Heat shock proteins (Hsps) are remarkably immunogenic, despite their high degree of evolutionary conservation. Experimental and clinical observations on autoimmune diseases indicate that immune ...responses to Hsps arise spontaneously during the disease process. Based on current evidence, Willem van Eden and colleagues argue that such immunity to Hsps is part of a normal immunoregulatory T-cell response with disease controlling potential.
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.
Highlights • Collaboration with young adults in developing transitional health care is crucial. • The eHealth interventions to support self-management are evaluated positive. • But focusing only on ...the support of self-management of young adults is not enough. • Also health professionals need to be supported towards patient-centered care. • Reflection may help implementing patient centered care in daily practice.
Recent progress in molecular medicine has provided important tools to identify antigen-specific T cells. In most cases, the approach is based on oligomeric combinations of recombinant major ...histocompatibility complex-peptide complexes fixed to various rigid supports available for binding by the T-cell receptor. These tools have greatly increased our insight into mechanisms of immune responses mediated by CD8+ T cells. Examples of the diverse fields of application for this technology include immunization, viral infections and oral tolerance induction.
T cell activation is associated with active clustering of relevant molecules in membrane microdomains defined as the supramolecular activation cluster. The contact area between these regions on the ...surface of T cells and APC is defined as the immunological synapse. It has been recently shown that preclustering of MHC-peptide complexes in membrane microdomains on the APC surface affects the efficiency of immune synapse formation and the related T cell activation. Disruption of such clusters may reduce the efficiency of stimulation. We describe here an entirely artificial system for Ag-specific, ex vivo stimulation of human polyclonal T cells (artificial APC (aAPC)). aAPC are based on artificial membrane bilayers containing discrete membrane microdomains encompassing T cell ligands (i.e., appropriate MHC-peptide complexes in association with costimulatory molecules). We show here that preclustering of T cell ligands triggered a degree of T cell activation significantly higher than the one achieved when we used either soluble tetramers or aAPC in which MHC-peptide complexes were uniformly distributed within artificial bilayer membranes. This increased efficiency in stimulation was mirrored by increased translocation from the cytoplasm to the membrane of protein kinase theta, a T cell signaling molecule that colocalizes with the TCR within the supramolecular activation cluster, thus indicating efficient engagement of T cell activation pathways. Engineered aAPC may have immediate application for basic and clinical immunology studies pertaining to modulation of T cells ex vivo.
To improve knowledge and to encourage active involvement of young adults with juvenile idiopathic arthritis (JIA), an informative website with written and video information and an online portal with ...access to the personal medical record, self-monitoring, and e-consult functionalities were developed. Before implementing these applications in daily practice, it is important to gain insight into their feasibility in terms of ease of use, perceived usefulness and intention to use.
The aim of this study was to evaluate and to examine the feasibility of the website and the online portal for young adults with JIA.
A qualitative, feasibility study was conducted among the first users: 13 young adults with JIA. After provided access to the website and online portal, patients were interviewed on perceived usefulness, ease of use, and intention to (re)use the applications.
Participants in the study considered the website and online portal as useful and easy-to-use. New medical information and feedback would motivate them to revisit the applications again. On the website, videos showing other young adults, telling how they handle their condition, were found as the most useful. On the portal, access to their medical records was most appreciated: it made the young JIA patients feel in control and it helped them monitor symptoms and disease activity. e-consults were thought to facilitate communication with physicians.
The young adults considered both the website and the online portal as feasible, but they also had valuable suggestions to improve accessibility and use. Based on these findings, a news and event section was added on the website and a direct link was made to a discussion board and social media. To provide and support health information, the website is actively used in daily care. Considering the online portal, the use of self-monitoring tools and e-consult can be stimulated if there is direct linkage to treatment and feedback from the multidisciplinary team. Feasibility testing, before implementing the website and online portal in daily practice, has proven to be a valuable step. Results led to improvements in terms of integration into standard care and topics for further research.
Heat shock proteins (Hsps) are remarkably immunogenic, despite their high degree of evolutionary conservation. Experimental and clinical observations on autoimmune diseases indicate that immune ...responses to Hsps arise spontaneously during the disease process. Based on current evidence, Willem van Eden and colleagues argue that such immunity to Hsps is part of a normal immunoregulatory T-cell response with disease controlling potential.
Objective
Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a ...tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.
Methods
One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.
Results
The dnaJP1 peptide was safe and well‐tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor α and a corresponding trend toward an increased percentage of T cells producing interleukin‐10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo.
Conclusion
Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down‐regulate adaptive immunity.
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