Home LiteratureArticle Details
PMID: 9632584 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mucosal delivery of murine interleukin-2 (IL-2) and IL-6 by recombinant strains of Lactococcus lactis coexpressing antigen and cytokine.

Infection and immunity ·Vol. 66 ·No. 7 ·1998-07-00 ·Pages 3183-9

Steidler L, Robinson K, Chamberlain L, Schofield KM, Remaut E, Le Page RW, Wells JM

Abstract

Lactococcus lactis is a nonpathogenic and noncolonizing bacterium which is being developed as a vaccine delivery vehicle for immunization by mucosal routes. To determine whether lactococci can also deliver cytokines to the immune system, we have constructed novel constitutive expression strains of L. lactis which accumulate a test antigen, tetanus toxin fragment C (TTFC), within the cytoplasmic compartment and also secrete either murine interleukin-2 (IL-2) or IL-6. When mice were immunized intranasally with various different expression strains of L. lactis, the anti-TTFC antibody titers increased more rapidly and were substantially higher in mice immunized with the bacterial strains which secreted IL-2 or IL-6 in addition to their production of TTFC. This adjuvant effect was lost when the recombinant strains of L. lactis were killed by pretreatment with mitomycin C and could therefore be attributed to the secretion of IL-2 or IL-6 by the recombinant lactococci. These results provide the first example of the use of a cytokine-secreting, noninvasive experimental bacterial vaccine vector to enhance immune responses to a coexpressed heterologous antigen and point the way to experiments which will test the possible therapeutic efficacy of this mode of cytokine delivery.

MeSH Terms
Administration, Intranasal Animals Antibodies, Bacterial/blood Female Immunization Immunoglobulin A/blood Interleukin-2/genetics Interleukin-6/genetics Lactococcus lactis/genetics Mice Mice, Inbred C57BL Peptide Fragments/genetics,immunology Recombination, Genetic Tetanus Toxin/genetics,immunology
Chemicals
Antibodies, Bacterial Immunoglobulin A Interleukin-2 Interleukin-6 Peptide Fragments Tetanus Toxin tetanus toxin fragment C
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Steidler L
Department of Molecular Biology, Flanders Inter-University Institute for Biotechnology, and University of Ghent, B-9000 Ghent, Belgium.
Robinson K
Chamberlain L
Schofield K M
Remaut E
Le Page R W
Wells J M
References (44)
44 references, click to expand
  1. T cell growth factor: parameters of production and a quantitative microassay for activity.
    J Immunol. 1978 Jun;120(6):2027-32 PMID: 307029
  2. Lactic acid bacteria as vaccine delivery vehicles.
    Antonie Van Leeuwenhoek. 1996 Oct;70(2-4):317-30 PMID: 8879413
  3. Unique structure of murine interleukin-2 as deduced from cloned cDNAs.
    Nature. 1985 Jan 31-Feb 6;313(6001):402-4 PMID: 2578624
  4. T cell unresponsiveness to the mitogenic activity of OKT3 antibody results from a deficiency of monocyte Fc gamma receptors for murine IgG2a and inability to cross-link the T3-Ti complex.
    J Immunol. 1985 Dec;135(6):3882-6 PMID: 2933454
  5. Tetanus toxin: primary structure, expression in E. coli, and homology with botulinum toxins.
    EMBO J. 1986 Oct;5(10):2495-502 PMID: 3536478
  6. Purification and NH2-terminal amino acid sequence of a T-cell-derived lymphokine with growth factor activity for B-cell hybridomas.
    Proc Natl Acad Sci U S A. 1986 Dec;83(24):9679-83 PMID: 2948184
  7. B cell growth modulating and differentiating activity of recombinant human 26-kd protein (BSF-2, HuIFN-beta 2, HPGF).
    EMBO J. 1987 May;6(5):1219-24 PMID: 3497029
  8. Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression.
    J Exp Med. 1987 Oct 1;166(4):967-81 PMID: 2821154
  9. High efficiency transformation of E. coli by high voltage electroporation.
    Nucleic Acids Res. 1988 Jul 11;16(13):6127-45 PMID: 3041370
  10. Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells.
    Proc Natl Acad Sci U S A. 1988 Oct;85(19):7099-103 PMID: 3262872
  11. High interleukin-6 serum levels and increased production by leucocytes in alcoholic liver cirrhosis. Correlation with IgA serum levels and lymphokines production.
    Clin Exp Immunol. 1989 Aug;77(2):221-5 PMID: 2505958
  12. Interleukin-6: an overview.
    Annu Rev Immunol. 1990;8:253-78 PMID: 2188664
  13. Cloning of usp45, a gene encoding a secreted protein from Lactococcus lactis subsp. lactis MG1363.
    Gene. 1990 Oct 30;95(1):155-60 PMID: 2123812
  14. In vivo adjuvant effect of interleukins 5 and 6 on rat tear IgA antibody responses.
    Immunology. 1991 May;73(1):19-23 PMID: 2045126
  15. Detection of IL-6 in human milk and its involvement in IgA production.
    J Reprod Immunol. 1991 Sep;20(3):267-76 PMID: 1960707
  16. PhoP/PhoQ: macrophage-specific modulators of Salmonella virulence?
    Mol Microbiol. 1991 Sep;5(9):2073-8 PMID: 1766380
  17. Serum interleukin-6 concentrations are elevated and associated with elevated tumor necrosis factor-alpha and immunoglobulin G and A concentrations in children with HIV infection.
    AIDS. 1991 Nov;5(11):1319-25 PMID: 1768380
  18. Expression of human IL-1 beta in Salmonella typhimurium. A model system for the delivery of recombinant therapeutic proteins in vivo.
    J Immunol. 1992 Feb 15;148(4):1176-81 PMID: 1737934
  19. Cytokines as immunological adjuvants.
    Vaccine. 1992;10(7):427-34 PMID: 1609545
  20. Intranasal immunization with liposomes containing IL-2 enhances bacterial polysaccharide antigen-specific pulmonary secretory antibody response.
    J Immunol. 1992 Dec 1;149(11):3719-26 PMID: 1431143
  21. Molecular and cellular basis of immune protection of mucosal surfaces.
    Physiol Rev. 1992 Oct;72(4):853-79 PMID: 1438580
  22. Immunoadjuvant activity of a liposomal IL-6 formulation.
    Vaccine. 1993;11(7):777-81 PMID: 8342326
  23. Improved cloning vectors and transformation procedure for Lactococcus lactis.
    J Appl Bacteriol. 1993 Jun;74(6):629-36 PMID: 8349525
  24. Lactococcus lactis: high-level expression of tetanus toxin fragment C and protection against lethal challenge.
    Mol Microbiol. 1993 Jun;8(6):1155-62 PMID: 8361360
  25. Expression of the murine interleukin-4 gene in an attenuated aroA strain of Salmonella typhimurium: persistence and immune response in BALB/c mice and susceptibility to macrophage killing.
    Infect Immun. 1993 Nov;61(11):4818-27 PMID: 8406883
  26. Modulation of antiviral immune responses by exogenous cytokines: effects of tumour necrosis factor-alpha, interleukin-1 alpha, interleukin-2 and interferon-gamma on the immunogenicity of an inactivated rabies vaccine.
    J Gen Virol. 1994 Jan;75 ( Pt 1):55-63 PMID: 8113740
  27. Interleukin 2 and its receptors: recent advances and new immunological functions.
    Immunol Today. 1996 Oct;17(10):481-6 PMID: 8908814
  28. Modifications of the follicle-associated epithelium by short-term exposure to a non-intestinal bacterium.
    J Pathol. 1996 Nov;180(3):326-32 PMID: 8958813
  29. Safety of live oral Salmonella typhi vaccine strains with deletions in htrA and aroC aroD and immune response in humans.
    Infect Immun. 1997 Feb;65(2):452-6 PMID: 9009296
  30. Cytokine-containing liposomes as vaccine adjuvants.
    Eur Cytokine Netw. 1996 Dec;7(4):693-8 PMID: 9010671
  31. Protection against tetanus toxin in mice nasally immunized with recombinant Lactococcus lactis expressing tetanus toxin fragment C.
    Vaccine. 1997 Apr-May;15(6-7):616-9 PMID: 9178460
  32. Oral vaccination of mice against tetanus with recombinant Lactococcus lactis.
    Nat Biotechnol. 1997 Jul;15(7):653-7 PMID: 9219268
  33. The role of interleukin-6 in mucosal IgA antibody responses in vivo.
    Science. 1994 Apr 22;264(5158):561-3 PMID: 8160012
  34. Study of gene transfer in vitro and in the digestive tract of gnotobiotic mice from Lactococcus lactis strains to various strains belonging to human intestinal flora.
    Microb Releases. 1994 Jul;2(4):183-9 PMID: 7921350
  35. Selective induction of immune responses by cytokines coexpressed in recombinant fowlpox virus.
    J Virol. 1994 Dec;68(12):8125-30 PMID: 7966603
  36. Secretion of biologically active murine interleukin-2 by Lactococcus lactis subsp. lactis.
    Appl Environ Microbiol. 1995 Apr;61(4):1627-9 PMID: 7747977
  37. An interleukin-6 transgene expressed in B lymphocyte lineage cells overcomes the T cell-dependent establishment of normal levels of switched immunoglobulin isotypes.
    Eur J Immunol. 1995 May;25(5):1332-7 PMID: 7774636
  38. Genetic marking of Lactococcus lactis shows its survival in the human gastrointestinal tract.
    Appl Environ Microbiol. 1995 Jul;61(7):2771-4 PMID: 7618890
  39. Mucosal and systemic immune responses to a recombinant protein expressed on the surface of the oral commensal bacterium Streptococcus gordonii after oral colonization.
    Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6868-72 PMID: 7624334
  40. Cytokines as adjuvants for vaccines: antigen-specific responses differ from polyclonal responses.
    Infect Immun. 1995 Sep;63(9):3241-4 PMID: 7543878
  41. The effects of transforming growth factor-beta and interleukins 2, 5 and 6 on immunoglobulin production in cultured rat salivary gland tissues.
    Oral Microbiol Immunol. 1995 Apr;10(2):81-6 PMID: 7675523
  42. Manipulation and potentiation of antimycobacterial immunity using recombinant bacille Calmette-Guérin strains that secrete cytokines.
    Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):934-9 PMID: 8570663
  43. Studies of immunity and bacterial invasiveness in mice given a recombinant salmonella vector encoding murine interleukin-6.
    Infect Immun. 1996 Jul;64(7):2730-6 PMID: 8698502
  44. What is BCG?
    Tubercle. 1983 Jun;64(2):129-39 PMID: 6412409
Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.66.7.3183-3189.1998
Published
1998-07-00
Pages
3183-9
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC108331
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1128/IAI.66.7.3183-3189.1998 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2