15 research outputs found
AntiāTNF-Ī± therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-Ī²
The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4+CD25hi T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4+CD25ā T cells. This defect, however, was overcome after antiātumor necrosis factor (TNF)-Ī± antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4+CD25hiFoxP3+ T reg cell population, which mediates suppression via transforming growth factor (TGF)-Ī² and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62Lā T reg cells from CD4+CD25ā T cells isolated from active RA patients, a process dependent on TGF-Ī². In spite of the potent suppressor capacity displayed by this CD62Lā T reg cell population, the natural CD62L+ T reg cells remained defective in infliximab-treated patients. These results suggest that antiāTNF-Ī± therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance
Zgodnji gigantoceliÄni arteritis
GigantoceliÄni arteritis (GCA) je najpogostejÅ”i primarni sistemski vaskulitis pri odraslih po 50. letu starosti v Evropi. Prizadene velike in srednje velike arterije in vnetni proces, ki zožuje ali popolnoma zapre svetlino žile, lahko dovede do hudih/trajnih ishemiÄnih zapletov kot so oslepitev, možganska kap ali miokardni infarkt. V zadnjem desetletju se je z vkljuÄitvijo slikovnih preiskav v diagnostiÄni postopek pomembno skrajÅ”al Äas do prepoznave bolezni (t.i. zgodnji GCA). PospeÅ”ena obravnava bolnikov (ang. āfast track clinicā) je vodila v zmanjÅ”anje pojavnosti najresnejÅ”ih ishemiÄnih zapletov bolezni in znižanje stroÅ”kov zdravljenja. Vendar pa bolezen praviloma poteka kroniÄno, s poslabÅ”anji, kar skupaj s kroniÄnim glukokortikoidnem zdravljenjem vodi v kopiÄenje okvar organov in tkiv. Prav zato se intenzivno preuÄuje patogeneza bolezni, z možnostjo implementacije izsledkov kot so sodobne molekularno in celiÄno usmerjene tarÄne terapije. Glavni cilji naÅ”ega preglednega Älanka so bili: a) analiza raziskav z navedenim Äasom trajanja od zaÄetka simptomov do postavitve diagnoze, b) raziskava obetavnih molekularnih tarÄ za zdravljenje GCA in c) prepoznava kliniÄno pomembnih celiÄnih podtipov. Najbolj obetavne tarÄne molekule za tarÄno zdravljenje so IL-6, IL-12/IL-23 in citototoksiÄni z limfociti T povezan protein 4, medtem ko terapija z zaviralci TNF-Ī± ni bila uspeÅ”na. KliniÄnih raziskav z uÄinkovinami, usmerjenimi proti IL-17, Å”e ni. V prispevku pa smo se dotaknili tudi drugih potencialnih terapevtskih tarÄ, vkljuÄno z molekulami, ki sodelujejujo v signalnih poteh
Lactate Regulates Metabolic and Proinflammatory Circuits in Control of T Cell Migration and Effector Functions
Licensed by the Creative Commons Attribution Licens
Regulatory T Cells in Rheumatoid Arthritis : Clinical Relevance and Mechanisms in Disease
EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Identification of an activated neutrophil phenotype in polymyalgia rheumatica during steroid treatment: a potential involvement of immune cell cross-talk.
We have reported the existence of a distinct neutrophil phenotype in giant cell arteritis (GCA) patients arising at week 24 of steroid treatment. In the present study, we investigated whether longitudinal analysis of neutrophil phenotype in patients with polymyalgia rheumatica (PMR) could reveal a novel association with disease status and immune cell cross-talk. Thus, we monitored PMR patient neutrophil phenotype and plasma microvesicle (MV) profiles in blood aliquots collected pre-steroid, and then at weeks 1, 4, 12 and 24 post-steroid treatment.Using flow cytometric and flow chamber analyses, we identified 12-week post-steroid as a pivotal time-point for a marked degree of neutrophil activation, correlating with disease activity. Analyses of plasma MVs indicated elevated AnxA1+ neutrophil-derived vesicles which, in vitro, modulated T-cell reactivity, suggesting distinct neutrophil phenotypic and cross-talk changes at 24 weeks, but not at 12-week post-steroid.Together, these data indicate a clear distinction from GCA patient neutrophil and MV signatures, and provide an opportunity for further investigations on how to 'stratify' PMR patients and monitor their clinical responses through novel use of blood biomarkers
Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain
A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1(+) monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1(+) monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain
Schematic of the proposed mechanism of lactate effects on T cells in the inflammatory site.
<p>(<b>A</b>) The motility of CD4<sup>+</sup> and CD8<sup>+</sup> T cells is blocked once they get exposed to elevated levels of lactate in the inflammatory site. Lactic acid also causes loss of cytolytic activity by CD8<sup>+</sup> T cells, and sodium lactate promotes the production of IL-17 by CD4<sup>+</sup> T cells. (<b>B</b>) Pharmacologic targeting of lactate transporters re-establish T cell migration away from the inflammatory site and block the production of high amounts of IL-17.</p