Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease

Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.European CommissionCOST (European Cooperation in Science and Technology

Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease

Copyright © 2022 Doglio, Crossland, Alho, Penack, Dickinson, Stary, Lacerda, Eissner and Inngjerdingen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.This work was supported by COST (European Cooperation in Science and Technology). www.cost.eu - COST Action 17138 EUROGRAFT.info:eu-repo/semantics/publishedVersio

Lymphodepletion – an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle

Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the in vivo activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens

Impact of mevalonate kinase deficiency (MKD) on the quality of life in children and young adults: a national multicentre study

The quality of life of children and young adults with mevalonate kinase deficiency has been explored in this national multicentre study

Metamorfosi dei Lumi 8

“L’età della storia”, così Foucault, in Les mots et les choses, definisce lo sconvolgimento dell’episteme occidentale avvenuto alla fine del Settecento e nei primi decenni dell’Ottocento che dà l’avvio all’era della modernità. Foucault teorizza il disfacimento del sapere classico e la conseguente mutazione dall’”ordine” alla “storia”: all’ordine del sapere classico, ai valori della tradizione, si è sostituita l’idea di progresso, nonché la visione frammentata di una realtà naturale molteplice, le cui variazioni sono legate allo scorrere del tempo. Il valore normativo della tradizione viene, d’altra parte, contestato, negli ultimi decenni del diciottesimo secolo, da vari sommovimenti politici che sconvolgono l’ordine tradizionale delle nazioni europee: la Rivoluzione americana crea un governo razionale fondato sul diritto naturale; la Rivoluzione francese recide traumaticamente i legami con i valori di una monarchia secolare; i suoi drammatici sviluppi, il Terrore, le guerre europee, il crollo dell’impero napoleonico impongono, nel corso degli anni, la consapevolezza concreta dell’incidere storico. Questa irruzione della dimensione storica nel mondo europeo è stata, nel biennio 2013-2015, al centro dei lavori del seminario “Metamorfosi dei Lumi” che presenta, nel suo ottavo volume, un insieme di articoli centrati sul processo di temporalizzazione che caratterizza il tournant des Lumières, nelle esperienze di vita e in tutti i settori dello scibile

Adenosine blood level : a biomarker of white matter damage in very low birth weight infants

Background: Very low birth weight infants are at risk of developing periventricular white matter lesions. We previously reported high blood adenosine levels in premature infants and infants with low birth weight. We asked whether blood adenosine levels could be related to the vulnerability of the maturing white matter to develop lesions. The present study aims at finding a biomarker for the early detection of brain white matter lesions that can profoundly influence the neurodevelopmental outcome, whose pathophysiology is still unclear. Methods: Dried blood spots were prospectively collected for the newborn screening program and adenosine concentration measurements. Fifty-six newborns who tested four times for blood adenosine concentration (at days 3, 15, 30, and 40 post-birth) were included in the program. All infants underwent brain MRI at term equivalent age. Neurodevelopmental outcomes were studied with Griffiths Mental Development Scales (GMDS) at 12 ± 2 months corrected age. Results: Blood adenosine concentration increased over time from a median of 0.75 μM at Day 3 to 1.46 μM at Day 40. Adenosine blood concentration &gt;1.58 μM at Day 15 was significantly associated with brain white matter lesions at MRI (OR (95 % CI) of 50.0 (3.6-688.3), p-value &lt; 0.001). A moderate negative correlation between adenosine at 15 days of life and GMDS at 12 ± 2 months corrected age was found. Conclusion: These findings suggest a potential role for blood adenosine concentration as a biomarker of creberal white matter lesions in very low birth weight infants.</p

A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry

Background: Hereditary recurrent fevers (HRF) are a group of rare monogenic diseases leading to recurrent inflammatory flares. A large number of variants has been described for the four genes associated with the best known HRF, namely MEFV, NLRP3, MVK, TNFRSF1A. The Infevers database (http://fmf.igh.cnrs.fr/ISSAID/infevers) is a large international registry collecting variants reported in these genes. However, no genotype-phenotype associations are provided, but only the clinical phenotype of the first patient(s) described for each mutation. The aim of this study is to develop a registry of genotype-phenotype associations observed in patients with HRF, enrolled and validated in the Eurofever registry

A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry

PubMed ID: 29047407Background: Hereditary recurrent fevers (HRF) are a group of rare monogenic diseases leading to recurrent inflammatory flares. A large number of variants has been described for the four genes associated with the best known HRF, namely MEFV, NLRP3, MVK, TNFRSF1A. The Infevers database (http://fmf.igh.cnrs.fr/ISSAID/infevers) is a large international registry collecting variants reported in these genes. However, no genotype-phenotype associations are provided, but only the clinical phenotype of the first patient(s) described for each mutation. The aim of this study is to develop a registry of genotype-phenotype associations observed in patients with HRF, enrolled and validated in the Eurofever registry. Results: Genotype-phenotype associations observed in all the patients with HRF enrolled in the Eurofever registry were retrospectively analyzed. For autosomal dominant diseases (CAPS and TRAPS), all mutations were individually analyzed. For autosomal recessive diseases (FMF and MKD), homozygous and heterozygous combinations were described. Mean age of onset, disease course (recurrent or chronic), mean duration of fever episodes, clinical manifestations associated with fever episodes, atypical manifestations, complications and response to treatment were also studied. Data observed in 751 patients (346 FMF, 133 CAPS, 114 MKD, 158 TRAPS) included in the Eurofever registry and validated by experts were summarized in Tables. A total of 149 variants were described: 46 TNFRSF1A and 27 NLRP3 variants, as well as various combinations of 48 MVK and 28 MEFV variants were available. Conclusions: We provide a potentially useful tool for physicians dealing with HRF, namely a registry of genotype-phenotype associations for patients enrolled in the Eurofever registry. This tool is complementary to the Infevers database and will be available at the Eurofever and Infevers websites. © 2017 The Author(s)