Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and ...regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8
+
T-cells, and natural killer (NK)1.1
+
cells, that express granzyme B associated with Lamp-1 and IFN-γ. Efficacy of iDC-vaccination was CD8
+
T-cell-dependent but NK1.1
+
cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses.
We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC.
To compare adult patients' characteristics suffering from idiopathic retroperitoneal fibrosis between "relapse-free" and relapsing patients at the diagnosis and identify factors associated with ...relapse at initial presentation.
We conducted a retrospective multicentric study in four hospitals in Eastern France, from 1993 to 2020, of adult patients suffering from idiopathic retroperitoneal fibrosis. We analyzed clinical, biological, and radiological features at diagnosis and during a forty-month follow-up.
Of 47 patients suffering from retroperitoneal fibrosis, 21 patients had idiopathic retroperitoneal fibrosis. Among them, 13 experienced one or more relapses during follow-up. At diagnosis, clinical characteristics, relevant comorbidities, biological and radiological features were similar between groups. Smoking cessation seems associated with decreased relapse risk (
: 0.0624). A total of 8 patients developed chronic renal failure during follow-up. Ureteral infiltration at diagnosis was associated with evolution to chronic renal failure (
: 0.0091).
No clinical, biological, or radiological features could predict relapse at retroperitoneal fibrosis diagnosis, but smoking cessation may prevent relapse.
Pregnancy in women with paroxysmal nocturnal hemoglobinuria is rare, with few reports on maternal and fetal mortality rates.
A specific questionnaire designed to solicit data on pregnancies in women ...with paroxysmal nocturnal hemoglobinuria was sent to all members of the French Society of Hematology in January 2008.
We identified 27 pregnancies in 22 women at 10 French Society of Hematology centers between 1978 and 2008. The median age was 21.5 years at diagnosis of paroxysmal nocturnal hemoglobinuria and 27 years at pregnancy. None of these women had received eculizumab during their pregnancy. Maternal complications, consisting mostly of cytopenias requiring transfusions, occurred in 95% of cases. Two cases of severe aplastic anemia (de novo in one case and relapse in the other) were recorded. No thrombotic events occurred during pregnancy, whereas 4 postpartum thromboses (16%) were recorded, 2 of which were fatal (maternal mortality rate 8%). Most patients received antithrombotic prophylaxis during pregnancy and postpartum (n=16; 64%). Delivery was preterm in 29% of cases, and birth weight was less than 3 kg in 53% of cases. Fetal mortality rate was 4%.
Pregnancy during paroxysmal nocturnal hemoglobinuria is associated with increased maternal and fetal mortality rates (8% and 4%, respectively, in this series). Maternal mortality is related to postpartum thromboses. Prophylactic anticoagulation is recommended during pregnancy and for six weeks postpartum.
ObjectivesTo analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the ...Physician Global Assessment (PGA).MethodsPatients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0–3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA.ResultsA total of 350 patients (89% female; median age: 42 years, IQR: 34–52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2–6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models.ConclusionFatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.
Background Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be ...isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells. Objective We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders. Methods HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo . The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc−/− NSG mice). Results CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo . The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3–positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice. Conclusion Ex vivo –generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3–positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD.
ObjectiveTo investigate whether antineutrophil cytoplasm antibody (ANCA)-negative and myeloperoxidase (MPO)-ANCA–positive granulomatosis with polyangiitis (GPA) differ from proteinase-3 ...(PR3)-ANCA–positive GPA.MethodsDiagnostic characteristics and outcomes of newly diagnosed French Vasculitis Study Group Registry patients with ANCA-negative, MPO-ANCA–positive or PR3-ANCA–positive GPA satisfying American College of Rheumatology criteria and/or Chapel Hill Conference Consensus Nomenclature were compared.ResultsAmong 727 GPA, 62 (8.5%) were ANCA-negative, 119 (16.4%) MPO-ANCA–positive and 546 (75.1%) PR3-ANCA–positive. ANCA-negative patients had significantly (p<0.05) more limited disease (17.7% vs 5.8%) and less kidney involvement (35.5% vs 58.9%) than those PR3-ANCA–positive or MPO-ANCA–positive, with comparable relapse-free (RFS) and overall survival (OS). MPO-ANCA–positive versus PR3-ANCA–positive and ANCA-negative patients were significantly more often female (52.9% vs 42.1%), older (59.8 vs 51.9 years), with more frequent kidney involvement (65.5% vs 55.2%) and less arthralgias (34.5% vs 55.1%), purpura (8.4% vs 17.1%) or eye involvement (18.5% vs 28.4%); RFS was similar but OS was lower before age adjustment. PR3-positive patients’ RFS was significantly lower than for ANCA-negative and MPO-positive groups combined, with OS higher before age adjustment. PR3-ANCA–positivity independently predicted relapse for all GPA forms combined but not when comparing only PR3-ANCA–positive versus MPO-ANCA–positive patients.ConclusionsBased on this large cohort, ANCA-negative versus ANCA-positive patients more frequently had limited disease but similar RFS and OS. MPO-ANCA–positive patients had similar RFS but lower OS due to their older age. PR3-ANCA–positive GPA patients’ RFS was lower than those of the two other subsets combined but that difference did not persist when comparing only PR3 versus MPO-ANCA–positive patients.
Pathogenesis of immune thrombocytopenia Audia, Sylvain; Mahévas, Matthieu; Samson, Maxime ...
Autoimmunity reviews,
06/2017, Volume:
16, Issue:
6
Journal Article
Peer reviewed
Open access
Abstract Immune thrombocytopenia (ITP) is a rare autoimmune disease due to an abnormal T cell response, notably supported by splenic T follicular helper cells, that stimulates the proliferation and ...differentiation of autoreactive B cells. The antiplatelet autoantibodies they produce facilitate platelet phagocytosis by macrophages, essentially in the spleen. Macrophages contribute to the perpetuation of the auto-immune response as the main antigen-presenting cell during ITP. CD8+ T cells also participate to thrombocytopenia by increasing platelet apoptosis. Besides this peripheral platelet destruction, inappropriate bone marrow production also exacerbates thrombocytopenia, due to an immune response against megakaryocytes. Moreover, the level of circulating thrombopoietin, the main growth factor of megakaryocytes, is low during ITP. In this review, the major mechanisms leading to thrombocytopenia, the role of the different immune cells and the different targets of treatments are described.
Immune thrombocytopenia (ITP) is a rare autoimmune disease due to autoantibodies targeting platelet glycoproteins (GP). The mechanism of platelet destruction could differ depending on the specificity ...of antiplatelet antibodies: anti-GPIIb/IIIa antibodies lead to phagocytosis by splenic macrophages, in a Fcγ receptor (FcγR)-dependent manner while anti-GPIb/IX antibodies induce platelet desialylation leading to their destruction by hepatocytes after binding to the Ashwell–Morell receptor, in a FcγR-independent manner. Considering the FcγR-dependent mechanism of action of intravenous immunoglobulins (IVIg), we assumed that the response to IVIg could be less efficient in the presence of anti-GPIb/IX antibodies. We conducted a multicentric, retrospective study including all adult ITP patients treated with IVIg who had antiplatelet antibodies detected between January 2013 and October 2017. Among the 609 identified, 69 patients were included: 17 had anti-GPIb/IX antibodies and 33 had anti-GPIIb/IIIa antibodies. The response to IVIg was not different between the patients with or without anti-GPIb/IX (88.2% vs. 73.1%). The response to IVIg was better in the case of newly diagnosed ITP (odds ratio (OR) = 5.4 (1.2–24.7)) and in presence of anti-GPIIb/IIIa (OR = 4.82 (1.08–21.5)), while secondary ITP had a poor response (OR = 0.1 (0.02–0.64)). In clinical practice, the determination of antiplatelet antibodies is therefore of little value to predict the response to IVIg.
Acute pneumonia (AP) induces an excess of mortality among the elderly. We evaluated the value of a new predictive biomarker index compared to usual prognosis scores for predicting in-hospital and ...1-year mortalities in elderly inpatients with AP.
Retrospective study in 6 clinical departments of a university hospital.
Burgundy university hospital (France).
All patients aged 75 and over with AP and hospitalized between January 1 and June 30, 2013, in the departments of medicine (5) and intensive care (1) of our university hospital.
A new index, which we named UBMo, was created by multiplying the uremia (U in the formula) by the N-terminal-pro-brain natriuretic peptide (NT-proBNP) plasmatic rate (B), divided by the monocyte count (Mo).
Among the 217 patients included, there were 138 community-acquired pneumonia, 56 nursing home-acquired pneumonia, and 23 hospital-acquired pneumonia. In-hospital and 1-year mortality rates were respectively 19.8% and 43.8%. In multivariate analysis, Pneumonia Severity Index (PSI), unlike CURB-65 (confusion, urea >7 mmol/L, respiratory rate ≥30 breaths/min, blood pressure <90 mmHg systolic or ≤60 mmHg diastolic, age ≥65) score, was associated with in-hospital and 1-year mortalities. UBMo index performed better than PSI and CURB-65 scores in predicting both in-hospital and 1-year mortalities. For in-hospital mortality, the areas under the receiver operating characteristic curves (AUCs) were 0.89 (95% CI = 0.84-0.94), 0.72 (95% CI = 0.65-0.80), and 0.63 (95% CI = 0.54-0.72), respectively, for the 3 scores. For 1-year mortality, the AUCs were 0.93 (95% CI = 0.89-0.98), 0.66 (95% CI = 0.59-0.74), and 0.58 (95% CI = 0.50-0.66), respectively, for the 3 scores. The cut point for the UBMo index of 20,000 × 10
ng·mmol/L had a sensitivity of 93.1% and 80.9% and a specificity of 76.3% and 95.8%, respectively, for in-hospital and 1-year mortalities.
If confirmed by prospective studies, the UBMo index appears very efficient in identifying patients at high risk of in-hospital and 1-year mortalities after an AP.
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