Efficacy of B cell depletion therapy for murine joint arthritis flare is associated with increased lymphatic flow

Abstract

Objective B cell depletion therapy (BCDT) ameliorates rheumatoid arthritis by mechanisms that are incompletely understood. Arthritic flare in tumor necrosis factor transgenic (TNF-Tg) mice is associated with efferent lymph node (LN) “collapse,” triggered by B cell translocation into lymphatic spaces and decreased lymphatic drainage. We examined whether BCDT efficacy is associated with restoration of lymphatic drainage due to removal of obstructing nodal B cells. Methods We developed contrast-enhancement (CE) MRI imaging, near-infrared indocyanine green (NIR-ICG) imaging, and intravital immunofluorescent imaging to longitudinally assess synovitis, lymphatic flow, and cell migration in lymphatic vessels in TNF-Tg mice. We tested to see if BCDT efficacy is associated with restoration of lymphatic draining and cell egress from arthritic joints. Results Unlike active lymphatics to normal and pre-arthritic knees, afferent lymphatic vessels to collapsed LNs in inflamed knees do not pulse. Intravital immunofluorescent imaging demonstrated that CD11b+ monocytes/macrophages in lymphatic vessels afferent to expanding LN travel at high velocity (186 ± 37 micrometer/sec), while these cells are stationary in lymphatic vessels afferent to collapsed PLN. BCDT of flaring TNF-Tg mice significantly decreased knee synovial volume by 50% from the baseline level, and significantly increased lymphatic clearance versus placebo (p<0.05). This increased lymphatic drainage restored macrophages egress from inflamed joints without recovery of the lymphatic pulse. Conclusion These results support a novel mechanism in which BCDT of flaring joints lessens inflammation by increasing lymphatic drainage and subsequent migration of cells and cytokines from the synovial space.

Lymphatic function measurements influenced by contrast agent volume and body position

“…These data show that restricting the analysis to only lymphatic contraction parameters is not sufficient to get a full understanding of lymphatic function. Several disease states show decreased lymphatic contraction but increased collecting lymphatic vessel diameter (2,16,32). Thus, it is possible that there is increased flow in these situations.…”

“…The lymphatic system has become heavily researched due to its potential role in many disease processes, including Alzheimer's disease, rheumatoid arthritis, glaucoma, hypertension, myocardial infarction, lymphedema, and cancer (1)(2)(3)(4)(5)(6). This research focus has catalyzed the advancement of techniques used to assess lymphatic function (7), including near-infrared fluorescence (NIRF) imaging, direct fluorescence imaging of lymphatic contraction, and Doppler optical coherence tomography (DOCT) (8)(9)(10).…”

Emerging lymphatic imaging technologies for mouse and man

“…Fluorescently labeling (77), radiolabeling (78), or conjugating magnetic nanoparticles (79) to a LYVE1 antibody has allowed investigators to visualize lymphatics through fluorescence, PET, and molecular MRI. Fluorescently labeled antibodies targeting CD11b and GR1 have allowed for imaging of immune cell migration within lymphatic vessels using intravital fluorescence imaging (58). Dendritic cell trafficking to LNs has been performed using non-invasive MRI techniques with ultra-small iron oxide particles (USPIOs) that are administered intradermally (80).…”

Recurrent lymphangitic cellulitis syndrome: A quintessential example of an immunocompromised district

“…Abnormalities of drainage on lymphatic scintigraphy were found in 77% of patients with recurrent cellulitis. 18 When lymphatics are scarred by surgery or trauma, repeated infections have the potential to further disrupt these damaged soft tissues. 2,13 When the lymphatic system is disrupted, varying degrees of local or generalized swelling, commonly referred to as lymphedema, may occur regardless of the normalcy of venous drainage.…”