Regression of cardiac growth in kidney transplant recipients using anti-m-TOR drugs plus RAS blockers: a controlled longitudinal study.

BACKGROUND Left ventricular hypertrophy (LVH) is common in kidney transplant (KT) recipients. LVH is associated with a worse outcome, though m-TOR therapy may help to revert this complication. We therefore conducted a longitudinal study to assess morphological and functional echocardiographic changes after conversion from CNI to m-TOR inhibitor drugs in nondiabetic KT patients who had previously received RAS blockers during the follow-up. METHODS We undertook a 1-year nonrandomized controlled study in 30 non-diabetic KT patients who were converted from calcineurin inhibitor (CNI) to m-TOR therapy. A control group received immunosuppressive therapy based on CNIs. Two echocardiograms were done during the follow-up. RESULTS Nineteen patients were switched to SRL and 11 to EVL. The m-TOR group showed a significant reduction in LVMi after 1 year (from 62 ± 22 to 55 ± 20 g/m2.7; P=0.003, paired t-test). A higher proportion of patients showing LVMi reduction was observed in the m-TOR group (53.3 versus 29.3%, P=0.048) at the study end. In addition, only 56% of the m-TOR patients had LVH at the study end compared to 77% of the control group (P=0.047). A significant change from baseline in deceleration time in early diastole was observed in the m-TOR group compared with the control group (P=0.019). CONCLUSIONS Switching from CNI to m-TOR therapy in non-diabetic KT patients may regress LVH, independently of blood pressure changes and follow-up time. This suggests a direct non-hemodynamic effect of m-TOR drugs on cardiac mass.

Estudio longitudinal del síndrome metabólico tras el trasplante renal.

BACKGROUND: The occurence of the metabolic syndrome (MS) between the renal receptors is one of the major complications after transplantation and is associated with an increased risk of graft failure and high rates of obesity and diabetes new appearance. AIMS: This study aims to investigate the prevalence and risk factors associated with the development of the MS and to evaluate the association between the same with the allograft dysfunction. METHODS: The samples consisted of 138 renal transplant patients, 83 men and 55 women, kidney transplant, which was attended by over five years for the transplant consultation. Were analyzed as potential risk factors for MS: age, sex, body mass index (BMI), weight, hypertension, diabetes, LDL, HDL, triglycerides in serum and immunosuppressive therapy (cyclosporine, tacrolimus, mycophenolate mofetil), was also assessed the prevalence of acute rejection episodes and renal function. RESULTS: The prevalence of MS was 39.85 %. As statistically significant risk factors were obtained the BMI, overweight, HDL cholesterol levels, triglycerides and LDL as well as hypertension and diabetes. There were high rates of acute rejection and differences in story to the glomerular filtration rate. CONCLUSIONS: There is a high prevalence of the MS that severely compromised renal function and graft survival in renal transplant patients, it is very important the control and strict monitoring of all risk factors identified.

Allergens Induce the Release of Lactoferrin by Neutrophils from Asthmatic Patients.

BACKGROUND Despite the evidence that Lactoferrin (Lf) is involved in allergic asthma processes, it is unknown whether neutrophils can be one of the main cellular sources of this key inflammatory mediator directly in response of an IgE mediated stimulus. The present study was undertaken to analyze this question. METHODS Neutrophils from healthy subjects (n = 34) and neutrophils from allergic asthmatic patients (n = 102) were challenged in vitro with specific allergens to which the patients were sensitized, PAF, or agonist mAbs against IgE-receptors, and the levels of Lf were measured in the culture supernatant. The levels of serum IgE together with the severity of symptoms were also analyzed. RESULTS Lf was released into the culture supernatant of neutrophils from allergic asthmatic patients in response to allergens and PAF. This response was highly allergen-specific, and did not happen in neutrophils from healthy donors. Allergen effect was mimicked by Abs against FcεRI and galectin-3 but not by FcεRII. The levels of released Lf correlated well with the levels of serum specific IgE and severity of asthma symptoms. These observations represent a novel view of neutrophils as an important source of Lf in allergic asthma. Importantly, the levels of released Lf by neutrophils could therefore be used to evaluate disease severity in allergic asthmatic patients.

Inflammatory responses in aggregating rat brain cell cultures subjected to different demyelinating conditions.

To study inflammatory reactions occurring in relation to demyelination, aggregating rat brain cell cultures were subjected to three different demyelinating insults, i.e., (i) lysophosphatidylcholine (LPC), (ii) interferon-gamma combined with lipopolysaccharide (IFN-gamma+LPS), and (iii) anti-MOG antibodies plus complement (alpha-MOG+C). Demyelination was assessed by measuring the expression of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG), and the activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP). The accompanying inflammatory reactions were examined by the quantification of microglia-specific staining, by immunostaining for glial fibrillary acidic protein (GFAP), and by measuring the mRNA expression of a panel of inflammation-related genes. It was found that all three demyelinating insults decreased the expression of MBP and MOG, and induced microglial reactivity. LPC and alpha-MOG+C, but not IFN-gamma+LPS, decreased CNP activity; they also caused the appearance of macrophagic microglia, and increased GFAP staining indicating astrogliosis. LPC affected also the integrity of neurons and astrocytes. LPC and IFN-gamma+LPS upregulated the expression of the inflammation-related genes IL-6, TNF-alpha, Ccl5, Cxcl1, and iNOS, although to different degrees. Other inflammatory markers were upregulated by only one of the three insults, e.g., Cxcl2 by LPC; IL-1beta and IL-15 by IFN-gamma+LPS; and IFN-gamma by alpha-MOG+C. These findings indicate that each of the three demyelinating insults caused distinct patterns of demyelination and inflammatory reactivity, and that of the demyelinating agents tested only LPC exhibited general toxicity.

Transforming growth factor-beta: the breaking open of a black box.

Transforming growth factor-beta (TGF-beta) and its related proteins regulate broad aspects of body development, including cell proliferation, differentiation, apoptosis and gene expression, in various organisms. Deregulated TGF-beta function has been causally implicated in the generation of human fibrotic disorders and in tumor progression. Nevertheless, the molecular mechanisms of TGF-beta action remained essentially unknown until recently. Here, we discuss recent progress in our understanding of the mechanism of TGF-beta signal transduction with respect to the regulation of gene expression, the control of cell phenotype and the potential usage of TGF-beta for the treatment of human diseases.

Maladies inflammatoires de l'intestin [Main therapeutic advances in IBD in 2007].

In 2008 three biological agents against TNFalpha will be available. The combination of infliximab with azathioprine is no longer recommended, as hepatosplenic lymphomas with a particularly bad prognosis have been associated with this combined therapy. Regular maintenance therapy with infliximab is as effective in preventing the development of anti-infliximab antibodies as co-administration of this anti-TNFalpha agent with an immunomodulator. The benefit of regular maintenance therapy is probably linked to the presence of residual trough levels of infliximab between perfusions.

Les connectivites: progrès thérapeutiques et place de la biothérapie [Connective tissue diseases: news in therapy, role of biologics agents].

Systemic lupus erythematosus and primary Sjögren's syndrom are the two major connective tissue diseases. A better knowledge of their physiopathology allows us today to propose an adapted therapy. Moreover progress concerns the oldest treatment, hydroxychloroquine, and biotherapy. Hydroxychloroquine is still an actual treatment for lupus, its positive effects are better understood today. Nevertheless it does not seem to be efficient to treat primitive Sjögren. Biotherapy targeting B lymphocytes seems efficient in these two connective tissue diseases. Anti TNF therapy is not recommended and seems to induce connective tissue diseases. The real news is the recent approval and reimbursement in Switzerland of the new drug belimumab (Benlysta) in case of moderate lupus.

Pregnancy and Crohn's disease.

Crohn's disease commonly affects women of childbearing age. Available data on Crohn's disease and pregnancy show that women with Crohn's disease can expect to conceive successfully, carry to term and deliver a healthy baby. Control of disease activity before conception and during pregnancy is critical, to optimize both maternal and fetal health. Generally speaking, pharmacological therapy for Crohn's disease during pregnancy is similar to pharmacological therapy for non-pregnant patients. Patients maintained in remission by way of pharmacological therapy should continue it throughout their pregnancy. Most drugs, including sulfasalazine, mesalazine, corticosteroids, and immunosuppressors such as azathioprine and 6-mercaptopurine, are safe, whereas methotrexate is contraindicated.

Rituximab dans le traitement des maladies rénales glomérulaires: indications et evidences cliniques [Rationale and clinical evidence for the use of rituximab in glomerular diseases].

Autoimmune glomerulopathies are an important cause of chronic kidney disease. Conventional treatments based on steroids, antiproliferative and cytotoxic agents are efficacious, but highly toxic. Because of their central role in the pathogenesis of autoimmunity, B cells have become an attractive therapeutic target. Rituximab is a monoclonal antibody directed against CD20 expressed on the surface of B cells, inducing profound depletion of B cells in the peripheral blood. In spite of encouraging results regarding the off-label use of Rituximab in membranous nephropathy, systemic lupus erythematosus and small vessel vasculitis, controlled, long-term data, and data with specific renal endpoints are currently lacking.

Les biothérapies dans le lupus érythémateux disséminé et tes connectivites: nouvelles thérapeutiques [Treatment of connective tissue diseases with biological agents]

As B-cells are crucial for the production of antibodies and also in antigen presentation, they can play an important role in autoimmune connective tissue disease. B-cell surface antigens and receptors which are capable of activating B-cell function have been proposed as targets for therapy in these diseases. Anti-B cell treatments have been used recently in SLE and primary Sjogren's syndrome in a number of open studies, notably anti-CD20 (rituximab), with encouraging results. An anti-BAFF antibody (belimumab) has been tested in patients with SLE and also showed positive results in patients with increased levels of autoantibodies. In contrast, anti-TNF therapy in connective tissue disease and in RA can increase the levels of autoantibodies. Further studies are needed to define the place of these novel treatments in the management of autoimmune connective tissue diseases.

Treatment of gastroduodenal Crohn's disease.

Symptomatic gastroduodenal manifestations of Crohn's disease (CD) are rare, with less than 4% of patients being clinically symptomatic. Gastroduodenal involvement may, however, be found endoscopically in 20% and in up to 40% of cases histologically, most frequently as Helicobacter pylori-negative focal gastritis, usually in patients with concomitant distal ileal disease. In practice, the activity of concomitant distal CD usually determines the indication for therapy, except in the presence of obstructive gastroduodenal symptoms. With the few data available, it seems correct to say that localized gastroduodenal disease should be treated with standard medical therapy used for more distal disease, with the exception of sulfasalazine and mesalanine with pH-dependent release. Presence of symptoms of obstruction needs aggressive therapy. If medical therapy with steroids and immunomodulatory drugs does not alleviate the symptoms, balloon dilation and surgery are the options to consider.

Histone deacetylase inhibitors impair antibacterial defenses of macrophages.

Histone deacetylases (HDACs) control gene expression by deacetylating histones and nonhistone proteins. HDAC inhibitors (HDACi) are powerful anticancer drugs that exert anti-inflammatory and immunomodulatory activities. We recently reported a proof-of-concept study demonstrating that HDACi increase susceptibility to bacterial infections in vivo. Yet, still little is known about the effects of HDACi on antimicrobial innate immune defenses. Here we show that HDACi belonging to different chemical classes inhibit at multiple levels the response of macrophages to bacterial infection. HDACi reduce the phagocytosis and the killing of Escherichia coli and Staphylococcus aureus by macrophages. In line with these findings, HDACi decrease the expression of phagocytic receptors and inhibit bacteria-induced production of reactive oxygen and nitrogen species by macrophages. Consistently, HDACi impair the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and inducible nitric oxide synthase. These data indicate that HDACi have a strong impact on critical antimicrobial defense mechanisms in macrophages.

In vitro characterization of immune-related properties of human fetal bone cells for potential tissue engineering applications.

We describe herein some immunological properties of human fetal bone cells recently tested for bone tissue-engineering applications. Adult mesenchymal stem cells (MSCs) and osteoblasts were included in the study for comparison. Surface markers involved in bone metabolism and immune recognition were analyzed using flow cytometry before and after differentiation or treatment with cytokines. Immunomodulatory properties were studied on activated peripheral blood mononuclear cells (PBMCs). The immuno-profile of fetal bone cells was further investigated at the gene expression level. Fetal bone cells and adult MSCs were positive for Stro-1, alkaline phosphatase, CD10, CD44, CD54, and beta2-microglobulin, but human leukocyte antigen (HLA)-I and CD80 were less present than on adult osteoblasts. All cells were negative for HLA-II. Treatment with recombinant human interferon gamma increased the presence of HLA-I in adult cells much more than in fetal cells. In the presence of activated PBMCs, fetal cells had antiproliferative effects, although with patterns not always comparable with those of adult MSCs and osteoblasts. Because of the immunological profile, and with their more-differentiated phenotype than of stem cells, fetal bone cells present an interesting potential for allogeneic cell source in tissue-engineering applications.

Safety concerns about CCR5 as an antiviral target.

PURPOSE OF REVIEW: Clinical trials of CCR5 antagonists attest to their efficacy and tolerance in HIV treatment. However, there has been debate on their long-term safety because of the role of CCR5 in innate immunity. This review highlights gaps in our understanding of epidemiology of infections that are modulated by CCR5, in particular, in HIV-infected individuals. RECENT FINDINGS: In the mouse model, CCR5 has a role in the response against pathogens as diverse as Toxoplama gondii, West Nile virus, Mycobacterium tuberculosis, herpes simplex virus, Trypanosoma cruzi, Cryptococcus neoformans, Chlamydia trachomatis, Listeria, and plasmodia. In human cohorts, individuals carrying the defective CCR5Delta32 allele present an increased susceptibility to flavivirus (West Nile virus and tickborne encephalitis virus). The selective pressures that led to the spread of loss-of-function CCR5 mutations in humans (CCR5Delta32), and in mangabeys (CCR5Delta24) are not understood. SUMMARY: The recent availability of CCR5 antagonists has raised concern that genetic, biological, or chemical CCR5 knockout, although beneficial against some pathogens (i.e. HIV), could be deleterious for other processes implicated in pathogen response. The consequences of long-term pharmaceutical intervention on CCR5 should be carefully assessed through rigorous postmarketing surveillance.

Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome.

Adjuvants are vaccine additives that stimulate the immune system without having any specific antigenic effect of itself. In this study we show that alum adjuvant induces the release of IL-1beta from macrophages and dendritic cells and that this is abrogated in cells lacking various NALP3 inflammasome components. The NALP3 inflammasome is also required in vivo for the innate immune response to OVA in alum. The early production of IL-1beta and the influx of inflammatory cells into the peritoneal cavity is strongly reduced in NALP3-deficient mice. The activation of adaptive cellular immunity to OVA-alum is initiated by monocytic dendritic cell precursors that induce the expansion of Ag-specific T cells in a NALP3-dependent way. We propose that, in addition to TLR stimulators, agonists of the NALP3 inflammasome should also be considered as vaccine adjuvants.