highway code of T cell trafficking Marelli-Berg, FM; Cannella, L; Dazzi, F ...
The Journal of pathology,
2008, 2008-01, January 2008, 2008-Jan, 2008-01-00, 20080101, Letnik:
214, Številka:
2
Journal Article
The properties of mesenchymal stem cells (MSC) have been widely investigated during the last decade, from their differentiation capacity to their immunosuppressive effect on any type of immune cell. ...These properties have been successfully harnessed for the treatment of inflammatory diseases such as graft versus host disease (GvHD). Different mechanisms have been proposed for their immunosuppressive properties, although it seems likely that they are used in concert. The inflammatory environment to which MSC are exposed plays a pivotal role in activating their functions. Conversely, the interplay of MSC with the immunoregulatory networks recruited during inflammation is fundamental to the delivery of immunosuppression. Since other types of terminally differentiated stromal cells share these properties, it is plausible that stemness is not a required feature. Therefore these functions may be involved in the physiological control of acute inflammation in various tissues. These notions highlight the importance of investigating the role of stromal cells as modulators of immune responses.
We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical ...presentation (acute or chronic GVHD) and onset time after the first DLI (early (< or =45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.
Abstract
The microquasar V404 Cygni underwent a series of outbursts in 2015, June 15–31, during which its flux in hard X-rays (20–40 keV) reached about 40 times the Crab nebula flux. Because of the ...exceptional interest of the flaring activity from this source, observations at several wavelengths were conducted. The MAGIC telescopes, triggered by the INTEGRAL alerts, followed-up the flaring source for several nights during the period June 18–27, for more than 10 h. One hour of observation was simultaneously conducted on a giant 22 GHz radio flare and a hint of signal at GeV energies seen by Fermi-LAT. The MAGIC observations did not show significant emission in any of the analysed time intervals. The derived flux upper limit, in the energy range 200–1250 GeV, is 4.8 × 10−12 photons cm−2 s−1. We estimate the gamma-ray opacity during the flaring period, which along with our non-detection points to an inefficient acceleration in the V404 Cyg jets if a very high energy emitter is located further than 1 × 1010 cm from the compact object.
Donor lymphocyte infusion (DLI) was originally administered as a single, relatively large dose of lymphocytes called a bulk dose regimen (BDR). It has since been suggested that the use of an ...escalating dose regimen (EDR) may be equally effective against leukemia while it induces less graft-versus-host disease (GVHD). We therefore compared the efficacy and incidence of complications in a nonrandomized sequential study of the 2 regimens in 48 consecutive patients who had relapses with cytogenetic or hematologic evidence of chronic myeloid leukemia after allogeneic stem cell transplantation. Twenty-eight patients were treated on a BDR (August 1990 to November 1995) and 20 were treated on an EDR (December 1995 to January 1998). Although the probability of achieving cytogenetic remission within 2 years of starting DLI did not differ significantly between the 2 groups (EDR, 91% CI, 63%-98% vs. BDR, 67% CI,49%-83%, P =.70), the incidence of GVHD was much lower using EDR (10% vs. 44%, P =.011). When we considered only subsets of patients treated by BDR or EDR who had received comparable total lymphoid cell doses, the incidence and severity of acute and chronic GVHD were both significantly lower for recipients treated by EDR than for recipients treated by BDR (P =.005 and P =.031, respectively). These findings suggest that the incidence of GVHD associated with the EDR is low, not because the final cell dose is small, but because lymphocytes are administered over a considerable number of months. (Blood. 2000;95:67-71)
. Evidence is growing in support of the role of stem cells as an attractive alternative in treatment of liver diseases. Recently, we have demonstrated the feasibility and safety of infusing CD34+ ...adult stem cells; this was performed on five patients with chronic liver disease. Here, we present the results of long‐term follow‐up of these patients. Between 1 × 106 and 2 × 108 CD34+ cells were isolated and injected into the portal vein or hepatic artery. The patients were monitored for side effects, toxicity and changes in clinical, haematological and biochemical parameters; they were followed up for 12–18 months. All patients tolerated the treatment protocol well without any complications or side effects related to the procedure, also there were no side effects noted on long‐term follow‐up. Four patients showed an initial improvement in serum bilirubin level, which was maintained for up to 6 months. There was marginal increase in serum bilirubin in three of the patients at 12 months, while the fourth patient's serum bilirubin increased only at 18 months post‐infusion. Computed tomography scan and serum α‐foetoprotein monitoring showed absence of focal lesions. The study indicated that the stem cell product used was safe in the short and over long term, by absence of tumour formation. The investigation also illustrated that the beneficial effect seemed to last for around 12 months. This trial shows that stem cell therapy may have potential as a possible future therapeutic protocol in liver regeneration.
The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent ...intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5 micromol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-gamma production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3+ T cells was significantly reduced in the presence of imatinib (1-5 micromol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.
Clinical trials of mesenchymal stromal cell therapies reveal a challenging heterogeneous landscape, including diverse therapeutic targets, patient categories, cell sources, and potential mechanisms ...of action.
We present the first results from very-high-energy observations of the dwarf spheroidal satellite candidate Triangulum II with the MAGIC telescopes from 62.4 h of good-quality data taken between ...August 2016 and August 2017. We find no gamma-ray excess in the direction of Triangulum II, and upper limits on both the differential and integral gamma-ray flux are presented. Currently, the kinematics of Triangulum II are affected by large uncertainties leading to a bias in the determination of the properties of its dark matter halo. Using a scaling relation between the annihilation J-factor and heliocentric distance of well-known dwarf spheroidal galaxies, we estimate an annihilation J-factor for Triangulum II for WIMP dark matter of logJann(0.5°)∕GeV2cm−5=19.35±0.37. We also derive a dark matter density profile for the object relying on results from resolved simulations of Milky Way sized dark matter halos. We obtain 95% confidence-level limits on the thermally averaged annihilation cross section for WIMP annihilation into various Standard Model channels. The most stringent limits are obtained in the τ−τ+ final state, where a cross section for annihilation down to 〈σannv〉=3.05×10−24 cm3 s−1 is excluded.
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