Immunological monitoring of the B-cell compartment in renal transplant recipients.

PhDB cells contribute to chronic allograft deterioration, negatively impacting graft survival, and curtailing the lifespan of a resource already in short supply. Given this, identifying alloreactive B cells could generate an important target in the battle against rejection. This study described an IgG-detecting ELISPOT used to determine if the risk of developing antibody-mediated rejection (AMR) could be predicted pretransplantation by in vitro analysis of allospecific B cells. This method failed to discriminate accurately B-cell responses to donor antigen. An alternative approach used was to detect peripheral HLA-specific B cells. Circulating HLA–A*0201 and – DQB1*0301 B cells were identified at higher frequency in sensitised patients, and this correlated with the level of serum alloantibody. Expression of HLA-DQB1*0301 B cells were at a higher frequency than HLA-A*0201 B cells in those with serum de novo donor-specific antibody (dnDSA). Next, levels of B-cell activating factor (BAFF) were investigated. Excess BAFF has been related to rejection and the development of DSA. Here elevated serum BAFF, low BAFF-receptor and DSA were all associated with deteriorating graft function. In addition intrarenal CD19+ cells, BAFF and BAFFreceptor identified with acute AMR. In contrast to a pathogenic role of B cells, a small population may be protective. The presence of regulatory B cells, defined by IL-10 production were higher in those with stable graft function, and identified with naïve B cells rather than memory B cells when compared to those with deteriorating grafts. The CD19+CD24highCD38high subset was also elevated in stable patients, and the ability to supress T-cell activation and secretion of the Th1 cell pro-inflammatory cytokine, IFN-γ was altered as a function of allograft stability. These data demonstrated characteristics within the B-cell compartment associated with stable graft function. The ability to monitor these cells may have clinical implications for predicating the risk of rejection, to dictate immunosuppressive therapy and promote allograft survival.Central London Research Ethics Committee (REC1: 07/H0707/10) Funding: NHS Blood and Transplant (UKT06-4

Mixed valence Mn(II)/Mn(III) [3 x 3] grid complexes: structural, electrochemical, spectroscopic, and magnetic properties

Mn(II)(9) grid complexes with a [Mn-9(?-O)(12)] core, obtained by self-assembly of a series of tritopic picolinic dihydrazone ligands with Mn(II) salts, have been oxidized by both chemical and electrochemical methods to produce mixed oxidation state systems. Examples involving [Mn(III)(3)Mn(II)(6)] and [Mn(III)(4)Mn(II)(5)] combinations have been produced. Structures are reported for [Mn-9(2poap-2H)(6)](NO3)(6).14H(2)O (1), [Mn-9(2poap-2H)(6)](ClO4)(10).14H(2)O (3), and [Mn-9(Cl(2)poap-2H)(6)](ClO4)(9).10H(2)O-3CH(3)CN (10). Structural studies show distinct contraction of the corner grid sites on oxidation, with overall magnetic properties consistent with the resulting changes in electron distribution. Antiferromagnetic exchange in the outer ring of eight metal centers creates a ferrimagnetic subunit, which undergoes antiferromagnetic coupling to the central metal, leading to S = 1/2 (3) and S = 2/2 (10) ground states. Two moderately intense absorptions are observed on oxidation of the Mn(II) grids in the visible and near-infrared (1000 nm, 700 nm), associated with charge transfer transitions (LMCT, IVCT respectively). Compound 1 crystallized in the monoclinic system, space group P2(1)/n, with a = 21.308(2) ?, b = 23.611(2) ?, c = 32.178(3) ?, ? = 93.820(2)°. Compound 3 crystallized in the tetragonal system, space group I-(4), with a = b = 18.44410(10) ?, c = 24.9935(3) ?. Compound 10 crystallized in the triclinic system, space group P-(1) over bar, with a = 19.1150(10) ?, b = 19,7221 (10) ?, c = 26.8334(14) ?, ? = 74.7190(10)°, ? = 77.6970(10)°, ? = 64.7770(10)°. The facile oxidation of the Mn(II)(9) grids is highlighted in terms of their potential use as molecular based platforms for switching and data storage

VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy