K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis:
an in vivo study using the severe combined immunodeficient mouse-human skin
model.
Raychaudhuri SP, Sanyal M, Weltman H, Kundu-Raychaudhuri S.
Psoriasis Research Institute, Palo Alto, California, USA.
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.
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