Late Breaking NewsSaturday, October 05, 2013, 08:30 - 08:42
Dynamic biomarkers for clinical efficacy and individual PML prevention under natalizumab therapyT. Schneider-Hohendorf, N. Schwab, H. Wiendl (Münster, DE)
How the adaptive immune system and especially immune surveillance is influenced by long-term natalizumab therapy is still unclear. This is of special interest as the development of natalizumab-associated PML is a major health concern and highly correlated to long-term treatment.
We assessed 381 long-term natalizumab-treated (18-80 months) MS patients, including 16 having developed PML. There were no major changes in the peripheral T-cell compartments, but T cells in the CSF of natalizumab-treated patients showed an almost exclusive effector-memory signature. This pattern was not found in MS patients treated with other drugs, where central-memory cells dominated the CSF, but was seen in non-inflammatory neurological diseases. CD49d expression on peripheral T cells was immediately downregulated upon treatment initiation, but recovered to the value of healthy controls during long-term therapy. This CD49d downregulation was absent in patients testing positive for natalizumab-neutralizing antibodies (nabs) or during a relapse. CD49d expression on CSF T cells was completely absent, indicating that there might be alternative mechanisms for T cells to enter the CSF and probably also the CNS compartment without using CD49d for adhesion to luminal endothelium. In contrast to the downregulation of CD49d, PSGL-1 was strongly upregulated in the periphery, presumably due to the strong and persistent T-cell activation by natalizumab. This upregulation has significant functional relevance as shear-flow experiments with glass capillaries coated with P-Selectin (PSGL-1 ligand) as well as with cultured primary human brain-derived microvascular endothelial cells revealed enhanced capturing and rolling of patient-derived CD4+ T cells. Strikingly, L-selectin (CD62L) showed a strong correlation with PML development. Eight patients had given blood before the diagnosis of PML and the percentage of CD62L expressing CD4+ T cells was significantly lower in all of these patients (4.6%) when compared with non-PML natalizumab-treated patients (40.2%; p<=0.0001). Natalizumab treatment induces a normalization of the central T-cell effector/memory compartments and strong peripheral T-cell activation with consequences for adhesion molecule expression. Measurement of CD49d on CD4+ T cells can help with detection of patients with continued clinical activity (nabs, non-responders); lack of CD62L expression on CD4+ T cells provides a biomarker for individual PML risk assessment.
T. Schneider-Hohendorf and N. Schwab have nothing to disclose.
H. Wiendl received speaker honoraria, consultation fees, and grant support from Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Sanofi-Aventis, TEVA Pharma, and Novo Nordisk.