Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity

R. Nadler, Y. Luo, W. Zhao, J. K. Ritchey, James (Christopher) Austin, M. B. Cohen, M. A. O'Donnell, Timothy L. Ratliff

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-γ and TNF-α, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-γ, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-γ versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.

Original languageEnglish (US)
Pages (from-to)206-216
Number of pages11
JournalClinical and Experimental Immunology
Volume131
Issue number2
DOIs
StatePublished - Feb 1 2003
Externally publishedYes

Fingerprint

Delayed Hypersensitivity
Mycobacterium bovis
Interleukin-10
Bacillus
Cytokines
Urinary Bladder
Interleukin-5
Interleukin-4
Therapeutics
Interleukin-12
Reverse Transcriptase Polymerase Chain Reaction
Urinary Bladder Neoplasms
Interleukin-2
Immunity
Catheters
Enzyme-Linked Immunosorbent Assay
Urine
RNA

Keywords

  • Antitumour immunity
  • BCG
  • Cytokine
  • DTH

ASJC Scopus subject areas

  • Immunology

Cite this

Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity. / Nadler, R.; Luo, Y.; Zhao, W.; Ritchey, J. K.; Austin, James (Christopher); Cohen, M. B.; O'Donnell, M. A.; Ratliff, Timothy L.

In: Clinical and Experimental Immunology, Vol. 131, No. 2, 01.02.2003, p. 206-216.

Research output: Contribution to journalArticle

@article{02bf7a150bea41a4b12b57f139011a73,
title = "Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Gu{\'e}rin (BCG) mediated antitumour activity",
abstract = "Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-γ and TNF-α, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-γ, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-γ versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.",
keywords = "Antitumour immunity, BCG, Cytokine, DTH",
author = "R. Nadler and Y. Luo and W. Zhao and Ritchey, {J. K.} and Austin, {James (Christopher)} and Cohen, {M. B.} and O'Donnell, {M. A.} and Ratliff, {Timothy L.}",
year = "2003",
month = "2",
day = "1",
doi = "10.1046/j.1365-2249.2003.02071.x",
language = "English (US)",
volume = "131",
pages = "206--216",
journal = "Clinical and Experimental Immunology",
issn = "0009-9104",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Interleukin 10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumour activity

AU - Nadler, R.

AU - Luo, Y.

AU - Zhao, W.

AU - Ritchey, J. K.

AU - Austin, James (Christopher)

AU - Cohen, M. B.

AU - O'Donnell, M. A.

AU - Ratliff, Timothy L.

PY - 2003/2/1

Y1 - 2003/2/1

N2 - Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-γ and TNF-α, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-γ, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-γ versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.

AB - Intravesical BCG therapy is effective in the treatment of superficial bladder cancer. Both clinical and experimental results suggest a role for cytokines and delayed-type hypersensitivity (DTH) in BCG-induced antitumour immunity. We characterized the modulatory effects of BCG on bladder cytokine expression and determined the relationship between DTH and BCG antitumour activity. The bladders of mice were instilled with BCG through a catheter. Bladder tissue RNA and urine were collected for evaluation of cytokine expression using reverse transcriptase-polymerase chain reaction (RT-PCR) and/or ELISA. IFN-γ and TNF-α, the two major cytokines associated with DTH, were efficiently induced by BCG. IL10, an important down-regulator of DTH, was also induced by BCG. Constitutive levels of IL4 and IL5 were observed, but neither IL4 nor IL5 were modulated by BCG. Similar results were observed in the kinetic analysis of urinary cytokines in patients after intravesical BCG therapy. Production of Th1 (T helper type 1) cytokines (IFN-γ, IL2 and IL12) preceded that of the Th2 (T helper type 2) cytokine IL10. A tendency toward higher ratios of IFN-γ versus IL10 for BCG responders also was observed. In animal studies the absence of IL10 abrogated either by antibody inhibition or the use of genetically modified, IL10 deficient (IL10-/-) mice resulted in enhanced DTH responses. Under conditions of enhanced DTH, a significant enhancement in antitumour activity was observed. These data demonstrate that DTH and its associated mononuclear infiltration and cytokine production are important to the antitumour activity of intravesical BCG therapy, and suggest that effects to diminish IL10 production may have therapeutic value.

KW - Antitumour immunity

KW - BCG

KW - Cytokine

KW - DTH

UR - http://www.scopus.com/inward/record.url?scp=0037318434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037318434&partnerID=8YFLogxK

U2 - 10.1046/j.1365-2249.2003.02071.x

DO - 10.1046/j.1365-2249.2003.02071.x

M3 - Article

C2 - 12562379

AN - SCOPUS:0037318434

VL - 131

SP - 206

EP - 216

JO - Clinical and Experimental Immunology

JF - Clinical and Experimental Immunology

SN - 0009-9104

IS - 2

ER -