Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis

Shelton, David L.; Zeller, Jörg; Ho, Wei-Hsien; Pons, Jaume; Rosenthal, Arnon

doi:10.1016/j.pain.2005.03.039

Cited by 102 publications

(97 citation statements)

References 55 publications

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“…βNGF binds and activates its cognate receptor, tropomyosin-related kinase A receptor (TrkA), up-regulating the expression and activity of pathways that enhance acute and chronic pain. Antagonism of the βNGF/TrkA signaling pathway has been shown in animal and clinical studies to be a potent means of attenuating pain sensation in a number of clinical indications (27,28).…”

Section: Resultsmentioning

confidence: 99%

Coupling mammalian cell surface display with somatic hypermutation for the discovery and maturation of human antibodies

Bowers

Horlick

Neben

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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A novel approach has been developed for the isolation and maturation of human antibodies that replicates key features of the adaptive immune system by coupling in vitro somatic hypermutation (SHM) with mammalian cell display. SHM is dependent on the action of the B cell specific enzyme, activation-induced cytidine deaminase (AID), and can be replicated in non-B cells through expression of recombinant AID. A library of human antibodies, based on germline V-gene segments with recombined human D J regions was used to isolate low-affinity antibodies to human β nerve growth factor (hβNGF). These antibodies, initially naïve to SHM, were subjected to AID-directed SHM in vitro and selected using the same mammalian cell display system, as illustrated by the maturation of one of the antibodies to low pM K D . This approach overcomes many of the previous limitations of mammalian cell display, enabling direct selection and maturation of antibodies as full-length, glycosylated IgGs. affinity maturation | mammalian display

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Section: Resultsmentioning

confidence: 99%

Coupling mammalian cell surface display with somatic hypermutation for the discovery and maturation of human antibodies

Bowers

Horlick

Neben

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Anti-NGF antibody injected 6 h after LC completely blocked DOMS. Since the bradykinin released during exercise had already initiated the DOMS process 6 h after LC and the biological half-life of the antibody is reported to be several days (Shelton et al, 2005), NGF antibody might have continuously reversed DOMS rather than suppressing initiation of the processes that led to DOMS. Only 10 g of anti-NGF antibody was needed to suppress DOMS with an early injection (at 6 h after LC), but 30 g was needed with later injection (10 g was ineffective) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bradykinin and Nerve Growth Factor Play Pivotal Roles in Muscular Mechanical Hyperalgesia after Exercise (Delayed-Onset Muscle Soreness)

Murase

Terazawa²,

Queme³

et al. 2010

J. Neurosci.

160

183

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Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes delayed-onset muscle soreness (DOMS), a kind of muscular mechanical hyperalgesia. The substances that induce this phenomenon are largely unknown. Peculiarly, DOMS is not perceived during and shortly after exercise, but rather is first perceived after ϳ1 d. Using B 2 bradykinin receptor antagonist HOE 140, we show here that bradykinin released during exercise plays a pivotal role in triggering the process that leads to muscular mechanical hyperalgesia. HOE 140 completely suppressed the development of muscular mechanical hyperalgesia when injected before LC, but when injected 2 d after LC failed to reverse mechanical hyperalgesia that had already developed. B 1 antagonist was ineffective, regardless of the timing of its injection. Upregulation of nerve growth factor (NGF) mRNA and protein occurred in exercised muscle over a comparable time course (12 h to 2 d after LC) for muscle mechanical hyperalgesia. Antibodies to NGF injected intramuscularly 2 d after exercise reversed muscle mechanical hyperalgesia. HOE 140 inhibited the upregulation of NGF. In contrast, shortening contraction or stretching induced neither mechanical hyperalgesia nor NGF upregulation. Bradykinin together with shortening contraction, but not bradykinin alone, reproduced lasting mechanical hyperalgesia. We also showed that rat NGF sensitized thin-fiber afferents to mechanical stimulation in the periphery after 10 -20 min. Thus, NGF upregulation through activation of B 2 bradykinin receptors is essential (though not satisfactory) to mechanical hyperalgesia after exercise. The present observations explain why DOMS occurs with a delay, and why lengthening contraction but not shortening contraction induces DOMS.

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“…NGF has also been implicated as a mediator of weight loss (26). Progressive unintentional weight loss, also known as cachexia, can be a clinical consequence of a chronic systemic inflammation, such as RA (42).…”

Section: Suppression Of Weight Loss In Ciamentioning

confidence: 99%

“…Recognition of NGF as a mediator of pain and its involvement in persistent pain in adults has stimulated the development of numerous biologics and pharmaceuticals that antagonize its activity (5,11). Neutralization of NGF by specific Abs has been shown to decrease thermal and mechanical hyperalgesia in animal models of acute and chronic pain that include: cutaneous injection of CFA (17,25), arthritis-associated pain (26), and bone cancer (27). A phase II clinical trial with the anti-NGF mAb tanezumab demonstrated suppression of osteoarthritic pain (28).…”

mentioning

confidence: 99%

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

Röhn¹,

Ralvenius

Paul

et al. 2011

The Journal of Immunology

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Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. For a substantial proportion of patients, conventional drug treatments do not provide adequate pain relief. Consequently, novel approaches to pain management, involving alternative targets and new therapeutic modalities compatible with chronic use, are being sought. Nerve growth factor (NGF) is a major mediator of chronic pain. Clinical testing of NGF antagonists is ongoing, and clinical proof of concept has been established with a neutralizing mAb. Active immunization, with the goal of inducing therapeutically effective neutralizing autoreactive Abs, is recognized as a potential treatment option for chronic diseases. We have sought to determine if such a strategy could be applied to chronic pain by targeting NGF with a virus-like particle (VLP)-based vaccine. A vaccine comprising recombinant murine NGF conjugated to VLPs from the bacteriophage Qβ (NGFQβ) was produced. Immunization of mice with NGFQβ induced anti-NGF–specific IgG Abs capable of neutralizing NGF. Titers could be sustained over 1 y by periodic immunization but declined in the absence of boosting. Vaccination with NGFQβ substantially reduced hyperalgesia in collagen-induced arthritis or postinjection of zymosan A, two models of inflammatory pain. Long-term NGFQβ immunization did not change sensory or sympathetic innervation patterns or induce cholinergic deficits in the forebrain, nor did it interfere with blood-brain barrier integrity. Thus, autovaccination targeting NGF using a VLP-based approach may represent a novel modality for the treatment of chronic pain.

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Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis

Cited by 102 publications

References 55 publications

Coupling mammalian cell surface display with somatic hypermutation for the discovery and maturation of human antibodies

Coupling mammalian cell surface display with somatic hypermutation for the discovery and maturation of human antibodies

Bradykinin and Nerve Growth Factor Play Pivotal Roles in Muscular Mechanical Hyperalgesia after Exercise (Delayed-Onset Muscle Soreness)

A Virus-Like Particle-Based Anti-Nerve Growth Factor Vaccine Reduces Inflammatory Hyperalgesia: Potential Long-Term Therapy for Chronic Pain

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