Abstract
Kv1.3 channels regulate the activation/proliferation of effector memory T cells and thus play a critical role in the pathogenesis of autoimmune diseases. Using a combination of immunohistochemistry, confocal microscopy, flow cytometry and electrophysiology methods we observed a significant enrichment of activated Kv1.3+ memory T cells in psoriasis plaques and synovial fluid from patients with psoriasis/psoriatic arthritis (PsA) compared to non-lesional psoriatic skin, normal skin or peripheral blood lympho-mononuclear cells. In invitro studies performed with lesional mononuclear cells or T cells derived from skin and joints of psoriatic disease, the small molecule Kv1.3 blocker PAP-1 dose-dependently inhibited proliferation and suppressed IL-2 and IFN-γ production. To further substantiate the pathologic role of Kv1.3high TEM cells in psoriatic disease we tested whether PAP-1 is able to improve psoriatic disease pathology in the SCID mouse-psoriasis skin xenograft model. Following four weeks of daily treatment with 2% PAP-1 ointment we noticed about 50% reduction in the epidermal thickness (rete peg length) and the number of CD3+ lymphocytes/mm2 of dermis decreased by 85%. Vehicle treated and untreated plaques in contrast remained unchanged and showed no reduction in epidermis thickness and infiltrating CD3+ T cells and HLA-DR+ T cells. Based on these results we propose the development of Kv1.3 targeted topical immunotherapy for psoriasis and possibly for other inflammatory skin conditions, where effector memory T cells are involved in the pathogenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 63-72 |
| Number of pages | 10 |
| Journal | Journal of Autoimmunity |
| Volume | 55 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2015 |
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Keywords
- Effector memory T cells
- Kv1.3 channel
- PAP-1
- Pathogenesis
- Psoriasis skin xenograft model
- Psoriatic diseases
ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
Cite this
Kv1.3 in psoriatic disease : PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis - Xenograft model. / Kundu-Raychaudhuri, Smriti; Chen, Yi-Je; Wulff, Heike; Raychaudhuri, Siba P.
In: Journal of Autoimmunity, Vol. 55, No. 1, 2015, p. 63-72.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Kv1.3 in psoriatic disease
T2 - PAP-1, a small molecule inhibitor of Kv1.3 is effective in the SCID mouse psoriasis - Xenograft model
AU - Kundu-Raychaudhuri, Smriti
AU - Chen, Yi-Je
AU - Wulff, Heike
AU - Raychaudhuri, Siba P
PY - 2015
Y1 - 2015
N2 - Kv1.3 channels regulate the activation/proliferation of effector memory T cells and thus play a critical role in the pathogenesis of autoimmune diseases. Using a combination of immunohistochemistry, confocal microscopy, flow cytometry and electrophysiology methods we observed a significant enrichment of activated Kv1.3+ memory T cells in psoriasis plaques and synovial fluid from patients with psoriasis/psoriatic arthritis (PsA) compared to non-lesional psoriatic skin, normal skin or peripheral blood lympho-mononuclear cells. In invitro studies performed with lesional mononuclear cells or T cells derived from skin and joints of psoriatic disease, the small molecule Kv1.3 blocker PAP-1 dose-dependently inhibited proliferation and suppressed IL-2 and IFN-γ production. To further substantiate the pathologic role of Kv1.3high TEM cells in psoriatic disease we tested whether PAP-1 is able to improve psoriatic disease pathology in the SCID mouse-psoriasis skin xenograft model. Following four weeks of daily treatment with 2% PAP-1 ointment we noticed about 50% reduction in the epidermal thickness (rete peg length) and the number of CD3+ lymphocytes/mm2 of dermis decreased by 85%. Vehicle treated and untreated plaques in contrast remained unchanged and showed no reduction in epidermis thickness and infiltrating CD3+ T cells and HLA-DR+ T cells. Based on these results we propose the development of Kv1.3 targeted topical immunotherapy for psoriasis and possibly for other inflammatory skin conditions, where effector memory T cells are involved in the pathogenesis.
AB - Kv1.3 channels regulate the activation/proliferation of effector memory T cells and thus play a critical role in the pathogenesis of autoimmune diseases. Using a combination of immunohistochemistry, confocal microscopy, flow cytometry and electrophysiology methods we observed a significant enrichment of activated Kv1.3+ memory T cells in psoriasis plaques and synovial fluid from patients with psoriasis/psoriatic arthritis (PsA) compared to non-lesional psoriatic skin, normal skin or peripheral blood lympho-mononuclear cells. In invitro studies performed with lesional mononuclear cells or T cells derived from skin and joints of psoriatic disease, the small molecule Kv1.3 blocker PAP-1 dose-dependently inhibited proliferation and suppressed IL-2 and IFN-γ production. To further substantiate the pathologic role of Kv1.3high TEM cells in psoriatic disease we tested whether PAP-1 is able to improve psoriatic disease pathology in the SCID mouse-psoriasis skin xenograft model. Following four weeks of daily treatment with 2% PAP-1 ointment we noticed about 50% reduction in the epidermal thickness (rete peg length) and the number of CD3+ lymphocytes/mm2 of dermis decreased by 85%. Vehicle treated and untreated plaques in contrast remained unchanged and showed no reduction in epidermis thickness and infiltrating CD3+ T cells and HLA-DR+ T cells. Based on these results we propose the development of Kv1.3 targeted topical immunotherapy for psoriasis and possibly for other inflammatory skin conditions, where effector memory T cells are involved in the pathogenesis.
KW - Effector memory T cells
KW - Kv1.3 channel
KW - PAP-1
KW - Pathogenesis
KW - Psoriasis skin xenograft model
KW - Psoriatic diseases
UR - http://www.scopus.com/inward/record.url?scp=84922278744&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922278744&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2014.07.003
DO - 10.1016/j.jaut.2014.07.003
M3 - Article
C2 - 25175978
AN - SCOPUS:84922278744
VL - 55
SP - 63
EP - 72
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
IS - 1
ER -