(A) Modified arthroscopic probe in which the tip was hooked and sharpened to a 2 mm internal length. (B) The distal MC3: D = dorsal, P = palmar, L = lateral, and M = medial.

<p>A woven pattern of 4 dorso-palmar and 4 radial grooves created on the weight-bearing area of the lateral and medial condyles. Blue arrows represent the direction the instrument was introduced. Red and green rectangles represent the dorsal histologic slices centered over the groove areas and the palmar histologic slices in the continuity of the dorsal slices.</p

Radiographic views of the MP joint of an individual at week 0 (A, B, C) and week 10 (D, E, F).

<p>A and D show the latero-medial view, B and E show the 45-degree oblique view, and C and F show the dorso-palmar view. Grade 1 to 2 osteophytes (white arrows) and grade 1 sclerosis (white triangles) are visible.</p

Lameness evaluation with the inertial sensor-based system.

<p>(A) Asymmetry of movement of the groove limb (red) as opposed to the sham limb (blue), measured by A1/A2. Mean ± SEM is shown. Asterisks represent significant differences between the groove and sham limbs (*<i>P</i> < 0.05, **<i>P</i> < 0.005). (B) Individual time-course of lameness measured by vector sum.</p

Median radiographic scores (± median absolute deviation) for groove and sham joints at weeks 0 and 10.

<p>* Values represent significant differences between groove joints at weeks 0 and 10 (<i>P</i> < 0.05).</p><p>^† Significant differences between groove joints and sham joints at week 10 (<i>P</i> < 0.05)</p><p>^‡ Significant differences between sham joints at weeks 0 and 10 (<i>P</i> < 0.05)</p><p>Median radiographic scores (± median absolute deviation) for groove and sham joints at weeks 0 and 10.</p

Median macroscopic and microscopic scores (± median absolute deviation) for groove and sham joints at week 10.

<p>* Significant difference between groove joints and sham joints (<i>P</i> < 0.05).</p><p>^† Significant differences between dorsal and palmar for the groove joints and sham joints (<i>P</i> < 0.05).</p><p>Chondrocyte necrosis = chondrocyte-free areas or empty chondrocyte lacunae, or focal cell loss.</p><p>Chondrocyte clusters = complex chondrone formation.</p><p>Cartilage matrix softening = cartilage matrix appeared more or less pale and loose, visible in all stains used.</p><p>Osteoblastic margination = basophilic osteoblastic cells aligned at the border of subchondral bone cavities.</p><p>Vertical grooves = surgically induced grooves crossing the entire thickness of the non-calcified cartilage extending to the junction with calcified cartilage.</p><p>Horizontal cracking = cracks at the junction of the non-calcified and calcified cartilage.</p><p>Median macroscopic and microscopic scores (± median absolute deviation) for groove and sham joints at week 10.</p

Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques

<div><p>Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.</p></div

CHIKV mAb treatment did not cause significant changes in CD4⁺ or CD8⁺ T cell proliferation.

<p>Rhesus macaques were inoculated with CHIKV and treated with control antibody SVIR002 or CHIKV mAb SVIR001. Blood was drawn daily 0–7 dpi, and PBMCs were examined for proliferative responses of different <b>(A-C)</b> CD4⁺ and <b>(D-F)</b> CD8⁺ T cell subsets. T cell subsets were defined in <b><a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005637#pntd.0005637.s002" target="_blank">S2 Fig</a></b> as Naïve (NV), Central Memory (CM), and Effector Memory (EM). The Ki67⁺ proliferative status was plotted as a percentage of the total population. <b>(G)</b> IFNγ ELISpot analysis was performed on PBMCs from rhesus macaques at 7 dpi. PBMCs from animals treated with SVIR001 (5 mg/kg or 15 mg/kg) or SVIR002 (15 mg/kg) were stimulated with CHIKV peptide pools (10 μg/well), inactivated CHIKV (iCHIKV) (10 μg/well), or PMA/Ionomycin as a positive control. DMSO was used as a negative control to establish the baseline number of IFNγ-producing T cells for each animal. Spots were quantified on an AID ELISpot plate reader (n = 4/group).</p