K252a, a High-Affinity Nerve Growth Factor Receptor Blocker, Improves Psoriasis: An In Vivo Study Using the Severe Combined Immunodeficient Mouse–Human Skin Model

Abstract

The peripheral nervous system, in addition to its sensory and motor functions, can induce a local inflammatory response known as neurogenic inflammation. This phenomenon plays a critical role in several inflammatory diseases, e.g., asthma, atopy, rheumatoid arthritis, psoriasis, and ulcerative colitis. Neurogenic inflammation and the role of nerve growth factor (NGF) have been extensively studied in psoriasis. There are increased levels of NGF in the keratinocytes and upregulation of NGF receptor (NGF-R) in the cutaneous nerves of psoriatic plaques. NGF can influence all the salient pathologic events noticed in psoriasis such as proliferation of keratinocytes, angiogenesis, T cell activation, expression of adhesion molecules, proliferation of cutaneous nerves, and upregulation of neuropeptides. In this double-blinded, placebo-controlled study, we addressed the role of NGF/NGF-R in psoriasis in an in vivo system using the severe combined immunodeficient (SCID) mouse-human skin model of psoriasis. The transplanted psoriatic plaques on the SCID mice (n=12) were treated with K252a, a high-affinity NGF receptor blocker. Psoriasis significantly improved following 2 wk of therapy. The length of the rete pegs changed from 308.57+/-98.72 to 164.64+/-46.78 microm (p<0.01, Student's t test). A similar improvement of psoriasis was observed by directly inhibiting NGF with NGF-neutralizing antibody. NGF-neutralizing antibody in normal saline at 10 ng (n=4) and 20 ng (n=4) per kilogram of body weight doses were used. Both doses of NGF-neutralizing antibody reduced rete peg lengths significantly, e.g., from 298.5+/-42.69 to 150.52+/-32.93 microm (p<0.05, Student's t test). This study provides evidence for the role of NGF and its high-affinity receptor in the pathogenesis of psoriasis and insights to develop novel therapeutic modalities.

Revisiting the Koebner Phenomenon

“…Because up-regulation of p75 receptor is a marker of an in vivo effect of NGF, for quantification of nerve regeneration we used the data from p75 antibody staining. 19 The numbers of regenerated terminal cutaneous nerves positive for NGF-R were significantly higher (P Ͻ 0.01) in the transplanted psoriatic plaques ( Figure 6, C-E) compared to the normal human skin ( Figure 6A). Table 2 summarizes the quantitative differences in number of nerve fibers in transplanted plaques and transplanted normal skin.…”

“…26,30 We have further substantiated a critical role for NGF in wound healing by providing evidence that in addition to its effect on keratinocytes NGF promotes angiogenesis and regeneration of cutaneous nerves, the two other essential components of wound healing. 19,41 A wound induces a reaction characterized by proliferation of keratinocytes, fibroblasts, vascular elements, nerves, and accumulation of inflammatory cells. In nonpsoriatics, healing stops after a finite time depending on the nature of the wound.…”

“…26,38,41 Antagonism of NGF by a neutralizing antibody or blocking of trkA by an alkaloid K252a is therapeutically effective in psoriasis. 19 Putting all these evidences together, it is suggestive that NGF plays a critical role in the pathophysiology of psoriasis, and the regulatory role of NGF and its receptor system is functionally active in the early stage of developing lesions of psoriasis.…”

“…18 In a recent study we noticed that transplanted psoriasis plaques on SCID mice treated with NGF receptor (NGF-R)-modulating agent such as K252a and NGF antibody induces significant improvement of psoriasis. 19 These observations provide compelling evidence for the role of NGF and its receptor system in the pathogenesis of psoriasis. However, the role of NGF in relation to kinetics of the inflammatory and proliferative cascades of psoriasis is not known and no functional assay has been done to determine whether psoriatic keratinocytes are primed to produce increased level of NGF.…”

Effects of Anti-Nerve Growth Factor Antibody on Symptoms in the NC/Nga Mouse, an Atopic Dermatitis Model

“…Keratinocytes in lesional and nonlesional psoriatic tissue have been observed to express high levels of NGF (15,66), and NGF receptors markedly upregulate in cutaneous nerves of psoriatic lesions (67,68). Moreover, evidence from an in vivo study suggests that NGF and its high-affinity receptor play major roles in the pathogenesis of psoriasis (69). In atopic dermatitis, the roles played in pathogenesis by the two types of NGF receptors remain unclear.…”