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Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients : an in vitro assay

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Abstract
Background: Systemic sclerosis (SSc) is characterized by vasculopathy and progressive fibrosis. CTLA4-Ig (abatacept) is able to interact with the cell surface costimulatory molecule CD86 and downregulate the target cell. The aim of this study was to evaluate the in-vitro effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts isolated from the same SSc patient. Methods: Circulating fibrocytes and skin fibroblasts were obtained from eight SSc patients with "limited" cutaneous involvement and from four healthy subjects (HSs). Samples were analyzed by fluorescence-activated cell sorter analysis (FACS) at baseline (T0) and after 8 days of culture (T8) for CD45, collagen type I (COL I), CXCR4, CD14, CD86, and HLA-DRII expression. Circulating fibrocytes were treated for 3 h and skin fibroblasts for 24/48 h with CTLA4-Ig (10, 50, 100, 500 mu g/ml). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for CD86, COL I, FN, TGF beta, alpha SMA, S100A4, CXCR2, CXCR4, CD11a, and Western blotting was performed for COL I and FN. Results: Using qRT-PCR, the T8-cultured SSc circulating fibrocytes which had not been treated with CTLA4-Ig showed higher gene expression for CD86, aSMA, S100A4, TGF beta, and COL I compared with HS circulating fibrocytes. Interestingly, alpha SMA/COL I gene expression was significantly lower only in the SSc circulating fibrocytes treated with CTLA4-Ig for 3 h (p < 0.01, p < 0.05). On the contrary, no effects were observed for either SSc or HS skin fibroblasts after CTLA4-Ig treatment. COL I and FN protein expression was unchanged in both SSc and HS skin fibroblasts by Western blot. Conclusions: Circulating fibrocytes seem to be more responsive to CTLA4-Ig treatment than skin fibroblasts from the same SSc patient, likely due to their higher expression of CD86. CTLA4-Ig treatment might downregulate the fibrotic process in SSc patients by downregulating the fibrocytes, circulating progenitor cells.
Keywords
Fibrocytes, Skin fibroblasts, CTLA4-Ig, Systemic sclerosis, Connective tissue disease, RHEUMATOID-ARTHRITIS, T-CELLS, SCLERODERMA, EXPRESSION, ABATACEPT, MYOFIBROBLAST, INFLAMMATION, FIBROSIS, DISEASE

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MLA
Cutolo, Maurizio, Stefano Soldano, Paola Montagna, et al. “Effects of CTLA4-Ig Treatment on Circulating Fibrocytes and Skin Fibroblasts from the Same Systemic Sclerosis Patients : an in Vitro Assay.” ARTHRITIS RESEARCH & THERAPY 20 (2018): n. pag. Print.
APA
Cutolo, Maurizio, Soldano, S., Montagna, P., Trombetta, A. C., Contini, P., Ruaro, B., Sulli, A., et al. (2018). Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients : an in vitro assay. ARTHRITIS RESEARCH & THERAPY, 20.
Chicago author-date
Cutolo, Maurizio, Stefano Soldano, Paola Montagna, Amelia Chiara Trombetta, Paola Contini, Barbara Ruaro, Alberto Sulli, et al. 2018. “Effects of CTLA4-Ig Treatment on Circulating Fibrocytes and Skin Fibroblasts from the Same Systemic Sclerosis Patients : an in Vitro Assay.” Arthritis Research & Therapy 20.
Chicago author-date (all authors)
Cutolo, Maurizio, Stefano Soldano, Paola Montagna, Amelia Chiara Trombetta, Paola Contini, Barbara Ruaro, Alberto Sulli, Stefano Scabini, Emanuela Stratta, Sabrina Paolino, Carmen Pizzorni, Vanessa Smith, and Renata Brizzolara. 2018. “Effects of CTLA4-Ig Treatment on Circulating Fibrocytes and Skin Fibroblasts from the Same Systemic Sclerosis Patients : an in Vitro Assay.” Arthritis Research & Therapy 20.
Vancouver
1.
Cutolo M, Soldano S, Montagna P, Trombetta AC, Contini P, Ruaro B, et al. Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients : an in vitro assay. ARTHRITIS RESEARCH & THERAPY. 2018;20.
IEEE
[1]
M. Cutolo et al., “Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients : an in vitro assay,” ARTHRITIS RESEARCH & THERAPY, vol. 20, 2018.
@article{8576167,
  abstract     = {Background: Systemic sclerosis (SSc) is characterized by vasculopathy and progressive fibrosis. CTLA4-Ig (abatacept) is able to interact with the cell surface costimulatory molecule CD86 and downregulate the target cell. The aim of this study was to evaluate the in-vitro effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts isolated from the same SSc patient. 
Methods: Circulating fibrocytes and skin fibroblasts were obtained from eight SSc patients with "limited" cutaneous involvement and from four healthy subjects (HSs). Samples were analyzed by fluorescence-activated cell sorter analysis (FACS) at baseline (T0) and after 8 days of culture (T8) for CD45, collagen type I (COL I), CXCR4, CD14, CD86, and HLA-DRII expression. Circulating fibrocytes were treated for 3 h and skin fibroblasts for 24/48 h with CTLA4-Ig (10, 50, 100, 500 mu g/ml). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for CD86, COL I, FN, TGF beta, alpha SMA, S100A4, CXCR2, CXCR4, CD11a, and Western blotting was performed for COL I and FN. 
Results: Using qRT-PCR, the T8-cultured SSc circulating fibrocytes which had not been treated with CTLA4-Ig showed higher gene expression for CD86, aSMA, S100A4, TGF beta, and COL I compared with HS circulating fibrocytes. Interestingly, alpha SMA/COL I gene expression was significantly lower only in the SSc circulating fibrocytes treated with CTLA4-Ig for 3 h (p < 0.01, p < 0.05). On the contrary, no effects were observed for either SSc or HS skin fibroblasts after CTLA4-Ig treatment. COL I and FN protein expression was unchanged in both SSc and HS skin fibroblasts by Western blot. 
Conclusions: Circulating fibrocytes seem to be more responsive to CTLA4-Ig treatment than skin fibroblasts from the same SSc patient, likely due to their higher expression of CD86. CTLA4-Ig treatment might downregulate the fibrotic process in SSc patients by downregulating the fibrocytes, circulating progenitor cells.},
  articleno    = {157},
  author       = {Cutolo, Maurizio and Soldano, Stefano and Montagna, Paola and Trombetta, Amelia Chiara and Contini, Paola and Ruaro, Barbara and Sulli, Alberto and Scabini, Stefano and Stratta, Emanuela and Paolino, Sabrina and Pizzorni, Carmen and Smith, Vanessa and Brizzolara, Renata},
  issn         = {1478-6354},
  journal      = {ARTHRITIS RESEARCH & THERAPY},
  keywords     = {Fibrocytes,Skin fibroblasts,CTLA4-Ig,Systemic sclerosis,Connective tissue disease,RHEUMATOID-ARTHRITIS,T-CELLS,SCLERODERMA,EXPRESSION,ABATACEPT,MYOFIBROBLAST,INFLAMMATION,FIBROSIS,DISEASE},
  language     = {eng},
  pages        = {9},
  title        = {Effects of CTLA4-Ig treatment on circulating fibrocytes and skin fibroblasts from the same systemic sclerosis patients : an in vitro assay},
  url          = {http://dx.doi.org/10.1186/s13075-018-1652-6},
  volume       = {20},
  year         = {2018},
}

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