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Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+HLADR+ T cells, combined with a sustained enhancement of CD4+CD25+high lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+CD25+high T cells, which showed donor-Ag specificity. FOXP3+CD4+CD25+high Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.

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ObjectivesIt has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia (CAP). The aim of this prospective, randomised, double-blind, placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines.SettingA tertiary teaching hospital in Barcelona, Spain.ParticipantsThirty-four patients were randomly assigned and included in an intention-to-treat analysis (19 to the simvastatin group and 15 to the placebo group).InterventionPatients were randomly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days.OutcomePrimary end point was the time from hospital admission to clinical stability. The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen (PaO2/FiO2) at 48 h after treatment administration.ResultsThe trial was stopped because enrolment was much slower than originally anticipated. The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups. No significant differences in the time from hospital admission to clinical stability were found between study groups (median 3 days, IQR 2–5 vs 3 days, IQR 2–5; p=0.47). No significant differences in PaO2/FiO2 (p=0.37), C reactive protein (p=0.23), tumour necrosis factor-α (p=0.58), interleukin 6 (IL-6; p=0.64), and IL-10 (p=0.61) levels at 48 h of hospitalisation were found between simvastatin and placebo groups. Similarly, transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation (p=0.19, 0.08 and 0.53, respectively).ConclusionsOur results suggest that the use of simvastatin, 20 mg once daily for 4 days, since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP.Trial registration numberISRCTN91327214.

The "rods and rings" (RR) antinuclear antibody (ANA) pattern is believed to be restricted to hepatitis C virus (HCV) infection and related to the treatment. This is a 4-year retrospective study of all patients with RR pattern from the 20,000 serum samples received at the Hospital Universitari de Bellvitge for ANA testing. Two control groups with HCV patients without RR pattern: ANA-positive (n = 74) and ANA negative (n = 75) were included. Eighty-seven patients had samples with the RR pattern. Seventy-three were infected with HCV (prevalence of 15% in the HCV population). The RR pattern could not be related to ribavirin treatment, clinical status, biochemistry data, hepatic fibrosis, IL28B genotype, HCV genotype or the presence of autoantibodies related with autoimmune hepatitis. As 14 cases presented other diseases, mainly of autoimmune origin, the presence of RR antibodies may also be explained by alterations in immune regulation caused by autoimmunity or HCV in a particular genetic background.

The effect of coinfection with hepatitis C virus (HCV) on immune restoration in 39 human immunodeficiency virus (HIV)-infected patients during treatment with combined antiretroviral therapy (cART) was prospectively evaluated. After 48 weeks of treatment, HCV-coinfected patients had lower increases in CD4% (P = .05), total CD4+ (P = .01), and naïve CD4+ (P = .06) T cells than did single-infected subjects. Higher baseline naïve CD4+ T-cell levels were associated with better CD4+ (P = .05) and naïve CD4+ (P < .001) T-cell recovery. After a 4-year follow up, the differences disappeared (median CD4+ increase: 291 and 306 cells for HCV-positive and HCV-negative patients, respectively, P = .9). No significant differences were seen in memory CD4+ T cells (P = .30), and CD8+ cells expressing CD38 (P = .10) and CD28 (P = .73). These results suggest that, independently of other factors, infection with HCV blunts early CD4+ T-cell recovery in HIV-infected patients treated with combined antiretroviral therapy (cART). However, as good control of viral replication is maintained, satisfactory long-term immune restoration can nonetheless be achieved.

The aim of this study was to assess the expression of CD23 on peripheral blood B-cells, and its in vitro modulation by recombinant human interferon-gamma (IFN-gamma) in phytohaemagglutinin-(PHA) or recombinant human interleukin-4 (IL-4)-stimulated cultures in atopic patients with Dermatophagoides pteronyssinus hypersensitivity and in healthy non-atopic subjects. Atopic patients with asthma not receiving allergen-specific immunotherapy (n = 21) were studied and further compared with a group of atopic subjects with asthma under allergen-specific immunotherapy (n = 21). They were age-(+/- 5 yr) and sex-matched. The results were also compared with those obtained in the non-atopic group (n = 11). CD23 expression on B-lymphocytes and its modulation were analyzed by flow cytometry using conjugated monoclonal antibodies with a double immunofluorescence method. Atopic patients had an increase in the percentage of B-cells expressing CD23 in peripheral blood. Phytohaemagglutinin and IL-4 induced a rise in the percentage of CD23-positive B-cells in both atopic groups and non-atopic subjects. Phytohaemagglutinin provoked an increase in the intensity of CD23 expression on B-cells from stimulated cultures in all groups, while IL-4 only produced a significant increase in atopic patients. The presence of IFN-gamma decreased the CD23 expression on B-cells in PHA-stimulated culture of atopic patients, whereas it caused an increase in CD23 expression in the non-atopic group. Furthermore, the presence of IFN-gamma in IL-4-stimulated cultures induced a decrease in CD23 expression on B-cells in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)