TY - JOUR
T1 - Functional energetics of cd4+-cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders
AU - Haghikia, Aiden
AU - Perrech, Moritz
AU - Pula, Bartosz
AU - Ruhrmann, Sabrina
AU - Potthoff, Anja
AU - Brockmeyer, Norbert H.
AU - Goelz, Susan
AU - Wiendl, Heinz
AU - Lindå, Hans
AU - Ziemssen, Tjalf
AU - Baranzini, Sergio E.
AU - Käll, Tor Björn
AU - Bengel, Dietmar
AU - Olsson, Tomas
AU - Gold, Ralf
AU - Chan, Andrew
N1 - Funding Information:
S.G. is an employee of Biogen Idec and contributed to study design. S.G. and Biogen Idec supported the study by a limited grant from Biogen Idec for purchasing the bioenergetic kit material. The authors declare that this circumstance does not alter their adherence to all the PLoS ONE policies on sharing data and materials. A.H., H.W., T.Z., R.G. and A.C. have received speakers' honoraria and limited research support from Biogen Idec, Bayer Health, Merck Serono and Teva. All other authors declare no competing financial interests.
PY - 2011
Y1 - 2011
N2 - 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. Methodology/Principal Findings: 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 3rd 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 (ΔΨm) (iATP/ΔΨm-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 3rd percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations. Conclusion: Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders.
AB - 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. Methodology/Principal Findings: 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 3rd 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 (ΔΨm) (iATP/ΔΨm-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 3rd percentile of HC, whereas 10/58 (17%) of the patients treated for more than 24 months had such low iATP-concentrations. Conclusion: Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders.
UR - http://www.scopus.com/inward/record.url?scp=79955424380&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0018506
DO - 10.1371/journal.pone.0018506
M3 - Article
C2 - 21533133
AN - SCOPUS:79955424380
SN - 1932-6203
VL - 6
JO - PLoS ONE
JF - PLoS ONE
IS - 4
M1 - e18506
ER -