T cell therapy with EBV-specific cytotoxic T-lymphocytes for patients with nasopharyngeal carcinoma

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De Novo Donor-Specific HLA Antibodies Developing Early or Late after Transplant Are Associated with the Same Risk of Graft Damage and Loss in Nonsensitized Kidney Recipients

De novo posttransplant donor-specific HLA-antibody (dnDSA) detection is now recognized as a tool to identify patients at risk for antibody-mediated rejection (AMR) and graft loss. It is still unclear whether the time interval from transplant to DSA occurrence influences graft damage. Utilizing sera collected longitudinally, we evaluated 114 consecutive primary pediatric kidney recipients grafted between 2002 and 2013 for dnDSA occurrence by Luminex platform. dnDSAs occurred in 39 patients at a median time of 24.6 months. In 15 patients, dnDSAs developed within 1 year (early-onset group), while the other 24 seroconverted after the first posttransplant year (late-onset group). The two groups were comparable when considering patient- and transplant-related factors, as well as DSA biological properties, including C1q and C3d complement-binding ability. Only recipient age at transplant significantly differed in the two cohorts, with younger patients showing earlier dnDSA development. Late AMR was diagnosed in 47% of the early group and in 58% of the late group. Graft loss occurred in 3/15 (20%) and 4/24 (17%) patients in early- and late-onset groups, respectively (p = ns). In our pediatric kidney recipients, dnDSAs predict AMR and graft loss irrespective of the time elapsed between transplantation and antibody occurrence

Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia

Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9-14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9-14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ-producing and IL2-producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients

Retrospective Study of Indications and Outcomes of Open Abdomen with Negative Pressure Wound Therapy Technique for Abdominal Sepsis in a Tertiary Referral Centre

: In patients with advanced sepsis from abdominal disease, the open abdomen (OA) technique as part of a damage control surgery (DCS) approach enables relook surgery to control infection, defer intestinal anastomosis, and prevent intra-abdominal hypertension. Limited evidence is available on key outcomes, such as mortality and rate of definitive fascial closure (DFC), which are needed for surgeons to select patients and adequate therapeutic strategies. Abdominal closure with negative pressure wound therapy (NPWT) has shown rates of DFC around 90%. We conducted a retrospective study to evaluate in-hospital survival and factors associated with mortality in acute, non-trauma patients treated using the OA technique and NPWT for sepsis from abdominal disease. Fifty consecutive patients treated using the OA technique and NPWT between February 2015 and July 2022 were included. Overall mortality was 32%. Among surviving patients, 97.7% of cases reached DFC, and the overall complication rate was 58.8%, with one case of entero-atmospheric fistula. At univariable analysis, age (p = 0.009), ASA IV status (<0.001), Mannheim Peritonitis Index > 30 (p = 0.001) and APACHE II score (p < 0.001) were associated with increased mortality. At multivariable analysis, higher APACHE II was a predictor of in-hospital mortality (OR 2.136, 95% CI 1.08-4.22; p = 0.029). Although very resource-intensive, DCS and the OA technique are valuable tools to manage patients with advanced abdominal sepsis, allowing reduced mortality and high DFC rates

Failure to remove de novo donor-specific HLA antibodies is influenced by antibody properties and identifies kidney recipients with late antibody-mediated rejection destined to graft loss \u2013 a retrospective study

Current research is focusing on identifying bioclinical parameters for risk stratification of renal allograft loss, largely due to antibody-mediated rejection (AMR). We retrospectively investigated graft outcome predictors in 24 unsensitized pediatric kidney recipients developing HLA de novo donor-specific antibodies (dnDSAs), and treated for late AMR with plasmapheresis+low-dose IVIG+Rituximab or high-dose IVIG+Rituximab. Renal function and DSA properties were assessed before and longitudinally post-treatment. The eGFR decline after treatment was dependent on a negative % eGFR variation in the year preceding treatment (p=0.021) but not on eGFR at treatment (p=0.74). At a median follow-up of 36 months from AMR diagnosis, 10 patients lost their graft. Altered eGFR (p<0.001) and presence of C3d-binding DSAs (p=0.005) at treatment, and failure to remove DSAs (p=0.01) were negatively associated with graft survival in the univariable analysis. Given the relevance of DSA removal for therapeutic success, we analyzed antibody properties dictating resistance to anti-humoral treatment. In the multivariable analysis, C3d-binding ability (p<0.05), but not C1q-binding, and high mean fluorescence intensity (p<0.05) were independent factors characterizing DSAs scarcely susceptible to removal. The poor prognosis of late AMR is related to deterioration of graft function prior to treatment and failure to remove C3d binding and/or high-MFI DSAs. This article is protected by copyright. All rights reserved

BCR-ABL-specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors

Although the emergence of bone marrow (BM)-resident p190BCR-ABL-specific T lymphocytes has been correlated with hematologic and cytogenetic remissions in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) undergoing maintenance tyrosine-kinase inhibitor treatment, little is known about the possibility of culturing these cells ex vivo and using them in T-cell therapy strategies. We investigated the feasibility of expanding/priming p190BCR-ABL-specific T cells in vitro by stimulation with dendritic cells pulsed with p190BCR-ABL peptides derived from the BCR-ABL junctional region and alternative splicing, and of adoptively administering them patients with relapsed disease. We report on the feasibility of producing clinical-grade BCR-ABL-specific cytotoxic T lymphocytes (CTLs), endowed with antileukemia activity, from Ph+ ALL patients and healthy donors. We treated 3 patients with Ph+ ALL with autologous or allogeneic p190BCR-ABL-specific CTLs. No postinfusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients achieved a molecular or hematologic complete remission (CR) after T-cell therapy, upon emergence of p190BCR-ABL-specific T cells in the BM. Our results show that p190BCR-ABL-specific CTLs are capable of controlling treatment-refractory Ph+ ALL in vivo, and support the development of adoptive immunotherapeutic approaches with BCR-ABL CTLs in Ph+ ALL

Combination Treatment with Hydroxytyrosol and Vitamin E Improves NAFLD-Related Fibrosis

Non-alcoholic fatty liver disease (NAFLD)-related liver fibrosis results in the encapsulation of injured liver parenchyma by a collagenous scar mainly imputable to hepatic stellate cells' activation. Approved pharmacological treatments against NAFLD-related fibrosis are still lacking, but natural compounds such as hydroxytyrosol (HXT) and vitamin E (VitE), are emerging as promising therapeutic opportunities. In this study, the potential anti-fibrotic effect of HXT + VitE combination therapy was investigated in vitro and in vivo. In particular, tumor growth factor (TGF)-beta-activated LX-2 cells as an in vitro model, and carbon tetrachloride plus a Western diet as a mice model were employed. The effect of HXT + VitE on fibrosis was also investigated in children with biopsy-proven NAFLD. Our results demonstrated that HXT + VitE caused a reduction of proliferation, migration, contractility, and expression of pro-fibrogenic genes in TGF-beta-activated LX-2 cells. HXT + VitE treatment also antagonized TGF-beta-dependent upregulation of pro-oxidant NOX2 by interfering with nuclear translocation/activation of SMAD2/3 transcription factors. The mouse model of NAFLD-related fibrosis treated with HXT + VitE showed a marked reduction of fibrosis pattern by histology and gene expression. Accordingly, in children with NAFLD, HXT + VitE treatment caused a decrease of circulating levels of PIIINP and NOX2 that was supported over time. Our study suggests that HXT + VitE supplementation may improve NAFLD-related fibrosis

Additional file 1: of Ex vivo immunosuppressive effects of mesenchymal stem cells on Crohn’s disease mucosal T cells are largely dependent on indoleamine 2,3-dioxygenase activity and cell-cell contact

Mesenchymal stem cells with T cells from inflamed Crohn’s mucosa. Representative time-lapse imaging of a co-culture with bone marrow-derived mesenchymal stem cells of a healthy donor and T cells isolated from inflamed mucosa of a patient with Crohn’s disease. A dynamic and intense interaction is clearly evident mostly during the first 6 h, when the binding between these two cell populations is non-fixed but instead appears as a continuous attachment and detachment, after which a growing number of cells with morphological features of apoptosis (those with nuclear fragmentation and cellular swelling) and apoptotic bodies become evident. The images were serially recorded every 30 min for 12 h. Magnification: 100×. (ZIP 6780 kb

High risk of congenital hypothyroidism in multiple pregnancies

Context: In Italy, the surveillance of congenital hypothyroidism (CH) is performed by the Italian National Registry of Infants with CH (INRICH). Up to now, about 3600 infants with CH are recorded in the INRICH, and a high number of twins are included. Objective: Our objective was to estimate the risk of CH in multiple and single deliveries and to compare neonatal features of CH twins with twins from the general population. Design: The Italian population of CH infants recorded in the INRICH from 1989-2000 was investigated. Results: A more than 3-fold higher frequency of twins was found in the CH population than in the general population, and for the first time, it was possible to estimate the CH incidence in multiple (10.1 in 10,000) and single deliveries (3.2 in 10,000 live births). Significantly higher frequencies of in situ gland as well as lower TSH mean level at screening were found in twin than in singleton CH babies. The concordance rate for permanent CH was very low (4.3%) and due to only three concordant couples. However, a high recurrence risk for CH was estimated in siblings of affected babies recorded in the INRICH, including twins considered as siblings. Conclusions: The high CH incidence observed in twins is worthy of interest for the high number of induced pregnancies in Italy as well as in other Western countries. Moreover, the low concordance rate for CH among twins together with a high recurrence risk for the disease among siblings indicates that environmental risk factors may act as a trigger on a susceptible genetic background in the etiology of the disease. Copyright © 2007 by The Endocrine Society