Current Research in Translational Medicine最新文献

Systemic sclerosis (SSc) is a rare autoimmune disease (AD), characterised by early diffuse vasculopathy, activation of the immune response and progressive skin and internal organ fibrosis. In severe progressive diffuse SSc (dSSc), autologous hematopoietic stem cell transplantation (aHSCT) improves survival, despite its own risk of complications and transplant related mortality (TRM).

We present herein the case of a dSSc patient undergoing aHSCT with low dose cyclophosphamide conditioning and sudden acute myopericarditis and cardiogenic shock, four weeks after a second mRNA SARS-CoV-2 vaccine (Pfizer) injection. Four days of extracorporeal membrane oxygenation (ECMO) support during the aplasia period, allowed to observe full cardiac function recovery and progressive SSc rehabilitation with sustained disease response at 30 months follow-up. This report illustrates, for the first time to our knowledge, that ECMO can be indicated despite aplasia during aHSCT and successfully used as a bridge towards heart function recovery in highly selected and fragile AD patients. We review the factors that may contribute to endothelial and myocardial stunning and acute reversible cardiac failure in SSc and aggravate intrinsic endothelial injury during the aHSCT procedure. These classically include: cyclophosphamide drug toxicity, viral infections and autoimmune activation with disease flair per se. In the COVID-19 pandemic times, acute myocarditis due to recent viral infection or mRNA vaccine per se, must also be considered.

The use of γδ T lymphocytes as advanced therapeutic medicinal product has attracted much interest in the last years. Indeed, such cells are an ideal tool for the reconstitution of the immune system in patients receiving hematopoietic stem cell transplantation, due to their MHC-independent anti-tumor and anti-viral activities. We have here setup a protocol for the production of pure and functional γδ T lymphocytes, expanded from healthy donors’ mononuclear cells, and validated the analytical methods to identify them and to analyze their potency. Next, we performed stability studies to ensure that the cell product (γδ T cells) can be used after freezing and thawing. Notably, such protocol can be promptly translated to GMP-facility, since it has been designed using only clinical grade reagents.

Background

One of the prominent causes of chronic liver disease worldwide is the hepatitis C virus (HCV). HCV believed that innate immunity contributes to a sustained virological response (SVR) to the treatment of Sofosbuvir (SOF) (+) Daclatasvir (DCV) (+) Ribavirin (RBV). This study aimed to evaluate the impact of SOF (+) DCV (+) RBV therapy and persistent HCV infection on the subset of natural killer cells (NK) in HCV genotype four patients from Egypt.

Materials and Methods

One hundred and ten patients with persistent HCV infections requiring SOF (+) DCV (+) RBV therapy were grouped, and a flow cytometry (FCM) study of the NK cell subset in peripheral blood was performed. The assessment was performed before and after three and/or six months of the cessation of viral suppression therapy when a patient had a long-term viral response (SVR). One hundred and ten volunteers from the National Liver Institute^’s (NLI) blood bank were selected as controls.

Results

Patients with chronic HCV infection before therapy had considerably lower CD16⁺ and CD3⁻ CD56⁺ cells than controls. Their levels increase during SOF (+) DCV (+) RBV therapy. In patients with SVR during treatment, CD16⁺ and CD3^– CD56⁺ cells increased significantly compared to those who did not get SVR. Furthermore, CD56⁺ cells were significantly higher in patients with persistent infection before treatment than controls but diminished with the response to treatment.

Conclusion

: NK cell activation following SOF (+) DCV (+) RBV therapy and polarization to cytotoxicity occurred early in HCV antiviral therapy and was elevated in the respondents. Our data illustrated that establishing an inhibitory cytotoxic NK profile is related to therapeutic outcomes.

Background

High self-renewal capacity and most permissive nature of umbilical cord blood (CB) results with successful transplant outcomes but low hematopoietic stem and progenitor cell (HSPC) counts limits wider use. In order to overcome this problem ex vivo expansion with small molecules such as Valproic acid (VPA) or Nicotinamide (NAM) have been shown to be effective. To the best of our knowledge, the combinatory effects of VPA and NAM on HSPC expansion has not been studied earlier. The aim of this study was to analyze ex vivo and in vivo efficacy of VPA and NAM either alone or in combination in terms of expansion and engraftment.

Methods

A total of 44 CB units were included in this study. To determine the ex vivo and in vivo efficacy, human CB CD34+ cells were expanded with VPA and/or NAM and colony forming unit (CFU) assay was performed on expanded HSPC. Xenotransplantation was performed simultaneously by intravenous injection of expanded HSPC to NOD-SCID gamma (NSG) mice (n = 22). Significance of the difference between the expansion groups or xenotransplantation models was analyzed using t-test, Mann-Whitney, ANOVA or Kruskal-Wallis tests as appropriate considering the normality of distributions and the number of groups analyzed.

Results

In vitro CD34+ HSPC expansion fold relative to cytokines-only was significantly higher with VPA compared to NAM [2.23 (1.07–5.59) vs 1.48 (1.00–4.40); p < 0.05]. Synergistic effect of VPA+NAM has achieved a maximum relative expansion fold at 21 days (D21) of incubation [2.95 (1.00–11.94)]. There was no significant difference between VPA and VPA+NAM D21 (p = 0.44). Fold number of colony-forming unit granulocyte-macrophage (CFU-GM) colonies relative to the cytokine-only group was in favor of NAM compared to VPA [1.87 (1.00–3.59) vs 1.00 (1.00–1.81); p < 0.01]. VPA+NAM D21 [1.62 (1.00–2.77)] was also superior against VPA (p < 0.05). There was no significant difference between NAM and VPA+NAM D21. Following human CB34+ CB transplantation (CBT) in the mouse model, fastest in vivo leukocyte recovery was observed with VPA+NAM expanded cells (6 ± 2 days) and the highest levels of human CD45 chimerism was detectable with VPA-expanded CBT (VPA: 5.42 % at day 28; NAM: 2.45 % at day 31; VPA+NAM 1.8 % at day 31).

Conclusion

Our study results suggest using VPA alone, rather than in combination with NAM or NAM alone, to achieve better and faster expansion and engraftment of CB HSPC.

Purpose

Chimeric antigen receptor therapy beyond oncology has gained increasing attention. While a substantial number of publications have emerged in recent years, there has been a paucity of conducted bibliometric studies. Our objective is to systematically summarize and visually analyze the literature in the field of chimeric antigen receptors therapy beyond oncology and explore hotspots in this field.

Methods

Web of Science Core Collection was selected as the data source, and the data was retrieved on December 23, 2022, according to the search strategy. CiteSpace 6.1.R6 and Vosviewer 1.6.18 were used to analyze publications and explore research hotspots and directions.

Results

A total of 338 publications written by 1832 authors from 516 institutions in 42 countries/regions were selected for the analysis. The number of publications is steadily increasing annually. The United States emerged as the primary contributor, and University of Pennsylvania was the leading institution. Frontiers in Immunology boasted the highest number of published papers. Kitchen SG, Riley JL, and Scott DW were the most productive researchers in this field. The keyword cluster analysis identified HIV, autoimmune diseases, transplant related diseases and COVID-19 as the primary focus areas within the realm of chimeric antigen receptor therapy beyond oncology.

Conclusion

The advancement of chimeric antigen receptor therapy beyond oncology has witnessed rapid progress in recent years. We have explored the hotspots and research directions in this field. It is hoped that this study could provide references and directions for future clinical researches.

Technological advances in high-throughput sequencing have opened the door for the interrogation of adaptive immune responses at unprecedented scale. It is now possible to determine the sequences of antibodies or T-cell receptors produced by individual B and T cells in a sample. This capability, termed immunosequencing, has transformed the study of both infectious and non-infectious diseases by allowing the tracking of dynamic changes in B and T cell clonal populations over time. This has improved our understanding of the pathology of cancers, autoimmune diseases, and infectious diseases. However, to date there has been only limited clinical adoption of the technology. Advances over the last decade and on the horizon that reduce costs and improve interpretability could enable widespread clinical use. Many clinical applications have been proposed and, while most are still undergoing research and development, some methods relying on immunosequencing data have been implemented, the most widespread of which is the detection of measurable residual disease. Here, we review the diagnostic, prognostic, and therapeutic applications of immunosequencing for both infectious and non-infectious diseases.

Genomic characterization is an essential part of the clinical management of hematological malignancies for diagnostic, prognostic and therapeutic purposes. Although CBA and FISH are still the gold standard in hematology for the detection of CNA and SV, some alternative technologies are intended to complement their deficiencies or even replace them in the more or less near future. In this article, we provide a technological overview of these alternatives. CMA is the historical and well established technique for the high-resolution detection of CNA. For SV detection, there are emerging techniques based on the study of chromatin conformation and more established ones such as RTMLPA for the detection of fusion transcripts and RNA-seq to reveal the molecular consequences of SV. Comprehensive techniques that detect both CNA and SV are the most interesting because they provide all the information in a single examination. Among these, OGM is a promising emerging higher-solution technique that offers a complete solution at a contained cost, at the expense of a relatively low throughput per machine. WGS remains the most adaptable solution, with long-read approaches enabling very high-resolution detection of CAs, but requiring a heavy bioinformatics installation and at a still high cost. However, the development of high-resolution genome-wide detection techniques for CAs allows for a much better description of chromoanagenesis. Therefore, we have included in this review an update on the various existing mechanisms and their consequences and implications, especially prognostic, in hematological malignancies.

Congenital sideroblastic anemia (CSA) is a group of disorders caused by different genetic mutations that result in low iron utilization and ineffective erythropoiesis. Current treatments are limited, and some patients do not respond to vitamin B6 therapy. Luspatercept is a novel erythropoietic maturation agent approved for adult β-thalassemia and Myelodysplastic syndromes with ring sideroblasts (MDS-RS) associated with ineffective erythropoiesis. Here we report 2 patients with CSA due to mutations in ALAS2 and SLC25A38 genes who became unresponsive after a period of treatment with vitamin B6 and iron chelators but achieved transfusion independence and a markedly reduced spleen after combination with luspatercept.