Skip to main content
PMC home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 Apr;65(4):1364–1369. doi: 10.1128/iai.65.4.1364-1369.1997

Interleukin-12 synthesis is a required step in trehalose dimycolate-induced activation of mouse peritoneal macrophages.

I P Oswald 1, C M Dozois 1, J F Petit 1, G Lemaire 1
PMCID: PMC175141  PMID: 9119475

Abstract

Trehalose dimycolate (TDM), a glycolipid present in the cell wall of Mycobacterium spp., is a powerful immunostimulant. TDM primes murine macrophages (Mphi) to produce nitric oxide (NO) and to develop antitumoral activity upon activation with low doses of lipopolysaccharide (LPS). In this study, we investigated the ability of TDM to induce interleukin 12 (IL-12) and the role of this cytokine in TDM-induced activation of murine Mphi. RNA isolated from peritoneal exudate cells (PEC) collected at different times after TDM injection was used to determine IL-12 (p35 and p40 subunits) and gamma interferon (IFN-gamma) mRNA levels by semiquantitative reverse transcriptase-PCR. Constitutive expression of IL-12p35 was observed in PEC from untreated as well as from TDM-injected mice. In contrast, expression of the IL-12p40 subunit was almost undetectable in control PEC but was dramatically upregulated in PEC from TDM-injected mice. IL-12p40 expression peaked at 8 h and subsided to baseline levels at 39 h postinjection. TDM was also able to induce IFN-gamma expression; however, kinetics of induction of IFN-gamma was different from that of IL-12p40. Maximal levels of IFN-gamma mRNA were reached by 24 h and did not return to baseline by 4 days. In addition, pretreatment of mice with neutralizing monoclonal antibodies directed against IL-12 (C15.6.7 and C15.1.2) blocked IFN-gamma mRNA induction in PEC from TDM-treated mice. We further determined if the induction of IL-12 and/or IFN-gamma contributes to the in vivo priming effect of TDM on peritoneal Mphi. TDM-injected mice were treated in vivo with anti-IL-12 or anti-IFN-gamma (XMG.1.6) monoclonal antibodies. TDM-primed Mphi were then activated in vitro with LPS and tested for their ability to produce NO and to develop cytostatic activity toward cocultivated L1210 tumor cells. Priming of Mphi by TDM was completely blocked by in vivo neutralization of either IL-12 or IFN-gamma as demonstrated by an absence of tumoricidal activity and NO production by TDM-elicited Mphi in the presence of LPS. Taken together our results show that TDM, a defined molecule from M. tuberculosis, induces in vivo production of IL-12. Moreover, synthesis of IL-12 mediates TDM priming of mouse peritoneal Mphi through IFN-gamma induction.

Full Text

The Full Text of this article is available as a PDF (144.6 KB).

Selected References

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

  1. Abe M., Goto T., Wolfenbarger D., Weiss D. T., Solomon A. Novel immunization protocol and ELISA screening methods used to obtain and characterize monoclonal antibodies specific for human light chain variable-region subgroups. Hybridoma. 1993 Aug;12(4):475–483. doi: 10.1089/hyb.1993.12.475. [DOI] [PubMed] [Google Scholar]
  2. Afonso L. C., Scharton T. M., Vieira L. Q., Wysocka M., Trinchieri G., Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994 Jan 14;263(5144):235–237. doi: 10.1126/science.7904381. [DOI] [PubMed] [Google Scholar]
  3. Afroun S., Oswald I. P., Lantier F., Petit J. F., Lemaire G. Stimulation of antimycobacterial activity in mouse peritoneal macrophages by priming with trehalose dimycolate (TDM). FEMS Microbiol Immunol. 1991 Oct;3(5):257–267. doi: 10.1111/j.1574-6968.1991.tb04222.x. [DOI] [PubMed] [Google Scholar]
  4. Azuma I. Synthetic immunoadjuvants: application to non-specific host stimulation and potentiation of vaccine immunogenicity. Vaccine. 1992;10(14):1000–1006. doi: 10.1016/0264-410x(92)90108-v. [DOI] [PubMed] [Google Scholar]
  5. Bermudez L. E., Wu M., Young L. S. Interleukin-12-stimulated natural killer cells can activate human macrophages to inhibit growth of Mycobacterium avium. Infect Immun. 1995 Oct;63(10):4099–4104. doi: 10.1128/iai.63.10.4099-4104.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brunda M. J., Luistro L., Warrier R. R., Wright R. B., Hubbard B. R., Murphy M., Wolf S. F., Gately M. K. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993 Oct 1;178(4):1223–1230. doi: 10.1084/jem.178.4.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Castro A. G., Silva R. A., Appelberg R. Endogenously produced IL-12 is required for the induction of protective T cells during Mycobacterium avium infections in mice. J Immunol. 1995 Aug 15;155(4):2013–2019. [PubMed] [Google Scholar]
  8. 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]
  9. Chong C., Bost K. L., Clements J. D. Differential production of interleukin-12 mRNA by murine macrophages in response to viable or killed Salmonella spp. Infect Immun. 1996 Apr;64(4):1154–1160. doi: 10.1128/iai.64.4.1154-1160.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [PubMed] [Google Scholar]
  11. Cleveland M. G., Gorham J. D., Murphy T. L., Tuomanen E., Murphy K. M. Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway. Infect Immun. 1996 Jun;64(6):1906–1912. doi: 10.1128/iai.64.6.1906-1912.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cooper A. M., Roberts A. D., Rhoades E. R., Callahan J. E., Getzy D. M., Orme I. M. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995 Mar;84(3):423–432. [PMC free article] [PubMed] [Google Scholar]
  13. D'Andrea A., Rengaraju M., Valiante N. M., Chehimi J., Kubin M., Aste M., Chan S. H., Kobayashi M., Young D., Nickbarg E. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. doi: 10.1084/jem.176.5.1387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Estaquier J., Idziorek T., Zou W., Emilie D., Farber C. M., Bourez J. M., Ameisen J. C. T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med. 1995 Dec 1;182(6):1759–1767. doi: 10.1084/jem.182.6.1759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fallarino F., Uyttenhove C., Boon T., Gajewski T. F. Endogenous IL-12 is necessary for rejection of P815 tumor variants in vivo. J Immunol. 1996 Feb 1;156(3):1095–1100. [PubMed] [Google Scholar]
  16. Flesch I. E., Hess J. H., Huang S., Aguet M., Rothe J., Bluethmann H., Kaufmann S. H. Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon gamma and tumor necrosis factor alpha. J Exp Med. 1995 May 1;181(5):1615–1621. doi: 10.1084/jem.181.5.1615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Flynn J. L., Goldstein M. M., Triebold K. J., Sypek J., Wolf S., Bloom B. R. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J Immunol. 1995 Sep 1;155(5):2515–2524. [PubMed] [Google Scholar]
  18. Fulton S. A., Johnsen J. M., Wolf S. F., Sieburth D. S., Boom W. H. Interleukin-12 production by human monocytes infected with Mycobacterium tuberculosis: role of phagocytosis. Infect Immun. 1996 Jul;64(7):2523–2531. doi: 10.1128/iai.64.7.2523-2531.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. 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]
  22. Grand-Perret T., Lepoivre M., Petit J. F., Lemaire G. Macrophage activation by trehalose dimycolate requirement for an expression signal in vitro for antitumoral activity; biochemical markers distinguishing primed and fully activated macrophages. Eur J Immunol. 1986 Apr;16(4):332–338. doi: 10.1002/eji.1830160403. [DOI] [PubMed] [Google Scholar]
  23. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer C. M., McComas W., Motyka R., Nabavi N., Wolitzky A. G., Quinn P. M., Familletti P. C. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. doi: 10.1073/pnas.88.10.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Guillemard E., Geniteau-Legendre M., Mabboux B., Poilane I., Kergot R., Lemaire G., Petit J. F., Labarre C., Quero A. M. Antiviral action of trehalose dimycolate against EMC virus: role of macrophages and interferon alpha/beta. Antiviral Res. 1993 Oct;22(2-3):201–213. doi: 10.1016/0166-3542(93)90096-2. [DOI] [PubMed] [Google Scholar]
  25. Heinzel F. P., Rerko R. M., Ling P., Hakimi J., Schoenhaut D. S. Interleukin 12 is produced in vivo during endotoxemia and stimulates synthesis of gamma interferon. Infect Immun. 1994 Oct;62(10):4244–4249. doi: 10.1128/iai.62.10.4244-4249.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Hunter C. A., Candolfi E., Subauste C., Van Cleave V., Remington J. S. Studies on the role of interleukin-12 in acute murine toxoplasmosis. Immunology. 1995 Jan;84(1):16–20. [PMC free article] [PubMed] [Google Scholar]
  29. Johnson W. J., Marino P. A., Schreiber R. D., Adams D. O. Sequential activation of murine mononuclear phagocytes for tumor cytolysis: differential expression of markers by macrophages in the several stages of development. J Immunol. 1983 Aug;131(2):1038–1043. [PubMed] [Google Scholar]
  30. Kato M. Site II-specific inhibition of mitochondria oxidative phosphorylation by trehalose-6,6'-dimycolate (cord factor) of Mycobacterium tuberculosis. Arch Biochem Biophys. 1970 Oct;140(2):379–390. doi: 10.1016/0003-9861(70)90079-2. [DOI] [PubMed] [Google Scholar]
  31. Lemaire G., Tenu J. P., Petit J. F., Lederer E. Natural and synthetic trehalose diesters as immunomodulators. Med Res Rev. 1986 Jul-Sep;6(3):243–274. doi: 10.1002/med.2610060302. [DOI] [PubMed] [Google Scholar]
  32. Lepoivre M., Tenu J. P., Lemaire G., Petit J. F. Antitumor activity and hydrogen peroxide release by macrophages elicited by trehalose diesters. J Immunol. 1982 Aug;129(2):860–866. [PubMed] [Google Scholar]
  33. 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]
  34. Mountford A. P., Anderson S., Wilson R. A. Induction of Th1 cell-mediated protective immunity to Schistosoma mansoni by co-administration of larval antigens and IL-12 as an adjuvant. J Immunol. 1996 Jun 15;156(12):4739–4745. [PubMed] [Google Scholar]
  35. Orbach-Arbouys S., Tenu J. P., Petit J. F. Enhancement of in vitro and in vivo antitumor activity by cord factor (6-6'-dimycolate of trehalose) administered suspended in saline. Int Arch Allergy Appl Immunol. 1983;71(1):67–73. doi: 10.1159/000233364. [DOI] [PubMed] [Google Scholar]
  36. Oswald I. P., Afroun S., Bray D., Petit J. F., Lemaire G. Low response of BALB/c macrophages to priming and activating signals. J Leukoc Biol. 1992 Sep;52(3):315–322. doi: 10.1002/jlb.52.3.315. [DOI] [PubMed] [Google Scholar]
  37. Oswald I. P., Caspar P., Jankovic D., Wynn T. A., Pearce E. J., Sher A. IL-12 inhibits Th2 cytokine responses induced by eggs of Schistosoma mansoni. J Immunol. 1994 Aug 15;153(4):1707–1713. [PubMed] [Google Scholar]
  38. Paganin C., Frank I., Trinchieri G. Priming for high interferon-gamma production induced by interleukin-12 in both CD4+ and CD8+ T cell clones from HIV-infected patients. J Clin Invest. 1995 Sep;96(3):1677–1682. doi: 10.1172/JCI118209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Parant M., Parant F., Chedid L., Drapier J. C., Petit J. F., Wietzerbin J., Lederer Enhancement of nonspecific immunity to bacterial infection by cord factor (6,6'-trehalose dimycolate). J Infect Dis. 1977 May;135(5):771–777. doi: 10.1093/infdis/135.5.771. [DOI] [PubMed] [Google Scholar]
  40. Raddassi K., Petit J. F., Lemaire G. LPS-induced activation of primed murine peritoneal macrophages is modulated by prostaglandins and cyclic nucleotides. Cell Immunol. 1993 Jun;149(1):50–64. doi: 10.1006/cimm.1993.1135. [DOI] [PubMed] [Google Scholar]
  41. Rao J. B., Chamberlain R. S., Bronte V., Carroll M. W., Irvine K. R., Moss B., Rosenberg S. A., Restifo N. P. IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression. J Immunol. 1996 May 1;156(9):3357–3365. [PMC free article] [PubMed] [Google Scholar]
  42. Rawlings D. J., Kaslow D. C. Adjuvant-dependent immune response to malarial transmission-blocking vaccine candidate antigens. J Exp Med. 1992 Nov 1;176(5):1483–1487. doi: 10.1084/jem.176.5.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ruco L. P., Meltzer M. S. Macrophage activation for tumor cytotoxicity: tumoricidal activity by macrophages from C3H/HeJ mice requires at least two activation stimuli. Cell Immunol. 1978 Nov;41(1):35–51. doi: 10.1016/s0008-8749(78)80026-4. [DOI] [PubMed] [Google Scholar]
  44. Sazaki K., Yoshida I., Azuma M. Mechanisms of augmented resistance of cyclosporin A-treated mice to influenza virus infection by trehalose-6,6'-dimycolate. Microbiol Immunol. 1992;36(10):1061–1075. doi: 10.1111/j.1348-0421.1992.tb02110.x. [DOI] [PubMed] [Google Scholar]
  45. Schijns V. E., Haagmans B. L., Horzinek M. C. IL-12 stimulates an antiviral type 1 cytokine response but lacks adjuvant activity in IFN-gamma-receptor-deficient mice. J Immunol. 1995 Sep 1;155(5):2525–2532. [PubMed] [Google Scholar]
  46. Sedegah M., Finkelman F., Hoffman S. L. Interleukin 12 induction of interferon gamma-dependent protection against malaria. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10700–10702. doi: 10.1073/pnas.91.22.10700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sharma A., Upadhyay S. N. Cellular immune responsiveness in rabbits with Setaria digitata filarial antigen and TDM adjuvant. Int J Immunopharmacol. 1993 Apr;15(3):395–400. doi: 10.1016/0192-0561(93)90050-9. [DOI] [PubMed] [Google Scholar]
  48. Skeen M. J., Miller M. A., Shinnick T. M., Ziegler H. K. Regulation of murine macrophage IL-12 production. Activation of macrophages in vivo, restimulation in vitro, and modulation by other cytokines. J Immunol. 1996 Feb 1;156(3):1196–1206. [PubMed] [Google Scholar]
  49. Skeiky Y. A., Guderian J. A., Benson D. R., Bacelar O., Carvalho E. M., Kubin M., Badaro R., Trinchieri G., Reed S. G. A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12. J Exp Med. 1995 Apr 1;181(4):1527–1537. doi: 10.1084/jem.181.4.1527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Stevenson M. M., Tam M. F., Wolf S. F., Sher A. IL-12-induced protection against blood-stage Plasmodium chabaudi AS requires IFN-gamma and TNF-alpha and occurs via a nitric oxide-dependent mechanism. J Immunol. 1995 Sep 1;155(5):2545–2556. [PubMed] [Google Scholar]
  51. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Takeda K., Seki S., Ogasawara K., Anzai R., Hashimoto W., Sugiura K., Takahashi M., Satoh M., Kumagai K. Liver NK1.1+ CD4+ alpha beta T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. J Immunol. 1996 May 1;156(9):3366–3373. [PubMed] [Google Scholar]
  53. Trinchieri G., Gerosa F. Immunoregulation by interleukin-12. J Leukoc Biol. 1996 Apr;59(4):505–511. doi: 10.1002/jlb.59.4.505. [DOI] [PubMed] [Google Scholar]
  54. Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–276. doi: 10.1146/annurev.iy.13.040195.001343. [DOI] [PubMed] [Google Scholar]
  55. 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]
  56. 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]
  57. Wang Z. E., Zheng S., Corry D. B., Dalton D. K., Seder R. A., Reiner S. L., Locksley R. M. Interferon gamma-independent effects of interleukin 12 administered during acute or established infection due to Leishmania major. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12932–12936. doi: 10.1073/pnas.91.26.12932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wynn T. A., Cheever A. W., Jankovic D., Poindexter R. W., Caspar P., Lewis F. A., Sher A. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature. 1995 Aug 17;376(6541):594–596. doi: 10.1038/376594a0. [DOI] [PubMed] [Google Scholar]
  59. Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]
  60. Wysocka M., Kubin M., Vieira L. Q., Ozmen L., Garotta G., Scott P., Trinchieri G. Interleukin-12 is required for interferon-gamma production and lethality in lipopolysaccharide-induced shock in mice. Eur J Immunol. 1995 Mar;25(3):672–676. doi: 10.1002/eji.1830250307. [DOI] [PubMed] [Google Scholar]
  61. Zhan Y., Liu Z., Cheers C. Tumor necrosis factor alpha and interleukin-12 contribute to resistance to the intracellular bacterium Brucella abortus by different mechanisms. Infect Immun. 1996 Jul;64(7):2782–2786. doi: 10.1128/iai.64.7.2782-2786.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Zitvogel L., Tahara H., Robbins P. D., Storkus W. J., Clarke M. R., Nalesnik M. A., Lotze M. T. Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts. J Immunol. 1995 Aug 1;155(3):1393–1403. [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES