Functional Energetics of CD4 -Cellular Immunity in Monoclonal Antibody-Associated Progressive Multifocal Leukoencephalopathy in Autoimmune DisordersReportar como inadecuado

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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.


Our results suggest that bioenergetic parameters such as iATP may assist in risk stratification under mAb-immunotherapy of autoimmune disorders.

Autor: Aiden Haghikia, Moritz Perrech, Bartosz Pula, Sabrina Ruhrmann, Anja Potthoff, Norbert H. Brockmeyer, Susan Goelz, Heinz Wiendl,



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