Immunosuppression for kidney transplant recipients: current strategies

lmmunosuppressive therapy aims to protect transplanted organs from host responses. The success achieved during the last two decades in patient and graft survival is mainly related to the development and clinical use of efficacious immnosuppressive drugs. Nevertheless, the challenge of achieving a balance of adequate graft protection while minimizing the adverse consequences of excessive immunosuppression in the long-term continues. Current maintenance immunosuppression for renal transplant recipients generally consists of a calcineurin inhibitor plus an adjunctive antiproliferative agent, and steroids. The addition of induction therapy with a variety of monoclonal or polyclonal antibodies provides a more potent immunosuppression and its use is more relevant in patients with a high immunological risk. More recently, mammalian target of rapamycin inhibitors have been incorporated in different schemes proven its efficacy in a number of protocols. The incidence of acute rejection is now in its lower historical percentage and excellent results are reported from many transplant centers all over the world due mainly to a judicious combination of these drugs evaluated through many clinical studies. However, long-term use of immunosuppressive drugs convey inherent risks which translate in an increase of cancers and infections, among others. Ongoing investigations and clinical protocols involving new immunosuppressive drugs and biological agents are yielding important information on how to obtain tolerance or the nearest to this goal. Furthermore, there should be a continuous improvement in patient and graft survival, as the use of different immunosuppressive agents for induction and maintenance are individualized (adapted to each patient).     

Binding and activation of human plasminogen by Mycobacterium tuberculosis

The first evidence of the interaction of Mycobacterium tuberculosis with the plasminogen system is herein reported. By FACScan analysis and affinity blotting, lysine-dependent binding of plasminogen to M. tuberculosis was demonstrated. The binding molecules were 30-, 60-, and 66-kDa proteins present in cell wall and soluble protein extracts. The activation of plasminogen, which occurred only in presence of fibrin and was not inhibited by the host serpin, alpha(2)-antiplasmin, was also demonstrated.     

Phosphate starvation enhances expression of the immunodominant 38-kilodalton protein antigen of Mycobacterium tuberculosis: demonstration by immunogold electron microscopy.

In this work, we grew Mycobacterium tuberculosis in an enriched Proskauer-Beck-Youmans culture medium in the presence and in the absence of phosphate salts. Immunoblot analysis of sonic extracts showed overexpression of the 38-kDa protein antigen by bacilli grown in the medium without phosphate. These observations were confirmed by immunogold electron microscopy, which showed that the number of gold particles was significantly higher in bacilli grown in medium without phosphate than in bacilli grown in medium with phosphate. The 38-kDa protein was located mainly in the wall and on the cell surface.     

Extraendothelial and constitutive COX‐2 expression is involved in the contractile effect of angiotensin II in the rat aorta

1 The role of the extraendothelial and constitutive isoforms of cyclo‐oxygenase‐2 (COX‐2) in the contractile effect of angiotensin II (Ang II) was investigated using thoracic and abdominal aortic rings without endothelium from young Wistar rats. 2 Ang II elicited similar contractions in both aortic segments, and the effect was inhibited by pretreatment with NS398 (a selective COX‐2 inhibitor) but not SC‐560 [selective cyclo‐oxygenase‐1 (COX‐1) inhibitor]. 3 COX‐2 mRNA was expressed under basal conditions in both aortic segments. Additionally, Ang II increased COX‐2 mRNA expression in the abdominal but not the thoracic segment, while cycloheximide (a protein synthesis inhibitor) did not affect the contractile response to Ang II in either of the two segments; this suggests that the effect is not associated with de novo COX‐2 synthesis. 4 In conclusion, the basal amount of COX‐2 found in aortic smooth muscle cells is sufficient to explain the production of the prostanoids related to the contractile effect of Ang II. The production of these prostanoids, which are derived from constitutive COX‐2, occurs independently of the endothelium vascular system.     

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs

Tumor secreted extracellular vesicles (EVs) are potent intercellular signaling platforms. They are responsible for the accommodation of the premetastatic niche (PMN) to support cancer cell engraftment and metastatic growth. However, complex cancer cell composition within the tumor increases also the heterogeneity among cancer secreted EVs subsets, a functional diversity that has been poorly explored. This phenomenon is particularly relevant in highly plastic and heterogenous triple-negative breast cancer (TNBC), in which a significant representation of malignant cancer stem cells (CSCs) is displayed. Herein, we selectively isolated and characterized EVs from CSC or differentiated cancer cells (DCC; EVs^CSC and EVs^DCC, respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVs^CSC and EVs^DCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVs^DCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVs^CSC promoted the activation of α-SMA+ myofibroblastic CAFs subpopulations and increased the endothelial remodeling, enhancing the invasive potential of TNBC cells in vitro and in vivo. In addition, solely the EVs^CSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.     

Dietary isoflavones affect sex hormone-binding globulin levels in postmenopausal women

The studies presented in this report were designed to further investigate the causal association between phytoestrogen action and increase in sex hormone-binding globulin (SHBG) levels. Phytoestrogens include isoflavones that bind to estrogen receptors and therefore exert estrogenic action. This study included 20 postmenopausal women that ingested 30 g soy milk daily for 10 weeks. Plasma concentrations of isoflavones and SHBG were measured. Total isoflavones significantly increased from 0.014 +/- 0.01 micromol/L (baseline) to 0.53 +/- 0.19 ,micromol/L, and paired responses showed that some subjects clearly increased their SHBG levels. The percent change in SHBG showed a positive correlation with phytoestrogen concentration; all women who had circulating phytoestrogen levels above 0.6 micromol/L increased by at least 30% their SHBG values. Results suggest that phytoestrogens may significantly increase SHBG in subjects whose SHBG concentrations are in the low end of the concentration range.     

Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients

The clinical profile of belatacept in kidney transplant recipients was evaluated to determine if earlier results in the BENEFIT study were sustained at 3 years. BENEFIT is a randomized 3 year, phase III study in adults receiving a kidney transplant from a living or standard criteria deceased donor. Patients were randomized to a more (MI) or less intensive (LI) regimen of belatacept, or cyclosporine. 471/666 patients completed ≥3 years of therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) of patients survived with a functioning graft. The mean calculated GFR (cGFR) was ～21 mL/min/1.73 m(2) higher in the belatacept groups versus cyclosporine at year 3. From month 3 to month 36, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m(2) /year (MI) and +1.2 mL/min/1.73 m(2) /year (LI) versus a decline of -2.0 mL/min/1.73 m(2) /year (cyclosporine). One cyclosporine-treated patient experienced acute rejection between year 2 and year 3. There were no new safety signals and no new posttransplant lymphoproliferative disorder (PTLD) cases after month 18. Belatacept-treated patients maintained a high rate of patient and graft survival that was comparable to cyclosporine-treated patients, despite an early increased occurrence of acute rejection and PTLD.