-Streilein J. Staphylococcal enterotoxin B activates purified NK cells to secrete IFN-gamma but requires T lymphocytes to augment NK cytotoxicity. J Immunol. 1995 Feb 1;154(3):1014–1023. [PubMed] [Google Scholar]
  10. Fikrig E., Barthold S. W., Flavell R. A. OspA vaccination of mice with established Borrelia burgdorferi infection alters disease but not infection. Infect Immun. 1993 Jun;61(6):2553–2557. doi: 10.1128/iai.61.6.2553-2557.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fikrig E., Barthold S. W., Kantor F. S., Flavell R. A. Long-term protection of mice from Lyme disease by vaccination with OspA. Infect Immun. 1992 Mar;60(3):773–777. doi: 10.1128/iai.60.3.773-777.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fikrig E., Barthold S. W., Kantor F. S., Flavell R. A. Protection of mice against the Lyme disease agent by immunizing with recombinant OspA. Science. 1990 Oct 26;250(4980):553–556. doi: 10.1126/science.2237407. [DOI] [PubMed] [Google Scholar]
  13. Fikrig E., Tao H., Kantor F. S., Barthold S. W., Flavell R. A. Evasion of protective immunity by Borrelia burgdorferi by truncation of outer surface protein B. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4092–4096. doi: 10.1073/pnas.90.9.4092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gazzinelli R. T., Wysocka M., Hayashi S., Denkers E. Y., Hieny S., Caspar P., Trinchieri G., Sher A. Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol. 1994 Sep 15;153(6):2533–2543. [PubMed] [Google Scholar]
  15. Hsieh C. S., Macatonia S. E., O'Garra A., Murphy K. M. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995 Feb 1;181(2):713–721. doi: 10.1084/jem.181.2.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hunter C. A., Subauste C. S., Van Cleave V. H., Remington J. S. Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha. Infect Immun. 1994 Jul;62(7):2818–2824. doi: 10.1128/iai.62.7.2818-2824.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kalish R. A., Leong J. M., Steere A. C. Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun. 1993 Jul;61(7):2774–2779. doi: 10.1128/iai.61.7.2774-2779.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kubin M., Kamoun M., Trinchieri G. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med. 1994 Jul 1;180(1):211–222. doi: 10.1084/jem.180.1.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lahesmaa R., Shanafelt M. C., Allsup A., Soderberg C., Anzola J., Freitas V., Turck C., Steinman L., Peltz G. Preferential usage of T cell antigen receptor V region gene segment V beta 5.1 by Borrelia burgdorferi antigen-reactive T cell clones isolated from a patient with Lyme disease. J Immunol. 1993 May 1;150(9):4125–4135. [PubMed] [Google Scholar]
  21. Malawista S. E., Barthold S. W., Persing D. H. Fate of Borrelia burgdorferi DNA in tissues of infected mice after antibiotic treatment. J Infect Dis. 1994 Nov;170(5):1312–1316. doi: 10.1093/infdis/170.5.1312. [DOI] [PubMed] [Google Scholar]
  22. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Matyniak J. E., Reiner S. L. T helper phenotype and genetic susceptibility in experimental Lyme disease. J Exp Med. 1995 Mar 1;181(3):1251–1254. doi: 10.1084/jem.181.3.1251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Murphy E. E., Terres G., Macatonia S. E., Hsieh C. S., Mattson J., Lanier L., Wysocka M., Trinchieri G., Murphy K., O'Garra A. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med. 1994 Jul 1;180(1):223–231. doi: 10.1084/jem.180.1.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Persing D. H., Rutledge B. J., Rys P. N., Podzorski D. S., Mitchell P. D., Reed K. D., Liu B., Fikrig E., Malawista S. E. Target imbalance: disparity of Borrelia burgdorferi genetic material in synovial fluid from Lyme arthritis patients. J Infect Dis. 1994 Mar;169(3):668–672. doi: 10.1093/infdis/169.3.668. [DOI] [PubMed] [Google Scholar]
  26. Radolf J. D., Arndt L. L., Akins D. R., Curetty L. L., Levi M. E., Shen Y., Davis L. S., Norgard M. V. Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages. J Immunol. 1995 Mar 15;154(6):2866–2877. [PubMed] [Google Scholar]
  27. Radolf J. D., Norgard M. V., Brandt M. E., Isaacs R. D., Thompson P. A., Beutler B. Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis. Analysis using a CAT reporter construct. J Immunol. 1991 Sep 15;147(6):1968–1974. [PubMed] [Google Scholar]
  28. Romani L., Mencacci A., Tonnetti L., Spaccapelo R., Cenci E., Puccetti P., Wolf S. F., Bistoni F. IL-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candidiasis. J Immunol. 1994 Dec 1;153(11):5167–5175. [PubMed] [Google Scholar]
  29. Romani L., Mencacci A., Tonnetti L., Spaccapelo R., Cenci E., Wolf S., Puccetti P., Bistoni F. Interleukin-12 but not interferon-gamma production correlates with induction of T helper type-1 phenotype in murine candidiasis. Eur J Immunol. 1994 Apr;24(4):909–915. doi: 10.1002/eji.1830240419. [DOI] [PubMed] [Google Scholar]
  30. Schaible U. E., Kramer M. D., Wallich R., Tran T., Simon M. M. Experimental Borrelia burgdorferi infection in inbred mouse strains: antibody response and association of H-2 genes with resistance and susceptibility to development of arthritis. Eur J Immunol. 1991 Oct;21(10):2397–2405. doi: 10.1002/eji.1830211016. [DOI] [PubMed] [Google Scholar]
  31. Schmitt E., Hoehn P., Huels C., Goedert S., Palm N., Rüde E., Germann T. T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-gamma and is inhibited by transforming growth factor-beta. Eur J Immunol. 1994 Apr;24(4):793–798. doi: 10.1002/eji.1830240403. [DOI] [PubMed] [Google Scholar]
  32. Shanafelt M. C., Anzola J., Soderberg C., Yssel H., Turck C. W., Peltz G. Epitopes on the outer surface protein A of Borrelia burgdorferi recognized by antibodies and T cells of patients with Lyme disease. J Immunol. 1992 Jan 1;148(1):218–224. [PubMed] [Google Scholar]
  33. Skeen M. J., Ziegler H. K. Activation of gamma delta T cells for production of IFN-gamma is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J Immunol. 1995 Jun 1;154(11):5832–5841. [PubMed] [Google Scholar]
  34. Steere A. C., Bartenhagen N. H., Craft J. E., Hutchinson G. J., Newman J. H., Rahn D. W., Sigal L. H., Spieler P. N., Stenn K. S., Malawista S. E. The early clinical manifestations of Lyme disease. Ann Intern Med. 1983 Jul;99(1):76–82. doi: 10.7326/0003-4819-99-1-76. [DOI] [PubMed] [Google Scholar]
  35. Steere A. C., Batsford W. P., Weinberg M., Alexander J., Berger H. J., Wolfson S., Malawista S. E. Lyme carditis: cardiac abnormalities of Lyme disease. Ann Intern Med. 1980 Jul;93(1):8–16. doi: 10.7326/0003-4819-93-1-8. [DOI] [PubMed] [Google Scholar]
  36. Steere A. C., Dwyer E., Winchester R. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med. 1990 Jul 26;323(4):219–223. doi: 10.1056/NEJM199007263230402. [DOI] [PubMed] [Google Scholar]
  37. Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
  38. Stern A. S., Podlaski F. J., Hulmes J. D., Pan Y. C., Quinn P. M., Wolitzky A. G., Familletti P. C., Stremlo D. L., Truitt T., Chizzonite R. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. doi: 10.1073/pnas.87.17.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. doi: 10.1016/0167-5699(93)90230-I. [DOI] [PubMed] [Google Scholar]
  40. Vieira L. Q., Hondowicz B. D., Afonso L. C., Wysocka M., Trinchieri G., Scott P. Infection with Leishmania major induces interleukin-12 production in vivo. Immunol Lett. 1994 May;40(2):157–161. doi: 10.1016/0165-2478(94)90187-2. [DOI] [PubMed] [Google Scholar]
  41. Yang L., Ma Y., Schoenfeld R., Griffiths M., Eichwald E., Araneo B., Weis J. J. Evidence for B-lymphocyte mitogen activity in Borrelia burgdorferi-infected mice. Infect Immun. 1992 Aug;60(8):3033–3041. doi: 10.1128/iai.60.8.3033-3041.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yang L., Weis J. H., Eichwald E., Kolbert C. P., Persing D. H., Weis J. J. Heritable susceptibility to severe Borrelia burgdorferi-induced arthritis is dominant and is associated with persistence of large numbers of spirochetes in tissues. Infect Immun. 1994 Feb;62(2):492–500. doi: 10.1128/iai.62.2.492-500.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yssel H., Nakamoto T., Schneider P., Freitas V., Collins C., Webb D., Mensi N., Soderberg C., Peltz G. Analysis of T lymphocytes cloned from the synovial fluid and blood of a patient with Lyme arthritis. Int Immunol. 1990;2(11):1081–1089. doi: 10.1093/intimm/2.11.1081. [DOI] [PubMed] [Google Scholar]
  44. Yssel H., Shanafelt M. C., Soderberg C., Schneider P. V., Anzola J., Peltz G. Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis. J Exp Med. 1991 Sep 1;174(3):593–601. doi: 10.1084/jem.174.3.593. [DOI] [PMC free article] [PubMed] [Google Scholar]

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