Decellularization reduces the immune response to aortic valve allografts in the rat

ObjectivesCryopreserved valve allografts used in congenital cardiac surgery are associated with a significant cellular and humoral immune response. This might be reduced by removal of antigenic cellular elements (decellularization). The aim of this study was to determine the immunologic effect of decellularization in a rat allograft valve model.MethodsBrown Norway and Lewis rat aortic valves were decellularized with a series of hypotonic and hypertonic buffers, protease inhibitors, gentle detergents (Triton X-100), and phosphate-buffered saline. Valves were implanted into Lewis rats in syngeneic and allogeneic combinations. Cellular (CD3 and CD8) infiltrates were assessed with morphometric analysis, and the humoral response was assessed with flow cytometry.ResultsMorphometric analysis identified a significant reduction in CD3+ cell infiltrates (cells per square millimeter of leaflet tissue) in decellularized allografts compared with that seen in nondecellularized allografts at 1 (79 ± 29 vs 3310 ± 223, P < .001), 2 (26 ± 11 vs 109 ± 20, P = .004), and 4 weeks (283 ± 122 vs 984 ± 145, P < .001). Anti-CD8 staining confirmed the majority of infiltrates were cytotoxic T cells. Flow cytometric mean channel fluorescence intensity identified a negative shift (abrogated antibody formation) for decellularized allografts compared with nondecellularized allografts at 2 (19 ± 1 vs 27 ± 3, P = .033), 4 (35 ± 2 vs 133 ± 29, P = .001), and 16 weeks (28 ± 2 vs 166 ± 54, P = .017).ConclusionsDecellularization significantly reduces the cellular and humoral immune response to allograft tissue. This could prolong the durability of valve allografts and might prevent immunologic sensitization of allograft recipients

Porcine Islet-Specific Tolerance Induced by the Combination of Anti-LFA-1 and Anti-CD154 mAbs is Dependent on PD-1

[EN]We previously demonstrated that short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) induces tolerance to neonatal porcine islet (NPI) xenografts that is mediated by regulatory T cells (Tregs) in B6 mice. In this study, we examined whether the coinhibitory molecule PD-1 is required for the induction and maintenance of tolerance to NPI xenografts. We also determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or xenogeneic rat islet grafts since we previously demonstrated that tolerance to NPI xenografts could be extended to second-party NPI xenografts. Finally, we determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or second-party porcine skin grafts. Diabetic B6 mice were transplanted with 2,000 NPIs under the kidney capsule and treated with short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs. Some of these mice were also treated simultaneously with anti-PD-1 mAb at >150 days posttransplantation. Spleen cells from some of the tolerant B6 mice were used for proliferation assays or were injected into B6 rag−/− mice with established islet grafts from allogeneic or xenogeneic donors. All B6 mice treated with anti-LFA-1 and anti-CD154 mAbs achieved and maintained normoglycemia until the end of the study; however, some mice that were treated with anti-PD-1 mAb became diabetic. All B6 rag−/− mouse recipients of first- and second-party NPIs maintained normoglycemia after reconstitution with spleen cells from tolerant B6 mice, while all B6 rag−/− mouse recipients of allogeneic mouse or xenogeneic rat islets rejected their grafts after cell reconstitution. Tolerant B6 mice rejected their allogeneic mouse or xenogeneic second-party porcine skin grafts while remaining normoglycemic until the end of the study. These results show that porcine islet-specific tolerance is dependent on PD-1, which could not be extended to skin grafts.SIWe acknowledge the technical assistance of Deb Dixon and Dawne Colwell and thoughtful discussions with Dr. Tsunehiro Kobayashi. We are grateful to the Canadian Diabetes Association, which provided major funding for this work as well as the Edmonton Civic Employees’ Charitable Assistance Fund, Stollery Children’s Hospital Foundation, the MacLachlan Fund University Hospital Foundation, Canadian Institutes of Health Research, Colliers International, Ken and Denise Cantor as well as Ewa and John Burton, who provided additional support. The Muttart Diabetes Research Training Centre provided scholarship for H.A. The authors declare no conflicts of interest

Investigating the TeV Morphology of MGRO J1908+06 with VERITAS

We report on deep observations of the extended TeV gamma-ray source MGRO J1908+06 made with the VERITAS very high energy (VHE) gamma-ray observatory. Previously, the TeV emission has been attributed to the pulsar wind nebula (PWN) of the Fermi-LAT pulsar PSR J1907+0602. We detect MGRO J1908+06 at a significance level of 14 standard deviations (14 sigma) and measure a photon index of 2.20 +/- 0.10_stat +/- 0.20_sys. The TeV emission is extended, covering the region near PSR J1907+0602 and also extending towards SNR G40.5--0.5. When fitted with a 2-dimensional Gaussian, the intrinsic extension has a standard deviation of sigma_src = 0.44 +/- 0.02 degrees. In contrast to other TeV PWNe of similar age in which the TeV spectrum softens with distance from the pulsar, the TeV spectrum measured near the pulsar location is consistent with that measured at a position near the rim of G40.5--0.5, 0.33 degrees away.Comment: To appear in ApJ, 8 page

The Polarised Valence Quark Distribution from semi-inclusive DIS

The semi-inclusive difference asymmetry A^{h^{+}-h^{-}} for hadrons of opposite charge has been measured by the COMPASS experiment at CERN. The data were collected in the years 2002-2004 using a 160 GeV polarised muon beam scattered off a large polarised ^6LiD target and cover the range 0.006 < x < 0.7 and 1 < Q^2 < 100 (GeV/c)^2. In leading order QCD (LO) the asymmetry A_d^{h^{+}-h^{-}} measures the valence quark polarisation and provides an evaluation of the first moment of Delta u_v + Delta d_v which is found to be equal to 0.40 +- 0.07 (stat.) +- 0.05 (syst.) over the measured range of x at Q^2 = 10 (GeV/c)^2. When combined with the first moment of g_1^d previously measured on the same data, this result favours a non-symmetric polarisation of light quarks Delta u-bar = - Delta d-bar at a confidence level of two standard deviations, in contrast to the often assumed symmetric scenario Delta u-bar = Delta d-bar = Delta s-bar = Delta s.Comment: 7 pages, 3 figures, COMPASS, revised: details added, author list update

Observations of the unidentified gamma-ray source TeV J2032+4130 by VERITAS

TeV J2032+4130 was the first unidentified source discovered at very high energies (VHE; E $>$ 100 GeV), with no obvious counterpart in any other wavelength. It is also the first extended source to be observed in VHE gamma rays. Following its discovery, intensive observational campaigns have been carried out in all wavelengths in order to understand the nature of the object, which have met with limited success. We report here on a deep observation of TeV J2032+4130, based on 48.2 hours of data taken from 2009 to 2012 by the VERITAS (Very Energetic Radiation Imaging Telescope Array System) experiment. The source is detected at 8.7 standard deviations ($\sigma$) and is found to be extended and asymmetric with a width of 9.5$^{\prime}$$\pm$1.2$^{\prime}$ along the major axis and 4.0$^{\prime}$$\pm$0.5$^{\prime}$ along the minor axis. The spectrum is well described by a differential power law with an index of 2.10 $\pm$ 0.14$_{stat}$ $\pm$ 0.21$_{sys}$ and a normalization of (9.5 $\pm$ 1.6$_{stat}$ $\pm$ 2.2$_{sys}$) $\times$ 10$^{-13}$TeV$^{-1}$ cm$^{-2}$ s$^{-1}$ at 1 TeV. We interpret these results in the context of multiwavelength scenarios which particularly favor the pulsar wind nebula (PWN) interpretation

Discovery of Very High Energy Gamma Rays from 1ES 1440+122

The BL Lacertae object 1ES 1440+122 was observed in the energy range from 85 GeV to 30 TeV by the VERITAS array of imaging atmospheric Cherenkov telescopes. The observations, taken between 2008 May and 2010 June and totalling 53 hours, resulted in the discovery of $\gamma$-ray emission from the blazar, which has a redshift $z$=0.163. 1ES 1440+122 is detected at a statistical significance of 5.5 standard deviations above the background with an integral flux of (2.8$\pm0.7_{\mathrm{stat}}\pm0.8_{\mathrm{sys}}$) $\times$ 10$^{-12}$ cm$^{-2}$ s$^{-1}$ (1.2\% of the Crab Nebula's flux) above 200 GeV. The measured spectrum is described well by a power law from 0.2 TeV to 1.3 TeV with a photon index of 3.1 $\pm$ 0.4$_{\mathrm{stat}}$ $\pm$ 0.2$_{\mathrm{sys}}$. Quasi-simultaneous multi-wavelength data from the Fermi Large Area Telescope (0.3--300 GeV) and the Swift X-ray Telescope (0.2--10 keV) are additionally used to model the properties of the emission region. A synchrotron self-Compton model produces a good representation of the multi-wavelength data. Adding an external-Compton or a hadronic component also adequately describes the data.Comment: 8 pages, 4 figures. Accepted for publication in MNRA