title: BCG-associated heterologous immunity, a historical perspective: experimental models and immunological mechanisms.
abstract: Randomized controlled trials indicate that bacille Calmette-Guerin (BCG) has beneficial heterologous ('non-specific') effects on mortality in high mortality settings. These findings have stimulated interest in understanding the immunological mechanisms underlying these effects in the hope of harnessing them to reduce all-cause mortality. This line of investigation is especially important in light of BCG being discontinued in some countries as the prevalence of TB falls. Stopping routine BCG in this situation may have the unintended consequence of depriving children of the beneficial immune modulating effects of this vaccine. BCG has been recognized as a potent immunomodulator for decades. This review details experimental studies involving BCG and any heterologous antigen that aimed to interrogate potential immunological mechanisms. To provide a historical perspective, the evidence is presented chronologically. The lines of immunological enquiry can be seen to mirror the evolution of our understanding of cell-mediated immunity and its components. As new clinical trials to investigate the heterologous effects of BCG are undertaken, an understanding of the history of BCG-induced immunity against heterologous antigens may provide information on immunological pathways worthy of further interrogation using modern immunological methods.
authors.affiliation: Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital Melbourne, Parkville, Vic 3052, Australia Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Vic 3052, Australia Infectious Diseases & Microbiology Research Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia bridget.freyne@rch.org.au.
authors.forename: Bridget
authors.initials: B
authors.lastname: Freyne
authors.affiliation: Institute for Medical Immunology, Université Libre de Bruxelles, 6041 Charleroi, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchant
authors.affiliation: Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital Melbourne, Parkville, Vic 3052, Australia Infectious Diseases Unit, The Royal Children's Hospital Melbourne, Parkville, Vic 3052, Australia Infectious Diseases & Microbiology Research Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Curtis
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D064789:Immunity, Heterologous / Q000187:drug effects* / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016032:Randomized Controlled Trials as Topic; D016176:T-Lymphocyte Subsets; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D014611:Vaccination
chemical_list: D001500:BCG Vaccine
keywords: BCG; Heterologous; History; Immunology; Non-specific