Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T-cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in-vitro expandability for potential clinical use. Using mass cytometry (CyTOF) and an unbiased multidimensional analytical approach, we identified two specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene-expression, expandability and function. Treg subpopulation B, predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4 and CD45RO within FOXP3hi, CD127lo Tregs), expresses the IL- 2/STAT5 pathway and cell-cycle commitment genes. Furthermore, in-vitro expanded Tregs become functional and with the characteristics of Treg subpopulation B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2 sensitive and expandable in-vitro, suggesting novel therapeutic approaches such as low dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration

First observation of the decay Bˉs0→D0K∗0\bar{B}^0_s \to D^0 K^{*0} and a measurement of the ratio of branching fractions B(Bˉs0→D0K∗0)B(Bˉ0→D0ρ0)\frac{{\cal B}(\bar{B}^0_s \to D^0 K^{*0})}{{\cal B}(\bar{B}^0 \to D^0 \rho^0)}

The first observation of the decay $\bar{B}^0_s \to D^0 K^{*0}$ using $pp$ data collected by the LHCb detector at a centre-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 36 pb$^{-1}$, is reported. A signal of $34.4 \pm 6.8$ events is obtained and the absence of signal is rejected with a statistical significance of more than nine standard deviations. The $\bar{B}^0_s \to D^0 K^{*0}$ branching fraction is measured relative to that of $\bar{B}^0 \to D^0 \rho^0$: $\frac{{\cal B}(\bar{B}^0_s \to D^0 K^{*0})}{{\cal B}(\bar{B}^0 \to D^0 \rho^0)} = 1.48 \pm 0.34 \pm 0.15 \pm 0.12$, where the first uncertainty is statistical, the second systematic and the third is due to the uncertainty on the ratio of the $B^0$ and $B^0_s$ hadronisation fractions.Comment: 10 pages, 3 figures, submitted to Phys. Lett. B; ISSN 0370-269

Measurement of the Λb0, Ξb-, and Ωb- Baryon Masses

Bottom baryons decaying to a J/ψ meson and a hyperon are reconstructed using 1.0  fb-1 of data collected in 2011 with the LHCb detector. Significant Λb0→J/ψΛ, Ξb-→J/ψΞ- and Ωb-→J/ψΩ- signals are observed and the corresponding masses are measured to be M(Λb0)=5619.53±0.13(stat.)±0.45(syst.)  MeV/c2, M(Ξb-)=5795.8±0.9(stat.)±0.4(syst.)  MeV/c2, M(Ωb-)=6046.0±2.2(stat.)±0.5(syst.)  MeV/c2, while the differences with respect to the Λb0 mass are M(Ξb-)-M(Λb0)=176.2±0.9(stat.)±0.1(syst.)  MeV/c2, M(Ωb-)-M(Λb0)=426.4±2.2(stat.)±0.4(syst.)  MeV/c2. These are the most precise mass measurements of the Λb0, Ξb- and Ωb- baryons to date. Averaging the above Λb0 mass measurement with that published by LHCb using 35  pb-1 of data collected in 2010 yields M(Λb0)=5619.44±0.13(stat.)±0.38(syst.)  MeV/c2

Search for the lepton number violating decays B+→π−μ+μ+B^{+}\to \pi^- \mu^+ \mu^+ and B+→K−μ+μ+B^{+}\to K^- \mu^+ \mu^+

A search is performed for the lepton number violating decay $B^{+}\to h^- \mu^+ \mu^+$, where $h^-$ represents a $K^-$ or a $\pi^-$, using data from the LHCb detector corresponding to an integrated luminosity of $36pb^{-1}$. The decay is forbidden in the Standard Model but allowed in models with a Majorana neutrino. No signal is observed in either channel and limits of $B(B^{+} \to K^- \mu^+ \mu^+) < 5.4\times 10^{-8}$ and $B(B^{+} \to \pi^- \mu^+ \mu^+) < 5.8\times 10^{-8}$ are set at the 95% confidence level. These improve the previous best limits by factors of 40 and 30, respectively

Measurement of b hadron production fractions in 7 TeV pp collisions

Measurements of $b$ hadron production ratios in proton-proton collisions at a centre-of-mass energy of 7 TeV with an integrated luminosity of 3 pb$^{-1}$ are presented. We study the ratios of strange $B$ meson to light $B$ meson production $f_s/(f_u+f_d)$ and $\Lambda_b^0$ baryon to light $B$ meson production $f_{\Lambda_b}/(f_u+f_d)$ as a function of the charmed hadron-muon pair transverse momentum $p_T$ and the $b$ hadron pseudorapidity $\eta$, for $p_T$ between 0 and 14 GeV and $\eta$ between 2 and 5. We find that $f_s/(f_u+f_d)$ is consistent with being independent of $p_{\rm T}$ and $\eta$, and we determine $f_s/(f_u+f_d)$ = 0.134$\pm$ 0.004 $^{+0.011}_{-0.010}$, where the first error is statistical and the second systematic. The corresponding ratio $f_{\Lambda_b}/(f_u+f_d)$ is found to be dependent upon the transverse momentum of the charmed hadron-muon pair, $f_{\Lambda_b}/(f_u+f_d)=(0.404\pm 0.017 (stat) \pm 0.027 (syst) \pm 0.105 (Br))\times[1 -(0.031 \pm 0.004 (stat) \pm 0.003 (syst))\times p_T(GeV)]$, where Br reflects an absolute scale uncertainty due to the poorly known branching fraction Br(\Lambda_c^+ \to pK^-\pi^+)$. We extract the ratio of strange$B$meson to light neutral$B$meson production$f_s/f_d$by averaging the result reported here with two previous measurements derived from the relative abundances of$\bar{B}_s \to D_S^+ \pi ^-$to$\bar{B}^0 \to D^+K^-$and$\bar{B}^0 \to D^+\pi^-$. We obtain$f_s/f_d=0.267^{+0.021}_{-0.020}$.Comment: 28 pages, 12 figures, version accepted for publication in Physical Review D, few more detailed explanations on analysis methods adde

Mixed T-Cell Chimerism after Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen is Shaped by Persistence of Recipient CD8 T Cells

AbstractPrevention of graft-versus-host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat nonmalignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide, and alemtuzumab (Campath-1H) (FCC) regimen is associated with a very low risk of GVHD and excellent clinical outcomes. We now report a single-center study of 45 patients with longer follow-up and investigation of lymphocyte recovery. Overall survival (OS) was 93%, and event-free survival (EFS) was 90.7%. Acute and chronic GVHD each occurred in 6 patients (13.3%), and only 1 case was severe. Mixed T cell chimerism was frequent and persisted after cessation of immunosuppression. T cells were extensively depleted, representing only 11.3% of lymphocytes at day 30 and rising to 43.8% by 1 year, but still significantly below normal levels (67.2%; P = .018), and deficiency persisted after immunosuppressive therapy (IST) withdrawal. Depletion of CD4 T cells was particularly profound, causing inversion of the normal CD4:CD8 T cell ratio. T cell subset composition was also abnormal, with memory and effector T cells predominating for at least 6 months after FCC HSCT. Analysis of T cell subset chimerism showed that CD4 T cells were predominantly donor-derived at 1 year, whereas recipient-derived CD8 T cells shaped mixed chimerism with a notable contribution of recipient effector CD8 T cells. The prolonged mixed T cell chimerism after IST withdrawal and low incidence of GVHD indicates the establishment of mutual tolerance, but the low incidence of viral disease suggests maintenance of antiviral immunity. Our study shows that despite the abnormal T cell profile after allogeneic HSCT for SAA using the FCC regimen, this regimen is conducive to an excellent clinical outcome