Blocking Potassium Channels (Kv1

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Blocking Potassium Channels (Kv1 Blocking Potassium Channels (Kv1.3): A New Treatment Option for Alopecia Areata? Amos Gilhar, Aviad Keren, Avner Shemer, Yehuda Ullmann, Ralf Paus Journal of Investigative Dermatology Volume 133, Issue 8, Pages 2088-2091 (August 2013) DOI: 10.1038/jid.2013.141 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Kv1.3/ CD3+ T cells in alopecia areata (AA) and human skin grafts transplanted onto SCID mice. (a) Double immunofluorescence demonstrates the presence of Kv1.3+/CD3+ cells around hair lesional hair follicles of AA patients and (b) in 11/15 human skin grafts injected with peripheral blood mononuclear cells (PBMCs) greatly enriched for NKG2D+ and CD56+ cells. Yet this was not seen in either normal skin of healthy volunteers (c) or in (d) 10/13 grafts injected with the same PBMC preparation but also injected with PAP-1 instead of vehicle alone. Counterstain was performed with ToPro3 (blue nuclei), Kv1.3 (green), and CD3 (red). (e) A significant increase in the number of Kv1.3/CD3 double-positive cells was found in lesional skin of AA patients compared with healthy scalp skin controls (3.8±1.2 vs. 0.1± 0.4, P<0.001). Similarly, a significantly increased number of Kv1.3/CD3 double-positive cells was found in the humanized AA mouse model, as compared with lesional human AA scalp skin (P=0.05) and with the PAP-1-treated responders (P<0.05). Kv1.3+/CD3+ cells were also largely absent in 7/8 human skin grafts injected with PHA-stimulated control PBMCs that had not developed AA lesions, as expected (Gilhar et al., 2013). Journal of Investigative Dermatology 2013 133, 2088-2091DOI: (10.1038/jid.2013.141) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 The Kv1.3 blocker PAP-1 suppresses AA development in human skin grafts. Administration of Kv1.3 blocker inhibited the activity of NKG2D+/CD56+-enriched cells and thereby suppressed the development of AA. A stable number of hairs in the responder grafts (treated with both NKG2D+/CD56+ cells and thereafter with PAP-1) clearly indicates a therapeutic benefit of PAP-1 injection in the humanized mouse of AA. Ten SCID mice, grafted with normal human skin and injected with autologous NKG2D+/CD56+-enriched cells, were used in this pilot study. Each mouse was grafted with three scalp skin transplants obtained from the same donor (n=30 grafts in total). Five mice were treated with the Kv1.3 blocker, PAP-1; the remaining five mice served as a control group and were injected with vehicle only (Cremophor EL/PBS). (a) The mean hair number is increased after Kv1.3 blockade. A significantly increased mean number of hairs was observed in PAP-1-treated responder grafts as compared with vehicle controls and with nonresponders (mean number of 5.8±2.1 vs. 3.9±1.5, P=0.05, respectively). A similar mean number of hairs was observed in the responder grafts (11/15) before and after treatment with PAP-1. However, significant hair loss was noted in grafts injected with NK-enriched cells and vehicle only (P<0.005), and in the nonresponder grafts from the PAP-1-treated group (3/11, P<0.05). (b) As expected, complete AA-like hair loss was observed in human skin grafts injected with peripheral blood mononuclear cells (PBMCs) greatly enriched for NKG2D+ and CD56+ cells and treated only with vehicle (Gilhar et al., 2013). (c) Histological evaluation confirmed the clinical observation of AA-like lesions by demonstrating the characteristic dense perifollicular lymphocytic infiltrates. (d) By performing immunohistochemistry, ectopic HLA-DR expression within the hair follicle epithelium was demonstrated. (e) In sharp contrast to control mice only injected with NKG2D+/CD56+ cells and vehicle, hair growth was observed in 3-mm grafts after treatment with PAP-1. This was accompanied by (f) histological and (g) immunohistochemical normalization of the phenotype of PAP-1-treated grafts. DP, dermal papilla; HB, hair bulb; HS, hair shaft. Bar=100μm. Journal of Investigative Dermatology 2013 133, 2088-2091DOI: (10.1038/jid.2013.141) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions