Showing papers by "Anil Chandraker published in 2007"

Endothelial-to-mesenchymal transition contributes to cardiac fibrosis

Abstract: Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.

Inhibition of Simian virus 40 large T antigen helicase activity by fluoroquinolones.

Abstract: Background Fluoroquinolones represent a potent group of antibiotics that inhibit bacterial DNA replication by targeting the essential bacterial enzymes gyrase and topoisomerase IV. Inhibition of gyrase activity by quinolones involves the interaction of these drugs with the helicase component of bacterial gyrase. DNA tumour viruses also encode helicases that are essential for their DNA replication in the host. Methods In this study we have evaluated the effect of fluoroquinolones on viral DNA replication using the DNA tumour virus Simian virus 40 (SV40) as our model. Four different fluoroquinolones, namely, levofloxacin, trovafloxacin, ciprofloxacin and ofloxacin, were tested for their ability to inhibit viral DNA replication. Results We show here that all four quinolones tested were effective in the inhibition of SV40 plaque formation and DNA replication in CV1-P cells. In addition, we found that each of these quinolones was inhibitory to the helicase activity of SV40 large tumour antigen. Conclusions Fluoroquinolones and their derivates may therefore be useful in the treatment and/or prevention of infection by SV40-homologous human DNA viruses that encode helicase activity for their survival.

Invasive fungal infections and antifungal therapies in solid organ transplant recipients

Abstract: Summary This manuscript will review the risk factors, prevalence, clinical presentation, and management of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients. Primary literature was obtained via MEDLINE (1966–April 2007) and EMBASE. Abstracts were obtained from scientific meetings or pharmaceutical manufacturers and included in the analysis. All studies and abstracts evaluating IFIs and/or antifungal therapies, with a primary focus on solid organ transplantation, were considered for inclusion. English-language literature was selected for inclusion, but was limited to those consisting of human subjects. Infectious complications following SOT are common. IFIs are associated with high morbidity and mortality rates in this patient population. Determining the best course of therapy is difficult due to the limited availability of data in SOT recipients. Well-designed clinical studies are infrequent and much of the available information is often based on case-reports or retrospective analyses. Transplant practitioners must remain aware of their therapeutic options and the advantages and disadvantages associated with the available treatment alternatives.

Differential inhibition of autoreactive memory- and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 (sCTLA4), CTLA4Ig and LEA29Y

Abstract: Cytotoxic T lymphocyte antigen 4 (CTLA4) is a potent inhibitory co-stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases. An association has been reported of both mRNA expression and serum levels of the soluble splice variant of CTLA4 (sCTLA4) with type 1 diabetes. Furthermore, recombinant fusion proteins CTLA4Ig and LEA29Y have been proposed as therapies for type 1 diabetes. We studied the role of (s)CTLA4 in islet autoimmunity. Binding capacity of the proteins to antigen-presenting cells was determined by flow cytometry in competition and binding assays. Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins CTLA4Ig and LEA29Y was measured in a dose-response lymphocyte stimulation test, using a panel of diabetes-associated T cell clones reactive to islet autoantigens. As controls, mixed lymphocyte reactions (MLR) were performed to assess functionality of these proteins in a primary alloreactive setting. All three CTLA4 molecules were able to bind to antigen-presenting cells and inhibit the expression of CD80/CD86. sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose-dependent manner, whereas CTLA4Ig and LEA29Y were not. Conversely, CTLA4Ig and LEA29Y, rather than sCTLA4, were able to suppress naive alloreactive proliferation in a MLR. Our results indicate a differential role for sCTLA4, CTLA4Ig and LEA29Y proteins in memory versus primary immune responses with implications for efficacy in intervention therapy.

A J‐shaped association between high‐sensitivity C‐reactive protein and mortality in kidney transplant recipients

Abstract: In kidney transplant recipients (KTR), C-reactive protein (CRP) has been shown to be associated with increased mortality, but data on this association within the high-sensitivity (hs) range of CRP ( 6 years. We thawed frozen plasma and measured baseline hs-CRP using an ultrasensitive assay. Detailed clinical and demographic baseline characteristics were available for study. We stratified patients by quartile of hs-CRP within the hs range ( 5-10 and >10 mg/l). We used multivariate proportional hazards models to test for independent associations. After careful multivariate adjustment, we found a J-shaped association between hs-CRP and mortality. Compared with KTR whose hs-CRP was in the second lowest quartile of hs-CRP (0.06-1.26 mg/l), patients in the lowest quartile ( or =2.44 mg/l (all HRs >2.27). No association was found between hs-CRP and death-censored allograft loss. In contrast to the general population, the association between hs-CRP and mortality in KTRs is not linear, but J-shaped, suggesting that KTRs with very low hs-CRP may also be at increased risk of death.

Transplant tolerance through costimulation blockade--are we there yet?

Abstract: Achieving a tolerant state specific to the transplanted graft without subjecting patients to the risks of non-specific immunosuppression is the goal of transplant immunologists. In spite of the success achieved with currently available immunosuppresive therapies over acute rejection, an ongoing T cell mediated alloimmune response still poses a major challenge to the health of an allograft through chronic rejection. Modulating these destructive alloresponses through T cell costimulation blockade is a promising area of interest. In this article, we review our current knowledge about the role of various positive and negative costimulatory pathways during an alloimmune response. The ultimate nature of that response depends on the complex interaction between these positive and negative costimulatory pathways. We discuss the progress that has been achieved so far, through targeting these individual pathways, their interaction with other costimulatory pathways and the currently available immunosuppressive agents in various organ transplant models.

Monocarboxylates for modifying macrophage function

Abstract: The present invention is directed to methods of inhibiting the production of proinflammatory agents by macrophages by contacting the cells with a monocarboxylate such as nicotinic acid. The invention also includes methods of treating diseases that are associated with macrophage activation such as atherosclerosis; systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease; and diabetes mellitus.