-
Tzu Chi Medical Journal 2022Hematopoietic stem cell (HSC) transplantation has been used to treat hematopoietic diseases for over 50 years. HSCs can be isolated from bone marrow (BM), umbilical cord... (Review)
Review
Hematopoietic stem cell (HSC) transplantation has been used to treat hematopoietic diseases for over 50 years. HSCs can be isolated from bone marrow (BM), umbilical cord blood, or peripheral blood. Because of lower costs, shorter hospitalization, and faster engraftment, peripheral blood has become the predominant source of HSCs for transplantation. The major factors determining the rate of successful HSC transplantation include the degree of human leukocyte antigen matching between the donor and recipient and the number of HSCs for transplantation. Administration of granulocyte colony-stimulating factor (G-CSF) alone or combined with plerixafor (AMD3100) are clinical used methods to promote HSC mobilization from BM to the peripheral blood for HSC transplantations. However, a significant portion of healthy donors or patients may be poor mobilizers of G-CSF, resulting in an insufficient number of HSCs for the transplantation and necessitating alternative strategies to increase the apheresis yield. The detailed mechanisms underlying G-CSF-mediated HSC mobilization remain to be elucidated. This review summarizes the current research on deciphering the mechanism of HSC mobilization.
PubMed: 35912054
DOI: 10.4103/tcmj.tcmj_98_21 -
The Journal of Clinical Investigation Oct 2023BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
Topics: Humans; Immunologic Deficiency Syndromes; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Cross-Over Studies; Quality of Life; Heterocyclic Compounds; Primary Immunodeficiency Diseases; Warts; Receptors, CXCR4
PubMed: 37561579
DOI: 10.1172/JCI164918 -
Short-range interactions between fibrocytes and CD8 T cells in COPD bronchial inflammatory response.ELife Jul 2023Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells....
Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8 T cells and its consequences were investigated using a combination of , experiments and mathematical modeling. We show that fibrocytes and CD8 T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8 T cells and fibrocytes are associated with altered lung function. Tissular CD8 T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8 T cells establish short-term interactions with fibrocytes, that trigger CD8 T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8 T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8 T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8 T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients.
Topics: Humans; CD8-Positive T-Lymphocytes; Pulmonary Disease, Chronic Obstructive; Bronchi; Epithelial Cells; Inflammation
PubMed: 37494277
DOI: 10.7554/eLife.85875 -
Nature Communications Mar 2021Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that...
Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.
Topics: Acetylation; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Bone Neoplasms; Carcinogenesis; Cell Line, Tumor; Cyclams; Docetaxel; Epithelial-Mesenchymal Transition; Humans; Interleukin-11; Kruppel-Like Transcription Factors; Male; Mice; Mutation; Osteogenesis; Prostatic Neoplasms, Castration-Resistant; Receptors, CXCR4; Signal Transduction; Transforming Growth Factor beta
PubMed: 33731701
DOI: 10.1038/s41467-021-21976-w -
Therapeutic Advances in Hematology 2023Hematopoietic stem-cell transplantation (HCT) and stem-cell-based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells... (Review)
Review
Hematopoietic stem-cell transplantation (HCT) and stem-cell-based gene therapies rely on the ability to collect sufficient CD34+ hematopoietic stem and progenitor cells (HSPCs), typically peripheral blood mobilization. Commonly used HSPC mobilization regimens include single-agent granulocyte colony-stimulating factor (G-CSF), plerixafor, chemotherapy, or a combination of these agents. These regimens, however, frequently require multiple days of injections and leukapheresis procedures to collect adequate HSPCs for HCT (minimum = >2 × 10 CD34+ cells/kg; optimal = 5-6 × 10 CD34+ cells/kg). In addition, these regimens frequently yield suboptimal CD34+ HSPC numbers for HSPC-based gene-edited therapies, given the significantly higher HSPC number needed for successful gene-editing and manufacturing. Meanwhile, G-CSF is associated with common adverse events such as bone pain as well as an increased risk of rare but potentially life-threatening splenic rupture. Moreover, G-CSF is unsafe in patients with sickle-cell disease, a key patient population that may benefit from autologous HSPC-based gene-edited therapies, where it has been associated with unacceptable rates of serious vaso-occlusive and thrombotic events. Motixafortide is a novel CXCR4 inhibitor with extended activity (>48 h) that has been shown in preclinical and clinical trials to rapidly mobilize robust numbers of HSPCs in preparation for HCT, while preferentially mobilizing increased numbers of more primitive HSPCs by immunophenotyping and single-cell RNA expression profiling. In this review, we present a history of stem-cell mobilization and update of recent innovations in novel mobilization strategies with a specific focus on the development of motixafortide, a long-acting CXCR4 inhibitor, as a novel HSPC mobilizing agent.
PubMed: 37250913
DOI: 10.1177/20406207231174304 -
Clinics in Laboratory Medicine Mar 2021Red blood cell (RBC) transfusion is critical in managing acute and chronic complications of sickle cell disease. Alloimmunization and iron overload remain significant... (Review)
Review
Red blood cell (RBC) transfusion is critical in managing acute and chronic complications of sickle cell disease. Alloimmunization and iron overload remain significant complications of transfusion therapy and are minimized with prophylactic Rh and K antigen RBC matching and iron chelation. Matched sibling donor hematopoietic stem cell transplant (HSCT) is a curative therapeutic option. Autologous hematopoietic stem cell (HSC)-based gene therapy has recently shown great promise, for which obtaining sufficient HSCs is essential for success. This article discusses RBC transfusion indications and complications, transfusion support during HSCT, and HSC mobilization and collection for autologous HSCT with gene therapy.
Topics: Anemia, Sickle Cell; Blood Group Antigens; Blood Transfusion; Cell- and Tissue-Based Therapy; Erythrocyte Transfusion; Humans
PubMed: 33494879
DOI: 10.1016/j.cll.2020.10.007 -
Pediatrics International : Official... Jan 2022Plerixafor is approved in Japan for hematopoietic stem cell mobilization prior to autologous transplant, but limited data are available on the use in children. This...
BACKGROUND
Plerixafor is approved in Japan for hematopoietic stem cell mobilization prior to autologous transplant, but limited data are available on the use in children. This study evaluates the safety and effectiveness of plerixafor in Japanese children aged <15 years.
METHODS
A multicenter, post-marketing surveillance study was conducted in Japan to evaluate the safety and effectiveness of plerixafor in routine clinical practice. This subgroup analysis examined the safety and effectiveness of plerixafor administered as a once-daily, subcutaneous injection in children aged <15 years. The primary effectiveness outcome was the proportion of patients with 2 × 10 cells CD34+ cells/kg collected via apheresis within 4 days.
RESULTS
Eighteen patients with solid tumors were included in this analysis; (median age 6.0 years, range, 1-13 years). In addition to granulocyte colony-stimulating factor, all patients had received chemotherapy immediately prior to plerixafor administration. The mean (SD) daily dose of plerixafor was 0.24 (0.01) mg/kg. Seven of the 18 patients (38.9%) developed adverse drug reactions (ADRs), all occurring in patients aged ≥6 years and weighing ≥16 kg. The most common ADRs were pyrexia (n = 4), vomiting (n = 3), nausea (n = 2), and abdominal pain (n = 2). Twelve patients (66.7%) achieved a CD34+ cell count ≥2 × 10 cells/kg within 4 days after the start of plerixafor administration.
CONCLUSIONS
The results provide an encouraging sign that plerixafor 0.24 mg/kg may be safe and effective in pediatric patients in routine clinical practice in Japan, but further research in larger studies is needed.
Topics: Benzylamines; Child; Cyclams; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Japan; Marketing
PubMed: 35396889
DOI: 10.1111/ped.15106 -
Cells Nov 2021Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the gene that encodes cystinosin,... (Review)
Review
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the cDNA, pCCL-CTNS, and showed its efficacy in Ctns mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34 HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis.
Topics: Amino Acid Transport Systems, Neutral; Animals; Cystinosis; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Kidney; Lysosomes; Transplantation, Homologous
PubMed: 34943781
DOI: 10.3390/cells10123273 -
International Journal of Molecular... Mar 2023Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients' samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.
Topics: Humans; Tobacco Smoke Pollution; Muscular Atrophy; Pulmonary Disease, Chronic Obstructive; Muscle, Skeletal; Inflammation; Hypoxia
PubMed: 37047427
DOI: 10.3390/ijms24076454 -
Cell Communication and Signaling : CCS Mar 2023Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which...
BACKGROUND
Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear.
METHODS
To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively.
RESULTS
In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model.
CONCLUSION
MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.
Topics: Animals; Humans; Mice; Bleomycin; Bosentan; Endothelial Cells; Epithelial-Mesenchymal Transition; Idiopathic Pulmonary Fibrosis; Lung; Monocytes; Matrix Metalloproteinases, Secreted
PubMed: 36915092
DOI: 10.1186/s12964-023-01040-4