Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guérin.
Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been accepted as the most effective agent in clinical use against superficial bladder cancer, its mechanism of action remains incompletely understood. A kinetic analysis in assessing the potential role of cytokines from BCG-stimulated murine splenocytes showed that IL-12 expression preceded that of other cytokines. Experiments subtracting endogenous BCG-driven IL-12 using neutralizing Ab or augmenting its activity with supplemental rIL-12 revealed not only that IL-12 plays a dominant role in IFN-gamma induction but also that it is normally dose limiting. A striking increase in IFN-gamma production could be generated in both mouse and human immunocompetent cell culture by the addition of even a small amount of rIL-12. Moreover, this same synergistic effect could be replicated during in vivo administration of BCG plus rIL-12 into the mouse bladder and was observed in a patient receiving intravesical combination therapy. In costimulation cultures, this synergy appeared to partially rely on IL-18 and IL-2 and could be down-regulated by IL-10. This suggests that a dynamic interplay between Th1 and Th2 cytokines is responsible for net IFN-gamma production. The ability of supplemental exogenous IL-12 to strongly shift this balance toward Th1 provides an immunological basis for using it in conjunction with intravesical BCG for bladder cancer immunotherapy.
O'Donnell
M A
MA
Division of Urology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. modonnel@bidmc.harvard.edu
Luo
Y
Y
Chen
X
X
Szilvasi
A
A
Hunter
S E
SE
Clinton
S K
SK
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology*; D000283:Administration, Intravesical; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007369:Interferon Inducers / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D018664:Interleukin-12 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D007106:Immune Sera; D007369:Interferon Inducers; D020382:Interleukin-18; D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma