Therapeutic Targeting of Th17/Tc17 Cells Leads to Clinical Improvement of Lichen Planus - PubMed (original) (raw)

doi: 10.3389/fimmu.2019.01808. eCollection 2019.

Robert Pollmann 1, Thomas Schmidt 1, Ansgar Schmidt 2, Xiang Zheng 3, Rajkumar Savai 3 4, Stefan Mühlenbein 1, Julia Pickert 1, Verena Eubel 1, Christian Möbs 1, Rüdiger Eming 1, Michael Hertl 1

Affiliations

Therapeutic Targeting of Th17/Tc17 Cells Leads to Clinical Improvement of Lichen Planus

Farzan Solimani et al. Front Immunol. 2019.

Abstract

Lichen planus (LP) is a common, chronic relapsing inflammatory disorder of the skin and mucous membranes which often poses a major therapeutic challenge due to its refractory course. Novel pathogenesis-based therapies are urgently needed. As several studies have shown that IL-17 may contribute to LP pathogenesis, we investigated whether therapeutic targeting of IL-17+ T cells leads to clinical improvement of mucosal and cutaneous LP lesions. A total of five patients with lichen planus were treated in a compassionate use trial with either secukinumab (anti-IL-17; 3 patients with acute and chronic recalcitrant muco-cutaneous LP), ustekinumab (anti-IL-12/IL-23; 1 patient with recalcitrant oral LP) or guselkumab (anti-IL-23; 1 patient with recalcitrant oral LP). The clinical course of the patients was assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) reflecting both extent and severity of disease and functional sequelae of oral involvement for at least 12 weeks. The inflammatory infiltrate in lesional and post-lesional skin was analyzed by immunohistochemistry before and after treatment. Furthermore, the cytokine profile of peripheral blood T cells from the treated patients was assessed by flow cytometry and/or ELISpot assay. Treatment with secukinumab induced rapid and prolonged clinical amelioration of muco-cutaneous LP. Clinical improvement was accompanied by a strong reduction of the Th1 and Th17/Tc17 cellular mucosal and cutaneous infiltrate. Moreover, long-term treatment of one patient with recalcitrant oral LP with ustekinumab led to healing of the ulcerative oral lesions and a reduction of peripheral blood and lesional IL-17+ T cells. Finally, treatment with guselkumab led to a marked clinical improvement in a patient with recalcitrant erosive oral LP. These findings show for the first time that therapeutic targeting of Th17/Tc17 cells leads to a pronounced clinical amelioration of mucosal and cutaneous LP and strongly suggests that IL-17-producing T cells are central to disease pathogenesis. Thus, therapeutic targeting of Th17/Tc17 cells opens new therapeutic avenues in the treatment of recalcitrant LP.

Keywords: IL-17; T cells; guselkumab; lichen planus; secukinumab; ustekinumab.

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Figures

Figure 1

Figure 1

Clinical and immunological response to treatment with the anti-IL-17 monoclonal antibody, secukinumab, in mucocutaneous lichen planus (LP). (A) Clinical appearance of three LP patients before (week 0; W0) and on treatment (W8, W12) with secukinumab. Patients 1 and 2 presented with muco-cutanous lesions while patient three had a recalcitrant LP of the oral mucosa unresponsive to systemic immunosuppressive treatment. Blockade of IL-17A led to a shift from erythematous inflammatory to hyperpigmented post-inflammatory skin lesions and an almost complete disappearance of the mucosal lesions by W12. Clinical course was assessed by the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) showing a marked decrease of cutaneous lesions (ABSIS Skin), mucosal lesions (ABSIS Mucosa I), and substantial improvement of the patients' ability to eat defined foods of increasing consistency without pain and/or bleeding (ABSIS Mucosa II). (B) Immunohistochemical analysis of the inflammatory skin infiltrate before (W0) and after 12 weeks (W12) of treatment (representative images of patient 1 are shown). Markers as below: CD3/CD4/CD8 (liquid permanent red), T-bet/GATA3/IL-17 (3,3′ diaminobenzide brown). The dermal, band-like CD4+ and CD8+ T cellular infiltrate was strongly reduced at W12 of secukinumab treatment compared to W0. Of note, blockade of IL-17A led to a marked decrease of both IL-17A+ and CD4+/T-bet+ (Th1) cells in the LP lesions (see Figure S1 in the supplement for description of image quantification). (C) Flow cytometric analysis of peripheral blood CD8+ and CD4+ (defined as CD8−) T cells in the three LP patients before (W0) and at W12 of treatment. In contrast to skin lesions, the number of CD3+, IFNγ+ (Th1), and IL-17A+ peripheral blood T cells remained largely unaffected by blockade of IL-17A. Notably, peripheral blood IL-21+ T cells were increased in all the three LP patients (see Figure S2 and Table S1 in the supplement for gating strategy and raw data).

Figure 2

Figure 2

Clinical and immunological response to treatment with the anti- IL-12/IL-23 monoclonal antibody, ustekinumab, patient 4 with recalcitrant oral lichen planus (OLP). (A) Clinical appearance before (week 0, W0) and at W8 and W12 of treatment with ustekinumab showing a striking clinical improvement of mucosal lesions by W8 and W12. The clinical course was characterized by a marked reduction of mucosal lesions (ABSIS Mucosa I) and a substantial improvement of the patient's ability to eat defined foods of different consistency without pain and/or bleeding (ABSIS Mucosa II). (B) Immunohistochemical analysis of inflammatory mucosal infiltrate before (W0) and at W12 of treatment with ustekinumab. Markers as below: CD3/CD4/CD8 (liquid permanent red), T-bet/GATA3/IL-17 (3,3' diaminobenzide brown). At W12, IL-17A+ cells were completely absent and the CD4+T-bet+ (Th1) cell infiltrate was strongly diminished (see Figure S1 for description of image quantification). (C) Flow cytometric analysis of peripheral blood CD8+ and CD4+ (defined as CD8−) T cells before (W0) and at W12 and W20 of ustekinumab treatment. While peripheral blood CD3+ T cells were not impaired, blockade of IL-12/IL-23 led to a strong decrease of peripheral blood IL-17A+ and IL-21+ T cells (see Figure S3 and Table S1 in the supplement for gating strategy and raw data).

Figure 3

Figure 3

Clinical response of oral lichen planus to treatment with guselkumab and phenotypical analysis of the T cell infiltrate by immunohistochemistry and multiplex immunohistochemistry. (A) Clinical appearance of the oral mucosa with marked ulcerative lesions (dotted blue line) of patient 5 on treatment with guselkumab before treatment at week 0 (W0) and at W4, W8, W26, and W30 with the clinical course assessed by ABSIS score. There is a complete resolution of the ulcerative lesions of the tongue by W30. (B) Immunohistochemical staining for CD4, CD8, and IL-17 before treatment with guselkumab. Single staining with CD4+, CD8+ (red), and IL-17 (green) as well as double positive-staining of CD4+ or CD8+ T cells with IL-17 (black) are highlighted by arrows. (C) Multiplexed immunohistochemistry images of skin lesions showing each of the individual markers in the composite image after spectral unmixing. Markers are as below: CD4 (Opal 620, pseudocoloured red), CD8 (Opal 690, pseudocoloured cyan), IL−17 (Opal 540, pseudocoloured green), and DAPI as a nuclear marker (blue) (upper row), Multiplexed immunohistochemistry images of CD4 or/and CD8 staining merged with IL-17 (middle row). Multiplexed immunohistochemistry images of CD4 or/and CD8 along with IL-17 merged with DAPI (lower row). The cell phenotyping map identifies CD4+IL17+ cells (red dots), CD8+IL17+ cells (yellow dots), CD4+IL17− cells (cyan dots), CD8+IL17− cells (green dots), and other cells (blue dots).

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