title: Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
abstract: We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs. unvaccinated MPTP-treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase-staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post-MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP-only-treated mice and elevated above those in saline-only-treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine-mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG-induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases.
authors.affiliation: Department of Molecular and Medical Pharmacology, the David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Goran
authors.initials: G
authors.lastname: Laćan
authors.forename: Hoa
authors.initials: H
authors.lastname: Dang
authors.forename: Blake
authors.initials: B
authors.lastname: Middleton
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.forename: William P
authors.initials: WP
authors.lastname: Melega
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D001921:Brain / Q000276:immunology / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000276:immunology*; D020734:Parkinsonian Disorders / Q000276:immunology* / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001500:BCG Vaccine; D018696:Neuroprotective Agents
keywords: MPTP; Parkinson's disease; T cells; immune response
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