Immune activation via TLRs is known to prevent transplantation tolerance in multiple animal models. To investigate the mechanisms underlying this barrier to tolerance induction, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4+Foxp3+ T regulatory cells (Tregs), and that the TLR9 ligand CpG prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that although Th17 cells differentiate from naive alloreactive T cells, these cells do not arise from natural Tregs in either CpG-treated or untreated graft recipients. Finally, we show that CpG impairs natural Treg suppressor capability and prevents Treg-dependent allograft acceptance in an IL-6-independent fashion. Our data therefore suggest that TLR signals do not prevent prolonged graft acceptance by directing natural Tregs into the Th17 lineage or by using other IL-6-dependent mechanisms. Instead, graft destruction results from the ability of CpG to drive Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4+Foxp3+ Tregs.

OBJECTIVETo investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal.RESEARCH DESIGN AND METHODSUsing allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig.RESULTSBALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice).CONCLUSIONSThe capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.

Purpose -The purpose of this paper is to develop a framework for measuring retail productivity. It intends to identify all the constituents of retail productivity exhaustively, along with their measures and integrate them with a comprehensive model. Design/methodology/approach -The paper summarizes the significant empirical works from the literature along with their study methods and identifies the gaps. The proposed methodology is a combination of various exploratory methods consisting of secondary data analysis, group interviews, depth interviews, observation and questionnaire survey. Findings -A regression-based conceptual model including each of the output and input variables of retail productivity. It also provides conception logic and measurement method for each of the variables. It identifies the control parameters too and proposes to handle them in the model. The empirical validation provides the significance of various input parameters.Research limitations/implications -The empirical validation is restricted to one retail format and one vertical (medium-sized stores and apparel-life style vertical). However, it provides significant input regarding the way to utilise retail productivity and the strategic directions to improve store level productivity. Practical implications -The most significant usage of the model is the standardization of retail productivity concept as a performance measurement tool and its applicability in individual retail stores (micro level). Hence, it is possible to determine the reasons for performance of retail stores and develop appropriate as well as effective strategies. The identification and elaboration of the various parameters of retail productivity would help retailers to redefine and focus on key decision areas. Originality/value -The paper presents the exhaustive framework for retail productivity with data from the Indian retail sector that is applicable at micro level. It provides direct measure of value component (services) in retail output determination.