Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a) - PubMed (original) (raw)

. 2005 Dec 27;102(52):19057-62.

doi: 10.1073/pnas.0509736102.

Francesca Chamian, Maria Veronica Abello, Judilyn Fuentes-Duculan, Shao-Lee Lin, Rachel Nussbaum, Inna Novitskaya, Henrietta Carbonaro, Irma Cardinale, Toyoko Kikuchi, Patricia Gilleaudeau, Mary Sullivan-Whalen, Knut M Wittkowski, Kim Papp, Marvin Garovoy, Wolfgang Dummer, Ralph M Steinman, James G Krueger

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Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a)

Michelle A Lowes et al. Proc Natl Acad Sci U S A. 2005.

Abstract

We find that CD11c(+) cells with many markers of dendritic cells (DCs) are a major cell type in the skin lesions of psoriasis. These CD11c(+) cells, which are evident in both epidermis and dermis, are the sites for the expression of two mediators of inflammation, inducible nitric oxide synthase (iNOS) and TNF-alpha in diseased skin. These cells express HLA-DR, CD40, and CD86, lack the Langerin and CD14 markers of Langerhans cells and monocytes, respectively, and to a significant extent express the DC maturation markers DC-LAMP and CD83. Treatment of psoriasis with efalizumab (anti-CD11a, Raptiva) strongly reduces infiltration by these DCs in patients responding to this agent. Disease activity after therapy was more related to DC infiltrates and iNOS mRNA levels than T cell infiltrates, and CD11c(+) cells responded more quickly to therapy than epidermal keratinocytes. Our results suggest that a type of DC, which resembles murine "Tip-DCs" that can accumulate during infection, has proinflammatory effects in psoriasis through nitric oxide and TNF-alpha production, and can be an important target for suppressive therapies.

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Figures

Fig. 1.

Fig. 1.

iNOS and TNF double-positive CD11c+ cells are greatly increased in psoriasis lesions. Single- and double-label immunofluorescence are shown. (Scale bar, 200 μm.) (Insets) Single color staining controls. (A) iNOS+ cells in the dermis of normal skin. (B) iNOS+ cells in the epidermis and dermis of psoriasis skin. (C) CD11c+ cells in the dermis of normal skin. (D) CD11c+ cells in the epidermis and dermis of psoriasis skin. No overlap with Langerin positive cells in the epidermis in C and D.(E and F) There is nearly complete overlap between CD11c and iNOS, and CD11c and TNF.

Fig. 2.

Fig. 2.

CD11c identifies a type of DC. (_A_-D) Double-label immunofluorescence. (Insets) Single-color staining controls. (A) CD11c+ cells are all HLA-DR+.(B and C) Some iNOS+ cells coproduce DC-LAMP and CD83. DC-LAMP and iNOS+ cells are mature dermal DCs. (D) TNF+ cells are predominantly HLA-DR+. (_E_-G) FACS of dermal emigrants from a psoriatic patient. (E) R1, cells gated based on large cell size (FSC) and high side scatter (SCC); R2, CD11c-positive cells. (F) HLA-DR versus IgG1, CD86, CD40, CD83 and CD14 expression (R1+R2). Percent double-positive cells is shown in the upper right quadrant. (G) A lymphocyte gate (R3) indicates CD3-positive cells that have low CD11c and CD83 staining.

Fig. 3.

Fig. 3.

CD11c+ DCs are significantly decreased after efalizumab (anti-CD11a) treatment. Histomicrographs and cell counts of skin biopsies from a normal control and a treatment group patient (responder, K16 negative), on days 0 and 56. (Scale bar, 200 μm.) Mean number of total cells per low power field (10×) for CD1a (A), CD11c (B), CD83 (C), CD3 (D), and CD8 (E) (±SD) in normal skin (N, black), nonlesional psoriasis skin (NL, gray), and lesional skin of patients in placebo (P), treatment (T; all patients), K16+ (non- and partial responders), and K16- (high responders) groups on days 0 (filled squares) and 56 (open squares). P values are shown for the indicated comparison.

Fig. 4.

Fig. 4.

Changes in number of CD11c and CD83 positive cells, as well as iNOS mRNA expression, correlate highly with disease improvement. (A) Correlation between response score and changes in DCs (CD11c+ and CD83+) and T cells (CD3+)(u score) between day 0 and 56 for patients in the efalizumab-treated group. Correlation coefficients (r) are shown. (B) Correlation between response score and change in iNOS mRNA in lesional tissue between day 0 and 56 (r = 0.83). (C) In vitro monocyte-derived DCs produce iNOS mRNA. INOS/HARP mRNA was measured by RT-PCR in lymphocytes (L), T cells activated by CD3/CD28 (ActT), monocytes (M), adherent monocytes (AdM), immature DCs (iDC), mature dendritic cells (mDC), and HaCaT cells (HC). (D) Dermal CD11c+ cell counts/low power field (straight black line) and epidermal thickness (dotted black line) during therapy. During the first 2 weeks of treatment, there is 50% reduction in dermal CD11c+ cells (*, P = 0.006) and a 14% reduction in epidermal thickness (not significant). **, CD11c+ cell counts and epidermal thickness at weeks 6 and 12 compared to baseline, P < 0.0001.

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