Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mφs), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis–derived material was detected in CD14−HLA-DR+DC-SIGN+ cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN–mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.

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Objective. To evaluate the efficacy and safety of intraarticular sprifermin (recombinant human fibroblast growth factor 18) in the treatment of symptomatic knee osteoarthritis (OA).Methods. The study was a randomized, doubleblind, placebo-controlled, proof-of-concept trial. Intraarticular sprifermin was evaluated at doses of 10 g, 30 g, and 100 g. The primary efficacy end point was change in central medial femorotibial compartment cartilage thickness at 6 months and 12 months as determined using quantitative magnetic resonance imaging (qMRI). The primary safety end points were nature, incidence, and severity of local and systemic treatment-emergent adverse events (AEs) and acute inflammatory reactions, as well as results of laboratory assessments. Secondary end points included changes in total and compartment femorotibial cartilage thickness and volume as assessed by qMRI, changes in joint space width (JSW) seen on radiographs, and pain scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results. One hundred ninety-two patients were randomized and evaluated for safety, 180 completed the trial, and 168 were evaluated for the primary efficacy end point. We found no statistically significant dose response in change in central medial femorotibial compartment cartilage thickness. Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral femorotibial cartilage thickness and volume and in JSW narrowing in the lateral femorotibial compartment. All groups had improved WOMAC pain scores, with statistically significantly less improvement at 12 months in patients receiving the 100-g dose of sprifermin as compared with those receiving placebo. There was no significant difference in serious AEs, treatment-emergent AEs, or acute inflammatory reactions between sprifermin and placebo groups. Conclusion. No statistically significant relation-ClinicalTrials.gov identifier: NCT01033994.

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Objective To study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (ROA), specifically healthy knees and knees with end-stage ROA. Methods One knee of 831 Osteoarthritis Initiative (OAI) participants was examined: 112 healthy, without ROA or risk factors for knee OA, and 719 ROA knees: 310 calculated Kellgren Lawrence [cKLG] grade 2, 300 cKLG3, and 109 cKLG4. Subregional change in thickness was assessed after segmentation of weight-bearing femorotibial cartilage at baseline and at one year from coronal MRI. Regional and ordered values (OV) of change were compared by baseline ROA status. Results Healthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed around zero. In cKLG2 knees, changes in cartilage thickness were small (≤1%; minimal SRM -0.22) and not significantly different from healthy knees. Knees with cKLG3 showed substantial loss of cartilage thickness (up to -2.5%; minimal SRM -0.35), with OV changes being significantly (p<0.05) greater than those in healthy knees. cKLG4 knees displayed the largest rate of loss across ROA grades (up to -3.9%; minimal SRM -0.51), with OV changes also significantly (p<0.05) greater than in healthy knees. Conclusion MRI-based cartilage thickness showed high rates of loss in knees with moderate and end-stage ROA, and small rates (indistinguishable from healthy knees) in mild ROA. From the perspective of sensitivity to change, end-stage ROA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an endpoint.