HLA‐G*01:04∼UTR3 Recipient Correlates With Lower Survival and Higher Frequency of Chronic Rejection After Lung Transplantation

Lung transplantation (LTx) is a valid therapeutic option for selected patients with end‐stage lung disease. Soluble HLA‐G (sHLA‐G) has been associated with increased graft survival and decreased rejection episodes in solid organ transplantation. HLA‐G haplotypes named UTRs, defined by SNPs from both the 5′URR and 3′UTR, have been reported to reliably predict sHLA‐G level. The aim of this retrospective study was to determine the impact of HLA‐G alleles and UTR polymorphism from LTx recipients on anti‐HLA allo‐immunization risk, overall survival and chronic rejection (CLAD). HLA‐G SNPs were genotyped in 124 recipients who underwent LTx from 1996 to 2010 in Marseille, 123 healthy individuals and 26 cystic fibrosis patients not requiring LTx. sHLA‐G levels were measured for 38 LTx patients at D0, M3 and M12 and for 123 healthy donors. HLA‐G*01:06～UTR2 was associated with a worse evolution of cystic fibrosis (p = 0.005) but not of long‐term survival post‐LTx. HLA‐G*01:04～UTR3 haplotype was associated with lower levels of sHLA‐G at D0 and M3 (p = 0.03), impaired long‐term survival (p = 0.001), increased CLAD occurrence (p = 0.03) and the production of de novo donor‐specific antibodies (DSA) at M3 (p = 0.01). This study is the first to show the deleterious association of different HLA‐G alleles and UTRs in LTx.     

Assessing Antibody Strength: Comparison of MFI,C1q,and Titer Information

The presence of donor‐specific HLA antibodies before or after transplantation may have different implications based on the antibody strength. Yet, current approaches do not provide information regarding the true antibody strength as defined by antigen–antibody dissociation rate. To assess currently available methods, we compared between neat mean fluorescence intensity (MFI) values, C1q MFI values, ethylenediaminetetraacetic acid (EDTA)‐treated samples, as well as titration studies and peak MFI values of over 7000 Luminex‐based single‐antigen HLA antibody data points. Our results indicate that neat MFI values do not always accurately depict antibody strength. We further showed that EDTA treatment (6%) does not always remove all inhibitory factors compared with C1q or titration studies. In this study of patients presenting with multiple antibody specificities, a prozone effect was observed in 71% of the cohort (usually not affecting all antibody specificities within a single serum sample, though). Similar to titration studies, the C1q assay was able to address the issue of potential inhibition; however, its limitation is its low sensitivity and inability to detect the presence of weak antibodies. Titration studies are the only method among the approaches used in this study to provide information suggesting antigen–antibody dissociation rates and are, therefore, likely to provide better indication of true antibody strength.     

Vascular cell adhesion molecule-1 (VCAM-1), flow mediated dilatation (FMD) and carotid intima media thickness (IMT) in children with juvenile idiopathic arthritis: Relation to disease activity,functional status and fatigue

Background

There is risk of premature atherosclerosis in juvenile idiopathic arthritis (JIA) patients which predisposes to cardiovascular disease (CVD) in adulthood. This can be assessed by flow mediated dilatation (FMD) and carotid intima media thickness (IMT) of the arterial wall and by soluble vascular cell adhesion molecule (sVCAM-1).

A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.     

Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8+ T cells in an epitope‐specific manner

Little is known about whether presentation of endogenous and exogenous hepatitis B virus (HBV) surface antigens on APCs targeted by vaccination and/or virus‐harboring hepatocytes influences de novo priming of CD8⁺ T cells. We showed that surface antigen‐expressing transfectants exclusively display a K^b/S190 epitope, whereas cells pulsed with recombinant surface particles (rSPs) exclusively present a K^b/S208 epitope to CD8⁺ T cells. The differential presentation of these epitopes largely reflects the selective, but not exclusive, priming of K^b/S190‐ and K^b/S208‐specific T cells in C57BL/6 mice by endogenous/DNA‐ or exogenous/protein‐based vaccines, respectively. Silencing the K^b/S190 epitope (K^b/S190_V194F) in antigen‐expressing vectors rescued the presentation of the K^b/S208 epitope in stable transfectants and significantly enhanced priming of K^b/S208‐specific T cells in C57BL/6 mice. A K^b/S190‐mediated immunodominance operating in surface antigen‐expressing cells, but not in rSP‐pulsed cells, led to an efficient suppression in the presentation of the K^b/S208 epitope and a consequent decrease in the priming of K^b/S208‐specific T cells. This K^b/S190‐mediated immunodominance also operated in 1.4HBV‐S^mut transgenic (tg) hepatocytes selectively expressing endogenous surface antigens and allowed priming of K^b/S208‐ but not K^b/S190‐specific T cells in 1.4HBV‐S^mut tg mice. However, IFN‐γ⁺ K^b/S208‐specific T cells could not inhibit HBV replication in the liver of 1.4HBV‐S^mut tg mice. These results have practical implications for the design of T‐cell‐stimulating therapeutic vaccines.     

Well‐Defined Imidazolium ABA Triblock Copolymers as Ionic‐Liquid‐Containing Electroactive Membranes

Nitroxide‐mediated polymerization (NMP) affords the synthesis of well‐defined ABA triblock copolymers with polystyrene external blocks and a charged poly(1‐methyl‐3‐(4‐vinylbenzyl)­imidazolium bis(trifluoromethane sulfonyl)imide central block. Aqueous size‐exclusion chromatography (SEC) and ¹H NMR spectroscopy studies confirm the control of the composition and block lengths for both the central and external blocks. Dynamic mechanical analysis (DMA) reveals a room temperature modulus suitable for fabricating these triblock copolymers into electroactive devices in the presence of an added ionic liquid. Dielectric relaxation spectroscopy (DRS) elucidates the ion‐transport properties of the ABA triblock copolymers with varied compositions. The ionic conductivity in these single‐ion conductors exhibits Vogel–Fulcher–Tammann (VFT) and Arrhenius temperature dependences, and electrode polarization (EP) analysis determines the number density of simultaneously conducting ions and their mobility. The actuators derived from these triblock copolymer membranes experience similar actuation speeds at an applied voltage of 4 V DC, as compared with benchmark Nafion membranes. These tailorable ABA block copolymers are promising candidates for ionic‐polymer device applications.

     

Direct evidence for a magnetic f-electron–mediated pairing mechanism of heavy-fermion superconductivity in CeCoIn5

To identify the microscopic mechanism of heavy-fermion Cooper pairing is an unresolved challenge in quantum matter studies; it may also relate closely to finding the pairing mechanism of high-temperature superconductivity. Magnetically mediated Cooper pairing has long been the conjectured basis of heavy-fermion superconductivity but no direct verification of this hypothesis was achievable. Here, we use a novel approach based on precision measurements of the heavy-fermion band structure using quasiparticle interference imaging to reveal quantitatively the momentum space (k-space) structure of the f-electron magnetic interactions of CeCoIn₅. Then, by solving the superconducting gap equations on the two heavy-fermion bands Ekα,β with these magnetic interactions as mediators of the Cooper pairing, we derive a series of quantitative predictions about the superconductive state. The agreement found between these diverse predictions and the measured characteristics of superconducting CeCoIn₅ then provides direct evidence that the heavy-fermion Cooper pairing is indeed mediated by f-electron magnetism.Superconductivity of heavy fermions is of abiding interest, both in its own right (1–7) and because it could exemplify the unconventional Cooper pairing mechanism of high-temperature superconductors (8–11). Heavy-fermion compounds are intermetallics containing magnetic ions in the 4f- or 5f-electronic state within each unit cell. At high temperatures, each f-electron is localized at a magnetic ion (Fig. 1A). At low temperatures, interactions between f-electron spins (red arrows Fig. 1A) lead to the formation of a narrow but the subtly curved f-electron band εkf near the chemical potential (red curve, Fig. 1B), and Kondo screening hybridizes this band with the conventional c-electron band εkc of the metal (black curve, Fig. 1B). As a result, two new heavy-fermion bands Ekα,β (Fig. 1C) appear within a few millielectron volts of the Fermi energy. Their electronic structure is controlled by the hybridization matrix element s_k for interconversion of conduction c-electrons to f-electrons and vice-versa, such thatEkα,β=εkc+εkf2±(εkc−εkf2)2+sk2.[1]The momentum structure of the narrow bands of hybridized electronic states (Eq. 1 and Fig. 1C, blue curves at left) near the Fermi surface then directly reflects the form of magnetic interactions encoded within the parent f-electron band εkf. It is these interactions that are conjectured to drive the Cooper pairing (1–5) and thus the opening up of a superconducting energy gap (Fig. 1C, yellow curves at right).Open in a separate windowFig. 1.Effects of f-electron magnetism in a heavy-fermion material. (A) The magnetic subsystem of CeCoIn₅ consists of almost localized magnetic f-electrons (red arrows) with a weak hopping matrix element yielding a very narrow band with strong magnetic interactions between the f-electron spins. (B) The heavy f-electron band is shown schematically in red and the light c-electron band in black. (C) On the left, schematic of the result of hybridizing the c- and f-electrons in B into new composite electronic states referred to as heavy fermions (blue). On the right, the opening of a superconducting energy gap is schematically shown by back-bending bands near the chemical potential. The microscopic interactions driving Cooper pairing of these states, and thus of heavy-fermion superconductivity, have not been identified unambiguously for any heavy-fermion compound.