title: Functional energetics of CD4+-cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders.
abstract: BACKGROUND
  Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system- (CNS-) infection that typically occurs in a subset of immunocompromised individuals. An increasing incidence of PML has recently been reported in patients receiving monoclonal antibody (mAb) therapy for the treatment of autoimmune diseases, particularly those treated with natalizumab, efalizumab and rituximab. Intracellular CD4(+)-ATP-concentration (iATP) functionally reflects cellular immunocompetence and inversely correlates with risk of infections during immunosuppressive therapy. We investigated whether iATP may assist in individualized risk stratification for opportunistic infections during mAb-treatment.
  
  
  RESULTS
  iATP in PHA-stimulated, immunoselected CD4(+)-cells was analyzed using an FDA-approved assay. iATP of mAb-associated PML (natalizumab (n = 8), rituximab (n = 2), efalizumab (n = 1)), or other cases of opportunistic CNS-infections (HIV-associated PML (n = 2), spontaneous PML, PML in a psoriasis patient under fumaric acids, natalizumab-associated herpes simplex encephalitis (n = 1 each)) was reduced by 59% (194.5±29 ng/ml, mean±SEM) in comparison to healthy controls (HC, 479.9±19.8 ng/ml, p<0.0001). iATP in 14 of these 16 patients was at or below 3(rd) percentile of healthy controls, similar to HIV-patients (n = 18). In contrast, CD4(+)-cell numbers were reduced in only 7 of 15 patients, for whom cell counts were available. iATP correlated with mitochondrial transmembrane potential (ΔΨ(m)) (iATP/ΔΨ(m)-correlation:tau = 0.49, p = 0.03). Whereas mean iATP of cross-sectionally analysed natalizumab-treated patients was unaltered (448.7±12 ng/ml, n = 150), iATP was moderately decreased (316.2±26.1 ng/ml, p = 0.04) in patients (n = 7) who had been treated already during the pivotal phase III trials and had received natalizumab for more than 6 years. 2/92 (2%) patients with less than 24 months natalizumab treatment revealed very low iATP at or below the 3(rd) percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations.
  
  
  CONCLUSIONS
  Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders.
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Aiden
authors.initials: A
authors.lastname: Haghikia
authors.forename: Moritz
authors.initials: M
authors.lastname: Perrech
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pula
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ruhrmann
authors.forename: Anja
authors.initials: A
authors.lastname: Potthoff
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Brockmeyer
authors.forename: Susan
authors.initials: S
authors.lastname: Goelz
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Hans
authors.initials: H
authors.lastname: Lindå
authors.forename: Tjalf
authors.initials: T
authors.lastname: Ziemssen
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Tor-Björn
authors.initials: TB
authors.lastname: Käll
authors.forename: Dietmar
authors.initials: D
authors.lastname: Bengel
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000150:complications / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D006801:Humans; D007111:Immunity, Cellular; D016867:Immunocompromised Host; D007968:Leukoencephalopathy, Progressive Multifocal / Q000209:etiology* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal