Journal article
Recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity
Clinical and experimental immunology, Vol.137(1), pp.24-34
2004
DOI: 10.1111/j.1365-2249.2004.02522.x
PMCID: PMC1809079
PMID: 15196240
Abstract
Interleukin-18 (IL-18) has been demonstrated to synergize with BCG for induction of a T-helper-type 1 (Th1) immune response. Since successful treatment of superficial bladder cancer with BCG requires proper induction of Th1 immunity, we have developed a recombinant (r) BCG strain that functionally secretes mouse (m) IL-18. This rBCG-mIL-18 strain significantly increased production of the major Th1 cytokine IFN-gamma in splenocyte cultures, at levels comparable to that elicited by control BCG plus exogenous rIL-18. IFN-gamma production by splenocytes was eliminated by addition of neutralizing anti-IL-18 antibody. Endogenous IL-12 played a favourable role whereas IL-10 played an adverse role in rBCG-mIL-18-induced IFN-gamma production. Enhanced host antimycobacterial immunity was observed in mice infected with rBCG-mIL-18 which showed less splenic enlargement and reduced bacterial load compared to control mice infected with BCG. Further, splenocytes from rBCG-mIL-18-infected mice, in response to BCG antigen, displayed increased production of IFN-gamma and GMCSF, decreased production of IL-10, elevated cellular proliferation and higher differentiation of IFN-gamma-secreting cells. rBCG-mIL-18 also enhanced BCG-induced macrophage cytotoxicity against bladder cancer MBT-2 cells in a dose-dependent manner. Neutralizing all endogenous macrophage-derived cytokines tested (IL-12, IL-18 and TNF-alpha) as well as IFN-gamma severely diminished the rBCG-mIL-18-induced macrophage cytolytic activity, indicating a critical role for these cytokines in this process. Cytokine analysis for supernatants of macrophage-BCG mixture cultures manifested higher levels of IFN-gamma and TNF-alpha in rBCG-mIL-18 cultures than in control BCG cultures. Taken together, this rBCG-mIL-18 strain augments BCG's immunostimulatory property and may serve as a better agent for bladder cancer immunotherapy and antimycobacterial immunization.
Details
- Title: Subtitle
- Recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity
- Creators
- Y LUO - Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesH YAMADA - Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesX CHEN - Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesA. A RYAN - Mycobacterial Research Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, AustraliaD. P EVANOFF - Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, United StatesJ. A TRICCAS - Mycobacterial Research Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, Newtown, AustraliaM. A O'DONNELL - Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
- Resource Type
- Journal article
- Publication Details
- Clinical and experimental immunology, Vol.137(1), pp.24-34
- DOI
- 10.1111/j.1365-2249.2004.02522.x
- PMID
- 15196240
- PMCID
- PMC1809079
- NLM abbreviation
- Clin Exp Immunol
- ISSN
- 0009-9104
- eISSN
- 1365-2249
- Publisher
- Blackwell; Oxford
- Language
- English
- Date published
- 2004
- Academic Unit
- Urology
- Record Identifier
- 9984051772502771
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