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Nijmegen, Netherlands

De Kleer I.,University Utrecht | Vercoulen Y.,University Utrecht | Klein M.,University Utrecht | Meerding J.,University Utrecht | And 6 more authors.
Journal of Immunology | Year: 2010

In many animal models, the manifestations of inflammatory diseases can be prevented by the adoptive transfer of CD4+FOXP3+ regulatory T cells (Tregs). CD4+FOXP3+ Tregs can be obtained by isolation and expansion of polyclonal naturally occurring Tregs or by Ag-specific activation of CD4+CD25-FOXP3- T cells. Two major obstacles are hampering the translation of this latter protocol into therapeutic application. First, there is a lack of knowledge on relevant autoantigens. Second, the resulting population is contaminated with activated CD4+ T cells that transiently express Forkhead box P3 but gain no regulatory function. Therefore, these cells may not be safe for clinical application. In this study, we demonstrate that highly suppressive FOXP3 + Tregs can be induced in vitro by the activation of CD4 +CD25- T cells with the self-Ag human 60-kDa heat shock protein (HSP60). The activation induced suppressive FOXP3+ Tregs can be distinguished by surface expression of CD30 from nonsuppressive FOXP3 + effector cells. We confirm that the induced CD30 +FOXP3+ Tregs recognize HSP60 epitopes and that the induction of Tregs by HSP60 is enhanced by signaling via TLR4 on APCs. These findings have implications for the generation and isolation of pure populations of Ag-specific Tregs, with the potential to prevent and treat human inflammatory diseases. Copyright © 2010 by The American Association of Immunologists, Inc.


Madej W.,Orthopaedic Research Laboratory | van Caam A.,Experimental Rheumatology | Blaney Davidson E.N.,Experimental Rheumatology | Hannink G.,Orthopaedic Research Laboratory | And 2 more authors.
Osteoarthritis and Cartilage | Year: 2016

Objective: Mechanical signals control key cellular processes in articular cartilage. Previously we have shown that mechanical compression is an important ALK5/Smad2/3P activator in cartilage explants. However, age-related changes in the cartilage are known to affect tissue mechanosensitivity and also ALK5/Smad2/3P signaling. We have investigated whether ageing of cartilage is associated with an altered response to mechanical compression. Design: Articular cartilage explants of two different age groups (young-6-36 months old, aged-6 - 13 years old) were subjected to dynamic mechanical compression with 3 MPa (physiological) or 12 MPa (excessive) load. Subsequently, essential cartilage extracellular matrix (ECM) components and tissue growth factors gene expression was measured in young and aged cartilage by QPCR. Furthermore, the ability of young and aged cartilage, to activate the Smad2/3P signaling in response to compression was analyzed and compared. This was done by immunohistochemical (IH) Smad2P detection and Smad3-responsive gene expression analysis. Results: Aged cartilage showed a highly reduced capacity for mechanically-mediated activation of Smad2/3P signaling when compared to young cartilage. Compression of aged cartilage, induced collagen type II (Col2a1) and fibronectin (Fn1) expression to a far lesser extent than in young cartilage. Additionally, in aged cartilage no mechanically mediated up-regulation of bone morphogenetic protein 2 (Bmp2) and connective tissue growth factor (Ctgf) was observed. Conclusions: We identified age-related changes in cellular responses to mechanical stimulation of articular cartilage. We propose that these changes might be associated with age-related alterations in cartilage functioning and can underlie mechanisms for development of age-related cartilage diseases like osteoarthritis (OA). © 2015 Osteoarthritis Research Society International.

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