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Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified...
[Clinical analysis of the correlation between the expression of soluble B cell maturation antigen and the efficacy of chimeric antigen receptor T cell targeting B cell maturation antigen in patients with multiple myeloma].
The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified T-cell-targeting B cell maturation antigen (BCMA) in patients with multiple myeloma (MM) . This study involved 29 patients with relapsed or refractory MM (RRMM) who received humanized anti-BCMA CAR-T cell clinical trials from January 2018 to December 2021. The expression of sBCMA in bone marrow before and after anti-BCMA CAR-T cell treatment was detected by flow cytometry and compared. ①Two months after BCMA CAR-T cell treatment, 20 patients (68.97%) achieved an overall response (OR), whereas nine patients had stable disease (SD) or miner emission (MR). ②The expression of sBCMA in the bone marrow of 20 patients with OR was higher before treatment than after [26 926 (18 215, 32 488) ng/L 9 968 (6 634, 11 459) ng/L; <0.001]; no significant difference was observed in patients with MR and SD [41 187 (33 816, 47 046) ng/L 33 954 (31 569, 36 256) ng/L; =0.145]; sBCMA expression in patients with OR before CAR-T cell treatment was lower than in patients with MR and SD (=0.005). ③No significant linear correlation was found between the peak value of CAR-T cells and sBCMA expression in the bone marrow of all 29 patients with RRMM ((2)=0.035, =0.330). ④No significant difference in sBCMA expression was found between grades 0-1 CRS group (13 patients) and grades 2-4 CRS group [16 patients; 32 045 (18 742, 40 801) ng/L 29 102 (24 679, 38 776) ng/L, =0.879], nor between grade 0 ICANS group (22 patients) and grade 1-3 ICANS group [seven patients; 30 073 (19 375, 40 065) ng/L 33 816 (22 933, 43 459) ng/L, =0.763]. sBCMA expression in the bone marrow is related to the efficacy of BCMA CAR-T cell therapy in patients with RRMM, but is not significantly correlated with the severity of adverse events. It may serve as a predictive biomarker for the efficacy of BCMA CAR-T cell therapy in these patients.
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Bone Marrow; T-Lymphocytes; Male; Middle Aged; Female
PubMed: 38951066
DOI: 10.3760/cma.j.issn.0253-2727.2023.01.001 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024Flow cytometry plays an important role in the diagnosis and treatment of plasma cell diseases, particularly in the detection of circulating plasma cells (CPCs) in the...
Flow cytometry plays an important role in the diagnosis and treatment of plasma cell diseases, particularly in the detection of circulating plasma cells (CPCs) in the peripheral blood. A consensus about the normalized use of flow cytometry in detection of CPCs in peripheral blood in clinical practice has been achieved. This consensus is founded on evidence-based principles, which elucidates the timing and value of flow cytometry for the detection of CPCs in the monoclonal gammopathy of undetermined significance, smoldering myeloma, multiple myeloma, and plasma cell leukemia and standardizes flow cytometry in the detection of CPCs in plasma cell diseases.
Topics: Flow Cytometry; Humans; Plasma Cells; Multiple Myeloma; China; Paraproteinemias; Monoclonal Gammopathy of Undetermined Significance; Consensus; East Asian People
PubMed: 38951057
DOI: 10.3760/cma.j.cn121090-20240117-00026 -
The Journal of Clinical Investigation Apr 2024Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant...
Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.
Topics: Arthritis, Rheumatoid; Animals; Humans; Mice; Autoantigens; Germinal Center; Chaperonin 60; Autoantibodies; Autoimmunity; Male; Synoviocytes; Arthritis, Experimental; Female; B-Lymphocytes; Tertiary Lymphoid Structures
PubMed: 38950333
DOI: 10.1172/JCI169754 -
Pediatric Annals Jul 2024During the coronavirus disease 2019 (COVID-19) pandemic, reports of individuals experiencing new-onset type 1 diabetes (T1D) began to appear in the literature. This...
During the coronavirus disease 2019 (COVID-19) pandemic, reports of individuals experiencing new-onset type 1 diabetes (T1D) began to appear in the literature. This spurred subsequent epidemiological studies that demonstrated an increase in new diagnosis of T1D compared to prepandemic. Development of T1D is characterized by the development of an inappropriate T cell response directed against pancreatic beta-cells, leading to eventual loss of insulin secretion. This T cell response occurs in genetically susceptible individuals and may be triggered by viral illnesses. Abnormal cytokine production is another element of the pathogenesis of T1D. Infection with severe acute respiratory syndrome related coronavirus 2 induces a profound increase in the production of inflammatory cytokines and causes significant T-cell dysregulation. These disruptions of the immune system may be linked to the development of T1D following COVID-19. .
Topics: Child; Humans; COVID-19; Cytokines; Diabetes Mellitus, Type 1; Inflammation; SARS-CoV-2; T-Lymphocytes
PubMed: 38949876
DOI: 10.3928/19382359-20240502-05 -
The Journal of Experimental Medicine Aug 2024Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al....
Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al. (https://doi.org/10.1084/jem.20232091) propose a role for dysregulated IL-22 production by Th17 cells in causing some aspects of immune-mediated skin inflammation in human STAT3 GOF syndrome.
Topics: STAT3 Transcription Factor; Animals; Humans; Th17 Cells; Skin; Interleukin-22; Interleukins; Gain of Function Mutation; Mice; Inflammation
PubMed: 38949650
DOI: 10.1084/jem.20240849 -
The Journal of Experimental Medicine Sep 2024FOXP3 hijacks DNA-binding proteins to regulate gene expression. In this issue of JEM, He et al. (https://doi.org/10.1084/jem.20232068) propose a dynamic model in which...
FOXP3 hijacks DNA-binding proteins to regulate gene expression. In this issue of JEM, He et al. (https://doi.org/10.1084/jem.20232068) propose a dynamic model in which FOXP3 associates with DNA-binding proteins to regulate Treg cell function in response to environmental cues.
Topics: Forkhead Transcription Factors; Humans; T-Lymphocytes, Regulatory; Animals; Gene Expression Regulation; DNA-Binding Proteins; Transcription Factors
PubMed: 38949640
DOI: 10.1084/jem.20240940 -
Journal of Visualized Experiments : JoVE Jun 2024Viral infections can cause Endoplasmic Reticulum (ER) stress due to abnormal protein accumulation, leading to Unfolded Protein Response (UPR). Viruses have developed...
Viral infections can cause Endoplasmic Reticulum (ER) stress due to abnormal protein accumulation, leading to Unfolded Protein Response (UPR). Viruses have developed strategies to manipulate the host UPR, but there is a lack of detailed understanding of UPR modulation and its functional significance during HIV-1 infection in the literature. In this context, the current article describes the protocols used in our laboratory to measure ER stress levels and UPR during HIV-1 infection in T-cells and the effect of UPR on viral replication and infectivity. Thioflavin T (ThT) staining is a relatively new method used to detect ER stress in the cells by detecting protein aggregates. Here, we have illustrated the protocol for ThT staining in HIV-1 infected cells to detect and quantify ER stress. Moreover, ER stress was also detected indirectly by measuring the levels of UPR markers such as BiP, phosphorylated IRE1, PERK, and eIF2α, splicing of XBP1, cleavage of ATF6, ATF4, CHOP, and GADD34 in HIV-1 infected cells, using conventional immunoblotting and quantitative reverse transcription polymerase chain reaction (RT-PCR). We have found that the ThT-fluorescence correlates with the indicators of UPR activation. This article also demonstrates the protocols to analyze the impact of ER stress and UPR modulation on HIV-1 replication by knockdown experiments as well as the use of pharmacological molecules. The effect of UPR on HIV-1 gene expression/replication and virus production was analyzed by Luciferase reporter assays and p24 antigen capture ELISA, respectively, whereas the effect on virion infectivity was analyzed by staining of infected reporter cells. Collectively, this set of methods provides a comprehensive understanding of the Unfolded Protein Response pathways during HIV-1 infection, revealing its intricate dynamics.
Topics: Unfolded Protein Response; Humans; HIV-1; Virus Replication; Endoplasmic Reticulum Stress; HIV Infections; T-Lymphocytes
PubMed: 38949380
DOI: 10.3791/66522 -
Journal of Visualized Experiments : JoVE Jun 2024Extensive studies have proven the promise of chimeric antigen receptor T (CAR-T) cell therapy in treating hematological malignancies. However, treating solid tumors...
Extensive studies have proven the promise of chimeric antigen receptor T (CAR-T) cell therapy in treating hematological malignancies. However, treating solid tumors remains challenging, as exemplified by the safety concerns that arise when CAR-T cells attack normal cells expressing the target antigens. Researchers have explored various approaches to enhance the tumor selectivity of CAR-T cell therapy. One representative strategy along this line is the construction of hypoxia-sensitive CAR-T cells, which are designed by fusing an oxygen-dependent degradation domain to the CAR moiety and are strategized to attain high CAR expression only in a hypoxic environment-the tumor microenvironment (TME). This paper presents a protocol for the generation of such CAR-T cells and their functional characterization, including methods to analyze the changes in CAR expression and killing capacity in response to different oxygen levels established by a mobile incubator chamber. The constructed CAR-T cells are anticipated to demonstrate CAR expression and cytotoxicity in an oxygen-sensitive manner, thus supporting their capability to distinguish between hypoxic TME and normoxic normal tissues for selective activation.
Topics: Receptors, Chimeric Antigen; Humans; T-Lymphocytes; Immunotherapy, Adoptive; Cell Hypoxia; Tumor Microenvironment
PubMed: 38949315
DOI: 10.3791/66697 -
The Journal of Clinical Investigation Jul 2024
Topics: Humans; Killer Cells, Natural; Animals; Glucuronidase; Immunologic Surveillance; Neoplasm Invasiveness; Mice; Neoplasms
PubMed: 38949030
DOI: 10.1172/JCI183295 -
The Journal of Clinical Investigation Jul 2024
Topics: T-Lymphocytes, Regulatory; Humans; Receptors, Immunologic; Animals; Mice
PubMed: 38949028
DOI: 10.1172/JCI183278