title: An in vitro investigation of the effects of the nerve agent pretreatment pyridostigmine bromide on human peripheral blood T-cell function.
abstract: The current pretreatment against nerve agent poisoning deployed by the UK and US armed forces is the acetylcholinesterase (EC 3.1.1.7) inhibitor pyridostigmine bromide (PB). At higher doses, PB is also used to treat the autoimmune disease myasthenia gravis. In both cases, the therapeutic effect is mediated by inhibition of acetylcholinesterase (AChE) at cholinergic synapses. However, the location of AChE is not restricted to these sites. AChE, acetylcholine (ACh) receptors and choline acetyltransferase have been reported to be expressed by T cells, suggesting that cholinergic signalling may exert some modulatory influence on T-cell function and consequently on the immune system. The aim of this study was to investigate the role of the T-cell cholinergic system in the immunological activation process and to examine whether inhibitors of AChE such as PB affect immune function. To investigate this, human peripheral blood mononuclear cells (PBMC) were stimulated using either mitogen, cross-linking of the T-cell receptor and co-receptors with antibodies (anti-CD3/CD28) or by antigen presentation in the presence of various AChE inhibitors and ACh receptor agonists or antagonist. Several indices were used to assess T-cell activation, including the secretion of IL-2, cell proliferation and expression of CD69. Treatment with PB had no significant effect on the immunological assays selected. Physostigmine (PHY), a carbamate compound similar to PB, consistently showed inhibition of T-cell activation, but only at concentrations in excess of those required to inhibit AChE. No evidence was found to support previously published findings showing muscarinic enhancement of cell proliferation or IL-2 secretion.
authors.affiliation: Immune Modulation Research Laboratory, School of Pharmaceutical Sciences, University of Nottingham, The Boots Science Building, NG7 2RD, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Telford
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Wilkinson
authors.forename: Doreen S W
authors.initials: DS
authors.lastname: Hooi
authors.forename: Vivienne
authors.initials: V
authors.lastname: Worrall
authors.forename: A Christopher
authors.initials: AC
authors.lastname: Green
authors.forename: David L
authors.initials: DL
authors.lastname: Cook
authors.forename: David I
authors.initials: DI
authors.lastname: Pritchard
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Griffiths
mesh_terms: D000110:Acetylcholinesterase / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002619:Chemical Warfare Agents / Q000009:adverse effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003470:Culture Media; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008934:Mitogens / Q000494:pharmacology; D011729:Pyridostigmine Bromide / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D000110:Acetylcholinesterase; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D003470:Culture Media; D007376:Interleukin-2; D037181:Lectins, C-Type; D008934:Mitogens; D011729:Pyridostigmine Bromide; D000099192:CD69 Antigens