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Snowden J.A.,University of Sheffield | Saccardi R.,University of Florence | Allez M.,French Institute of Health and Medical Research | Ardizzone S.,University of Milan | And 14 more authors.
Bone Marrow Transplantation | Year: 2012

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized. © 2012 Macmillan Publishers Limited All rights reserved.

Slocombe K.E.,University of York | Alvarez I.,University of York | Branigan H.P.,University of Edinburgh | Jellema T.,University of Hull | And 7 more authors.
Journal of Autism and Developmental Disorders | Year: 2013

Individuals with Asperger's Syndrome (AS) often have difficulties with social interactions and conversations. We investigated if these difficulties could be attributable to a deficit in the ability to linguistically converge with an interlocutor, which is posited to be important for successful communication. To that end, participants completed two cooperative tasks with a confederate, which allowed us to measure linguistic alignment with the confederate in terms of lexical choice, syntactic structure and spatial frame of reference. There was no difference in the performance of individuals with AS and matched controls and both groups showed significant alignment with the confederate at all three levels. We conclude that linguistic alignment is intact in adults with AS engaged in structured, goal-directed social interactions. © 2012 Springer Science+Business Media New York.

Lutterotti A.,Institute for Neuroimmunology and Clinical MS Research | Lutterotti A.,Innsbruck Medical University | Yousef S.,Institute for Neuroimmunology and Clinical MS Research | Sputtek A.,University of Hamburg | And 14 more authors.
Science Translational Medicine | Year: 2013

Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this firstin- man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG 1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170, and PLP139-154). An open-label, singlecenter, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (<1 < 109) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved.

Steinbach K.,Institute for Neuroimmunology and Clinical MS Research | McDonald C.L.,Innsbruck Medical University | Reindl M.,Innsbruck Medical University | Schweigreiter R.,Innsbruck Medical University | And 3 more authors.
PLoS ONE | Year: 2011

Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4 + Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure. © 2011 Steinbach et al.

Heesen C.,Institute for Neuroimmunology and Clinical MS Research | Gaissmaier W.,Max Planck Institute for Human Development | Nguyen F.,Institute for Neuroimmunology and Clinical MS Research | Stellmann J.-P.,Institute for Neuroimmunology and Clinical MS Research | And 3 more authors.
PLoS ONE | Year: 2013

Background:Prognostic counseling in multiple sclerosis (MS) is difficult because of the high variability of disease progression. Simultaneously, patients and physicians are increasingly confronted with making treatment decisions at an early stage, which requires taking individual prognoses into account to strike a good balance between benefits and harms of treatments. It is therefore important to understand how patients and physicians estimate prognostic risk, and whether and how these estimates can be improved. An online analytical processing (OLAP) tool based on pooled data from placebo cohorts of clinical trials offers short-term prognostic estimates that can be used for individual risk counseling.Objective:The aim of this study was to clarify if personalized prognostic information as presented by the OLAP tool is considered useful and meaningful by patients. Furthermore, we used the OLAP tool to evaluate patients' and physicians' risk estimates. Within this evaluation process we assessed short-time prognostic risk estimates of patients with MS (final n = 110) and their physicians (n = 6) and compared them with the estimates of OLAP.Results:Patients rated the OLAP tool as understandable and acceptable, but to be only of moderate interest. It turned out that patients, physicians, and the OLAP tool ranked patients similarly regarding their risk of disease progression. Both patients' and physicians' estimates correlated most strongly with those disease covariates that the OLAP tool's estimates also correlated with most strongly. Exposure to the OLAP tool did not change patients' risk estimates.Conclusion:While the OLAP tool was rated understandable and acceptable, it was only of modest interest and did not change patients' prognostic estimates. The results suggest, however, that patients had some idea regarding their prognosis and which factors were most important in this regard. Future work with OLAP should assess long-term prognostic estimates and clarify its usefulness for patients and physicians facing treatment decisions. © 2013 Heesen et al.

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