Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an ...increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.
The immune control of hepatitis B virus (HBV) infection is essential for viral clearance. Therefore, restoring functional anti–HBV immunity is a promising immunotherapeutic approach to treatment of ...chronic infection. Plasmacytoid dendritic cells (pDCs) play a crucial role in triggering antiviral immunity through their ability to capture and process viral antigens and subsequently induce adaptive immune responses. We investigated the potential of pDCs to trigger antiviral cellular immunity against HBV. We used a human leukocyte antigen A (HLA–A)*0201+ pDC line loaded with HLA–A*0201‐restricted peptides derived from hepatitis B core/hepatitis B surface (HBc/HBs) antigens to amplify specific CD8 T cells ex vivo from chronic HBV patients and established a Hepato‐HuPBL mouse model to address the therapeutic potential of the strategy in vivo. Stimulation of PBMCs or liver‐infiltrating lymphocytes from HLA–A*0201+ chronic HBV patients by HBc peptide‐loaded pDCs elicited up to 23.1% and 76.1% HBV‐specific CD8 T cells in 45.8% of cases. The specific T cells from the “responder” group secreted interferon‐γ, expressed CD107 upon restimulation, and efficiently lysed HBV antigen‐expressing hepatocytes. Circulating hepatitis B e antigen (HBeAg) was found to distinguish the group of patients not responding to the pDC stimulation. The therapeutic efficacy of the pDC vaccine was evaluated in immunodeficient NOD‐SCID β2m−/− mice reconstituted with HBV patients' PBMCs and xenotransplanted with human HBV‐transfected hepatocytes. Vaccination of Hepato–HuPBL mice with the HBc/HBs peptide–loaded pDCs elicited HBV‐specific T cells able to specifically lyse the transfected hepatocytes and reduce the systemic viral load. Conclusion: pDCs loaded with HBV–derived peptides can elicit functional virus‐specific T cells. HBeAg appears to be critical in determining the outcome of immunotherapies in chronic HBV patients. A pDC‐based immunotherapeutic approach could be of interest in attempts to restore functional antiviral immunity, which is critical for the control of the virus in chronic HBV patients. (HEPATOLOGY 2012;56:1706–1718)
Background
Most children with peanut sensitisation do not have a clinical peanut allergy (PA). Oral food challenge (OFC) is then necessary to diagnose PA and assess the reactive dose of the allergen. ...However, OFC is laborious to perform, expensive and stressful. We evaluated whether in vitro tests, such as basophil activation test (BAT), allergen‐specific IgE (sIgE) and their combination, could be used to replace OFC for the diagnosis of PA in children.
Methods
Ninety‐one patients aged 6 months to 18 years with suspected PA were prospectively recruited. These patients then underwent an OFC to assess PA. Whole peanut‐sIgE, Ara h 2‐sIgE, Ara h 8‐sIgE and %CD63+ basophils (CCR3+/SCClow) to peanut measured by BAT were investigated for PA diagnosis.
Results
Forty‐one patients had a positive peanut OFC, and the remaining 50 were only sensitised. All patients with Ara h 2‐sIgE >7 kUA/L were allergic to peanut. A threshold of 6% for activated basophils yielded a sensitivity of 95% and a specificity of 54%. All patients with Ara h 2‐sIgE ≤7 kUA/L and BAT ≤6% (n = 22) had a negative OFC except for one who presented an oral syndrome due to PR‐10 sensitisation.
Conclusions
We have shown that Ara h 2‐sIgE >7 kUA/L is a discriminating threshold for the diagnosis of PA. Furthermore, when Ara h 2‐sIgE ≤7 kUA/L and BAT ≤6%, patients do not need to adjust their diet and, thus, do not need an OFC.
Autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19 are approved for the treatment of various CD19
hematological malignancies. While CAR T cells induce ...objective responses in a majority of patients, relapse frequently occurs upon loss of CD19 expression by neoplastic cells. Radiation therapy (RT) has been successfully employed to circumvent the loss of CAR targets in preclinical models of pancreatic cancer. At least in part, this reflects the ability of RT to elicit death receptor (DR) expression by malignant cells, enabling at least some degree of CAR-independent tumor killing. In a human model of CD19
acute lymphoblastic leukemia (ALL), we also observed DR upregulation by RT, both in vitro and in vivo. Moreover, low-dose total body irradiation (LD-TBI) delivered to ALL-bearing mice prior to CAR T cell infusion considerably extended the overall survival benefit afforded by CAR T cells alone. Such an improved therapeutic activity was accompanied by a superior expansion of CAR T cells in vivo. These data encourage the initiation of clinical trials combining LD-TBI with CAR T cells in patients with hematological malignancies.
Peanut allergy is one of the most severe food allergies in children. The diagnostic gold standard is the oral food challenge (OFC). However, OFC has inherent risks and is time consuming. The ...measurement of specific immunoglobulin E (sIgE) to peanut components in blood detects peanut sensitization, but the decision point predicting allergy is still unclear. The aim of this study was to determine the diagnostic value of these tests for the evaluation of child peanut allergy.
In this retrospective study, 81 children were referred for peanut allergy. The diagnosis of peanut allergy was based on the clinical context and a positive OFC. Levels of sIgE against whole peanuts or peanut components (Ara h 2 and Ara h 8) were determined by immunoassay.
The Ara h 2 sIgE assay has the best negative predictive value (0.93) and positive predictive value (1) at a cutoff of 0.1 kU/l. Ara h 2 sIgE titers can predict the risk of anaphylaxis (<0.44 kU/l, low risk; >14 kU/l, high risk). The Ara h 8 sIgE assay is not able to discriminate peanut-allergic patients but can be used to evaluate possible cross-reactions to birch pollen with a low risk of anaphylaxis. The best diagnostic strategy is to first determine the Ara h 2 sIgE level and, if negative, evaluate Ara h 8 sIgE.
We propose an algorithm for a better use of peanut component sIgE immunoassays that should improve their diagnostic value and avoid unnecessary OFC.
CAR-T cells are T cells expressing a chimeric antigen receptor (CAR) rendering them capable of killing tumor cells after recognition of a target antigen. CD19 CAR-T cells have revolutionized the ...treatment of hematological malignancies. Their function is typically assessed by cytotoxicity assays using human allogeneic cell lines expressing the target antigen CD19 such as Nalm-6. However, an alloreactive reaction is observed with these cells, leading to a CD19-independent killing. To address this issue, we developed a fluorescence microscopy-based potency assay using murine target cells to provide an optimized cytotoxicity assay with enhanced specificity towards CD19. Murine NIH/3T3 (3T3) fibroblast-derived cell line and EL4 T-cell lymphoma-derived cell line were used as targets (no xenoreactivity was observed after coculture with human T cells). 3T3 and EL4 cells were engineered to express eGFP (enhanced Green Fluorescent Protein) and CD19 or CD22 using retroviral vectors. CD19 CAR-T cells and non-transduced (NT) control T cells were produced from several donors. After 4 h or 24 h, alloreactive cytotoxicity against CD19
Nalm-6-GFP cells and CD19
Jurkat-GFP cells was observed with NT or CAR-T cells. In the same conditions, CAR-T but not NT cells specifically killed CD19
but not CD19
3T3-GFP or EL4-GFP cells. Both microscope- and flow cytometry-based assays revealed as sensitive as impedance-based assay. Using flow cytometry, we could further determine that CAR-T cells had mostly a stem cell-like memory phenotype after contact with EL4 target cells. Therefore, CD19
3T3-GFP or EL4-GFP cells and fluorescence microscopy- or flow cytometry-based assays provide convenient, sensitive and specific tools to evaluate CAR-T cell function with no alloreactivity.
The aim of this study was to evaluate the efficacy of intrasphincteric injections of autologous myoblasts (AMs) in fecal incontinence (FI) in a controlled study.
Adult stem cell therapy is expected ...to definitively cure FI by regenerating damaged sphincter. Preclinical data and results of open-label trials suggest that myoblast therapy may represent a noninvasive treatment option.
We conducted a phase 2 randomized, double-blind, placebo-controlled study of intrasphincteric injections of AM in 24 patients. The study compared outcome after AM (n = 12) or placebo (n = 12) injection using Cleveland Clinic Incontinence (CCI), score at 6 and 12 months. Patients in the placebo group were eligible to receive frozen AM after 1 year.
At 6 months, the median CCI score significantly decreased from baseline in both the AM (9 vs 15, P = 0.02) and placebo (10 vs 15, P = 0.01) groups. Hence, no significant difference was found between the 2 groups (primary endpoint) at 6 months. At 12 months, the median CCI score continued to ameliorate in the AM group (6.5 vs 15, P = 0.006), while effect was lost in the placebo group (14 vs 15, P = 0.35). Consequently, there was a higher response rate at 12 months in the treated than the placebo arm (58% vs 8%, P = 0.03). After delayed frozen AM injection in the placebo group, the response rate was 60% (6/10) at 12 months.
Intrasphincteric AM injections in FI patients have shown tolerance, safety, and clinical benefit at 12 months despite a transient placebo effect at 6 months.
Autoimmune diseases (AIDs) as a whole represent a major health concern and remain a medical and scientific challenge. Some of them, such as multiple sclerosis or type 1 diabetes, have been actively ...investigated for many decades. Autoimmune myopathies (AIMs), also referred to as idiopathic inflammatory myopathies or myositis, represent a group of very severe AID for which we have a more limited pathophysiological knowledge. AIM encompass a group of, individually rare but collectively not so uncommon, diseases characterized by symmetrical proximal muscle weakness, increased serum muscle enzymes such as creatine kinase, myopathic changes on electromyography, and several typical histological patterns on muscle biopsy, including the presence of inflammatory cell infiltrates in muscle tissue. Importantly, some AIMs are strongly related to cancer. Here, we review the current knowledge on the most prevalent forms of AIM and, notably, the diagnostic contribution of autoantibodies.
PDF
