Subcutaneous administration of polymerized type I collagen downregulates interleukin (IL)-17A, IL-22 and transforming growth factor-β1 expression, and increases Foxp3-expressing cells in localized scleroderma.
BACKGROUND
Localized scleroderma (LS) is a disfiguring inflammatory autoimmune disease of the skin and underlying tissue. As in systemic sclerosis, a key feature is the presence of T cells in inflammatory lesions.


OBJECTIVE
To evaluate the effect of polymerized type I collagen vs. methylprednisolone (MP) in LS, and to determine the influence of this polymerized collagen (PC) on CD4+ peripheral T cells expressing interleukin (IL)-4, IL-17A, interferon-γ and Forkhead box protein (Foxp)3, and on cells expressing transforming growth factor (TGF)-β1, IL-17A, IL-22 and Foxp3 in the skin.


METHODS
In total, 16 patients with LS were treated for 3 months with monthly subcutaneous intralesional injections of 0.1 mL MP (giving a total dose of 20 mg/mL each month) and 15 patients were treated, with weekly subcutaneous intralesional injections of PC, ranging from 0.2 mL (equivalent to 1.66 mg collagen) for a lesion of 50 mm in size, up to a maximum of 1.0 mL (8.3 mg collagen) for a lesion > 100 mm in size, and followed up for a further 6 months. Skin biopsies were obtained from lesions at baseline (before treatment) and 9 months later (6 months after treatment end). Tissue sections were evaluated by histology and immunohistochemistry (IL-17A, IL-22, TGF-β1 and Foxp3). CD4+ T-cell subsets were determined in peripheral blood by flow cytometry.


RESULTS
Abnormal tissue architecture was seen in the biopsies taken from patients treated with MP, whereas the PC treatment restored normal skin architecture. PC downregulated pro-inflammatory/profibrotic cytokine expression in peripheral cells, and upregulated the number of regulatory T cells (Tregs) in skin. PC was safe and well tolerated.


CONCLUSIONS
PC is not only an antifibrotic/fibrolytic agent but also an immunomodulator biodrug that restores the balance between T helper (Th)1, Th2, Th17 and Tregs, downregulates production of pro-inflammatory or profibrogenic cytokines (IL-17A, IL-22 and TGF-β1), and renews skin architecture, without adverse effects.
Department of Immunology and Rheumatology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico. jfuruzawa@gmail.com
J
J
Furuzawa-Carballeda
M
M
Ortíz-Ávalos
G
G
Lima
F
F
Jurado-Santa Cruz
L
L
Llorente
D000293:Adolescent; D000328:Adult; D000368:Aged; D024043:Collagen Type II / Q000008:administration & dosage* / Q000494:pharmacology; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012594:Scleroderma, Localized / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D055815:Young Adult; D000097043:Interleukin-22
D024043:Collagen Type II; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D007378:Interleukins; D053773:Transforming Growth Factor beta1; D000097043:Interleukin-22; C418974:FOXP3 protein, human