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Newcastle upon Tyne, United Kingdom

Kang E.,National Institute of Allergy and Infectious Diseases | Gennery A.,Institute of Cellular Medicine
Hematology/Oncology Clinics of North America | Year: 2014

Allogeneic hematopoietic stem cell transplantation has been shown to be curative for well-described as well as newly discovered immunodeficiencies. However, it is difficulty to define a universal transplant regimen given the rarity of these disorders and the varied pathophysiology these disorders encompass. This article discusses those primary immunodeficiencies most commonly treated by hematopoietic stem cell transplant and describes the transplant issues specific to these disorders. © 2014.


Gomez R.,Institute of Cellular Medicine | Villalvilla A.,Autonomous University of Madrid | Largo R.,Autonomous University of Madrid | Gualillo O.,University of Santiago de Compostela | Herrero-Beaumont G.,Autonomous University of Madrid
Nature Reviews Rheumatology | Year: 2015

Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint-space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs). © 2015 Macmillan Publishers Limited.


O'Reilly S.,Institute of Cellular Medicine
Clinical science (London, England : 1979) | Year: 2014

The innate immune system is a critical part of the response to pathogens and overall immunity. Compared with the adaptive immune response, these innate responses are not antigen-specific and recognize patterns in bacteria, viruses and fungi. Chief among these are TLRs (Toll-like receptors). TLRs are PRRs (pattern recognition receptors) that are germ-line-encoded and are also able to recognize endogenous molecules that are released upon cell damage or stress and have been demonstrated to have a key role in numerous autoimmune diseases, including RA (rheumatoid arthritis) and SSc (systemic sclerosis). SSc is an autoimmune disorder in which vascular injury occurs and there is a chronic low-grade inflammation followed by excessive ECM (extracellular matrix) deposition and ultimately fibrosis. The fibrosis ultimately leads to organ dysfunction and death. The preceding vascular damage and activation of the innate immune system leads to mobilization of the innate lymphoid cells and the up-regulation of multiple genes and pro-fibrotic cytokines. These locally released cytokines activate resident fibroblasts to differentiate into myofibroblasts. The aim of the present review is to explore the role of the innate immune system in SSc and TLRs and how these interact with stromal cells to produce fibrosis. Targeting the innate immune system or specific components of the TLR signalling cascade may be a novel therapeutic option in what is an incurable disease.


Ciechomska M.,Institute of Cellular Medicine
Expert reviews in molecular medicine | Year: 2013

Accumulative evidence demonstrates the crucial role of evolutionary conserved Toll-like receptors (TLRs) in identifying microbial or viral compounds. TLRs are also able to recognise endogenous molecules which are released upon cell damage or stress and have been shown to play a key role in numerous autoimmune diseases including systemic sclerosis (SSc). A classic feature of SSc, is vascular injury manifested as Raynaud's phenomenon and ischaemia of the skin, resulting in the release of endogenous TLR ligands during inflammation and local tissue damage. These locally released TLR ligands bind TLRs possibly complexed to autoantibodies, and initiate intracellular signalling pathways and may be one of the mechanisms that initiate and drive autoimmunity and subsequent fibrosis. Activation of the immune system results in interferon (IFN) sensitive gene transcription. There is also an IFN gene signature in SSc peripheral blood. TLRs may represent the link between immune activation, common in SSc, and tissue fibrosis. Therefore, a better understanding of the mechanisms of TLR-mediated pathogenesis and therapies targeting individual TLRs, may provide a more specific approach of treating multi-systemic autoimmune diseases. This review aims to integrate the current knowledge of TLR function in the autoimmune disorders with particular emphasis on SSc. We suggest the TLR system as a new therapeutic target.


Jackson M.J.,Institute of Cellular Medicine | Ivaz S.L.,University College London
Current Opinion in Urology | Year: 2015

Purpose of review: This article walks through some of the ideas behind patient-reported outcome measurement and quality of life research against the backdrop of urethral stricture disease and conditions of the lower urinary tract more generally, why measurement matters at all, future areas for research and development and potential opportunities for misuse and manipulation. Recent findings: It is the authors' opinion that only one published study has substantially advanced our understanding of the way men with urethral stricture disease manage this condition in the real world, and, in turn, the outcomes those men seek when they consent to surgery and its associated risks. There is, however, almost certainly greater acceptance now by reconstructive urologists of the utility of patient-reported outcome measures in audit; surgical performance evaluation; clinical research; and fair, logical and transparent healthcare resource allocation at a population level. This is evidenced by the recent proliferation of studies incorporating patient-reported outcomes, which appear today to be on parity at least with those that surgeons historically gave priority to. Summary: The next frontier in urethral stricture disease outcomes research is a better understanding of the impact of this condition on men's daily lives. That level of insight is likely to be gained through a mixture of qualitative and quantitative research methods applied to collaborative research ventures with men with the condition who, as those that have the most to gain and lose, must be majority stakeholders in this process. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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