Truncation of C-mip (Tc-mip), a New Proximal Signaling Protein, Induces c-maf Th2 Transcription Factor and Cytoskeleton Reorganization

Several arguments suggest that minimal change nephrotic syndrome (MCNS) results from yet unknown systemic disorder of T cell function. By screening a cDNA library from T cell relapse, we identified a new pleckstrin homology (PH) domain-containing protein encoded by a gene located on chromosome 16q24. Two alternative transcripts were identified. The first species (c-mip) was expressed in fetal liver, kidney, and peripheral blood mononuclear cells (PBMCs), but weakly detected in PBMCs from MCNS patients. The second form (Tc-mip, standing for truncated c-maf inducing protein), corresponds to subtracted transcript and lacks the NH(2)-terminal PH domain. The expression of Tc-mip was restricted to fetal liver, thymus, and MCNS PBMCs where it was specifically recruited in CD4(+) T cells subset. Overexpression of Tc-mip in T cell Jurkat induced c-maf, transactivated the interleukin 4 gene and down-regulated the interferon γ expression, characteristic of a Th2 commitment. Moreover, the overexpression of Tc-mip induced Src phosphorylation, T cell clustering, and a cellular redistribution of the cytoskeleton-associated L-plastin, by a PI3 kinase independent pathway. Tc-mip represents therefore the first identified protein, which links proximal signaling to c-maf induction

First evidence of subclinical renal tubular injury during sickle-cell crisis

International audienceBACKGROUND: The pathophysiologic mechanisms classically involved in sickle-cell nephropathy include endothelial dysfunction and vascular occlusion. Arguments demonstrating that ischemia-reperfusion injury-related kidney damage might coincide with vaso-occlusive crisis (VOC) are lacking. METHODS: In this prospective study, we sought to determine whether tubular cells and glomerular permeability might be altered during VOC. Urine neutrophil gelatinase-associated lipocalin (NGAL) levels and albumin-excretion rates (AER) of 25 patients were evaluated prospectively during 25 VOC episodes and compared to their steady state (ST) values. RESULTS: During VOC, white blood-cell counts (WBC) and C-reactive protein (CRP) were significantly higher than at ST but creatinine levels were comparable. Urine NGAL levels were significantly increased during VOC vs ST (P = 0.007) and remained significant when normalized to urine creatinine (P = 0.004), while AER did not change significantly. The higher urine NGAL concentration was not associated with subsequent (24-48 hour) acute kidney injury. Univariate analysis identified no significant correlations between urine NGAL levels and laboratory parameters during VOC. CONCLUSIONS: These results demonstrated that subclinical ischemia-reperfusion tubular injury is common during VOC and highlight the importance of hydroelectrolyte monitoring and correction during VOC

Modulation of Macrophage Activation State Protects Tissue from Necrosis during Critical Limb Ischemia in Thrombospondin-1-Deficient Mice

International audienceBACKGROUND: Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI. METHODS AND FINDINGS: Using a genetic model of tsp-1(-/-) mice subjected to femoral artery excision, we report that tsp-1(-/-) mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1(-/-) and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1(-/-) mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1(-/-) mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1(-/-) mice, thereby demonstrating that macrophages mediated tissue protection in these mice. CONCLUSION: This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia

Étude des gènes surexprimés au cours du syndrome néphrotique à lésions glomérulaires minimes

Le syndrome néphrotique à lésions glomérulaires minimes (SNLGM) est une glomérulopathie fréquente dont l étiologie est inconnue. Afin d isoler les gènes activés au cours des phases actives de la maladie, nous avons entrepris la construction et le criblage différentiel d une banque d ADN complémentaire réalisé à partir des cellules mononuclées du sang périphérique d un patient. L étude de certains des gènes ainsi isolés a permis l identification d une voie de signalisation recrutée dans les lymphocytes T des patients en poussée de SNLGM impliquant une nouvelle protéine adaptatrice que nous avons appelé Tc-mip (c-maf inducing protéin). Nous avons également mis en évidence une anomalie de maturation de certains ARN messagers dans les lymphocytes T des patients liée à un défaut d expression des SR protéines SRp75 et SRp 40. Ces travaux permettent, grâce à la stratégie utilisée, une progression significative dans notre compréhension de l immunopathologie du SNLGM.Minimal change nephrotic syndrome (MCNS) is a giomerulopathy of unknown origin. In order to identify gene involved in the disase, we performed a substractive cDNA library from peripheral blood mononuclear cells of MCNS patient. This strategy Iead us to identify a new signaling pathway in T lymphocyte from MCNS patient including a new cytosolic adaptor protein we named Tc-mip (c-maf inducing protein). We also identify abnomalities in mRNA maturation during MCNS relapse, related to a lack of expression of two SR proteins (SRp4O and SRp75) involved in mRNA splicing. This study highlight the immunopathogeny of MCNS.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Pronostic des infiltrats "borderline" en transplantation rénale

La véritable signification pathologique et la prise en charge adaptée des patients transplantés rénaux présentant un infiltrat du greffon symptomatique, classé Borderline par la classification anatomopathologique de Banf restent incertaines.Dans le but d'identifier des facteurs pronostics influençant le devenir des patients présentant de tels infiltrats, nous avons repris de façon rétrospective 91 dossiers de patients ayant présentés un épisode d'infiltrat Borderline. L'analyse multivariée des résultats a montré que le grade histologique de l'infiltrat (i+t£ ou <2) et son délai de survenu par rapport à la greffe (£ ou < 3 mois) étaient deux facteurs pronostics indépendant qui influencent de façon négative la fonction rénale à un an de suivi (p=0.04 et p=0.02). On retrouve uniquement un effet significatif du délai de survenue de l'infiltrat sur la fonction rénale à deux ans (p=0.005). D'autre part, les résultats de l'analyse statistique univariée suggèrent que les thérapeutiques anti-rejet classiques n'apportent pas de bénéfice statistiquement significatif sur la fonction rénale des patients à court et long terme (de 1 mois à 2 ans).Les résultats de ce travail suggèrent que les infiltrats Borderline de scores histologiques supérieurs à i1t1 et de survenues tardives ont un pronostic péjoratif. Seule les résultats d'une étude prospective randomisée apporteront des résultats forts aux cliniciens pour traiter ou non ces infiltrats. Dans notre étude rétrospective, nous n'avons pas mis en évidence de bénéfices du traitement sur la fonction rénale à court et long terme, et sur la survie des greffons et des patients à deux ans de suiviPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

mTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now?

International audienceAntibody-mediated rejection (AMR) usually starts with generation of donor-specific anti-HLA antibodies (DSAs), arising from a B-cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR-mediated intracellular signaling pathway involved in AMR-related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects in~vivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR-regardless of the type of regimen-is patient adherence. To date, limited data from patients given mTOR inhibitor therapy with adequate concurrent immunosuppression, such as reduced-exposure calcineurin inhibitor (CNI) therapy, have not shown an adverse effect on the risk of dnDSA or AMR. Early switch to an mTOR inhibitor (\textless6-12~months post-transplant) in a CNI-free regimen, in contrast, can increase the risk of dnDSA, especially if adjunctive therapy is inadequate. Late conversion to CNI-free therapy with mTOR inhibition does not appear to affect the risk of dnDSA. More data, from prospective studies, are required to fully understand that association between use of mTOR inhibitors with different types of concomitant therapy and risk of dnDSA and AMR

Don d'organes et Judaïsme

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

Evaluation à 6 mois du traitement anti-rejet d'une allotransplantation de tissus composites faciaux

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

International audienceThe presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient’s blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient’s morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation

Dose-Related Efficacy of Irbesartan in Patients with Mild-to-Moderate Essential Hypertension

Objective: A prospective open multicentre study was conducted in patients with mild-to-moderate hypertension to compare the efficacy on diastolic blood pressure (DBP) and tolerance of treatment with either irbesartan 150 mg, od (once daily) or irbesartan 300 mg, od in patients who were defined as non-normalised responders with irbesartan 150 mg, od. Methods and results: A total of 14 820 hypertensive patients were included in the study. After 6 weeks with irbesartan 150 mg, od, in terms of their response to treatment, 8861 (61.9%) were normalised (DBP < 90 mmHg), 1963 (13.7%) non-normalised responders (DBP ≥ 90 mmHg with a decrease in DBP ≥ 10 mmHg) and 3154 (22%) non-normalised non-responders (DBP ≥ 90 mmHg with a decrease in DBP < 10 mmHg); 842 patients did not respect the protocol and could not be evaluated. The 1963 non-normalised responders were randomly assigned at week 6 to either irbesartan 150 mg, od (n = 963) or irbesartan 300 mg, od (n = 1000) for 5 weeks. A greater reduction in mean DBP was found in the group treated with irbesartan 300 mg (p < 0.001). There were no significant differences in terms of number or severity of adverse events between the two groups of patients