Rheumatoid arthritis (RA) is a destructive inflammatory joint disease associated with increased morbidity and mortality. While biologic therapies have improved treatment responses, many unmet clinical needs remain due to the refractory nature of RA, the high cost of these drugs, and the tendency of the disease to flare despite aggressive treatment. During the previous funding period, we discovered that prior to arthritic knee flare in TNF-Tg mice, the adjacent popliteal lymph node (PLN) expands due to the accumulation of lymph fluid and unactivated-polyclonal CD23+/CD21hi/CD1d hi B cells in inflamed nodes (Bin). New lymphatic vessels (lymphangiogenesis) are then formed that protect the adjacent knee from joint from flare until there is a sudden loss of the lymphatic pulse along the ipsilateral axis extending to the iliac LN, resulting in PLN collapse and Bin translocation fro the follicles to the sinuses, which results in clogging of the lymphatics. Interestingly, knee synovitis that occurs during PLN collapse can be ameliorated by B cell depletion with anti-CD20 therapy, which significantly correlates with increased extrinsic lymphatic drainage without recovery of the lymphatic pulse, which is regulated by eNOS. Most recently, we observed that age-dependent PLN collapse is associated with lymphatic endothelium (LE) and smooth muscle (SM) damage from chronic inflammation driven by iNOS producing macrophages that attach to the luminal surface. Serendipitously, we also found that similar LE-SM damage is induced by contrast-enhanced ultrasound (CE-US) in young TNF-Tg mice, which induces PLN collapse never seen in animals <4-months of age. Thus, we hypothesize that: 1) RA flare mediated by loss of efferent lymphatic flow is due to unrepaired LE-SM damage that compromises the lymphatic vessel barrier allowing squelching of the eNOS driven lymphatic pulse by NO- from iNOS expressing macrophages in the lumen. 2) Selective iNOS inhibition ameliorates arthritic flare secondary to PLN collapse by restoring the lymphatic pulse. 3) Alternatively, arthritic flare is treatable with vasodilator therapy that opens parallel lymphatic vessels to enhance and/or restore lymphatic flow. And, 4) Increased Bin accumulation in PLN, and loss of the lymphatic pulse, occur in human RA flare. To test these hypotheses we propose three Specific Aims that will: 1) establish the role of LE-SM damage/repair and NO- squelching of the lymphatic pulse in PLN collapse and knee flare in TNF-Tg mice; 2) demonstrate the efficacy of selective iNOS and PDE5 inhibitors on arthritic flare in TNF-Tg mice; and 3) provide clinical evidence that Bin accumulation and loss of the efferent lymphatic pulse occurs in human RA flare. As this research program has and will continue to provided paradigm changing information on the mechanisms of RA flare and novel therapies for this condition, the potential impact could be huge in terms of new interventions for refractory disease.

Public Health Relevance

Rheumatoid arthritis (RA) is the most prevalent autoimmune disease, which affects ~1% of our population, and is largely manifested by episodic flares of joint inflammation, pain and tissue destruction. Based on our findings in mice, and RA patients, we discovered that arthritic flare can be caused by the loss of lymphatic drainage from the affected joint, and that known drugs that can increase lymphatic drainage may be effective therapies to treat RA flair. Here we propose to test this theory in mouse models and RA patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056702-08
Application #
9261480
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mao, Su-Yau
Project Start
2009-08-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rochester
Department
Orthopedics
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Bell, Richard D; Rudmann, Christopher; Wood, Ronald W et al. (2018) Longitudinal micro-CT as an outcome measure of interstitial lung disease in TNF-transgenic mice. PLoS One 13:e0190678
Bouta, Echoe M; Kuzin, Igor; de Mesy Bentley, Karen et al. (2017) Brief Report: Treatment of Tumor Necrosis Factor-Transgenic Mice With Anti-Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress. Arthritis Rheumatol 69:1187-1193
Xu, Hao; Bouta, Echoe M; Wood, Ronald W et al. (2017) Utilization of longitudinal ultrasound to quantify joint soft-tissue changes in a mouse model of posttraumatic osteoarthritis. Bone Res 5:17012
Kuzin, Igor I; Kates, Stephen L; Ju, Yawen et al. (2016) Increased numbers of CD23(+) CD21(hi) Bin-like B cells in human reactive and rheumatoid arthritis lymph nodes. Eur J Immunol 46:1752-7
Rahimi, Homaira; Dieudonne, Gregory; Kheyfits, Valeriy et al. (2016) Relationship Between Lymph Node Volume and Pain Following Certolizumab Therapy for Rheumatoid Arthritis Flare: A Pilot Study. Clin Med Insights Arthritis Musculoskelet Disord 9:203-208
Liang, Qianqian; Ju, Yawen; Chen, Yan et al. (2016) Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice. Arthritis Res Ther 18:62
Rahimi, Homaira; Bell, Richard; Bouta, Echoe M et al. (2016) Lymphatic imaging to assess rheumatoid flare: mechanistic insights and biomarker potential. Arthritis Res Ther 18:194
Bouta, Echoe M; Li, Jie; Ju, Yawen et al. (2015) The role of the lymphatic system in inflammatory-erosive arthritis. Semin Cell Dev Biol 38:90-7
Kuzin, Igor I; Bouta, Echoe M; Schwarz, Edward M et al. (2015) TNF signals are dispensable for the generation of CD23+ CD21/35-high CD1d-high B cells in inflamed lymph nodes. Cell Immunol 296:133-7
Bouta, Echoe M; Banik, Peony D; Wood, Ronald W et al. (2015) Validation of power Doppler versus contrast-enhanced magnetic resonance imaging quantification of joint inflammation in murine inflammatory arthritis. J Bone Miner Res 30:690-4

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