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Journal of Clinical Immunology Aug 2019WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and... (Review)
Review
WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.
Topics: Adaptive Immunity; Alleles; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Immunity, Innate; Mutation; Phenotype; Precision Medicine; Primary Immunodeficiency Diseases; Warts
PubMed: 31313072
DOI: 10.1007/s10875-019-00665-w -
Frontiers in Immunology 2019Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to... (Review)
Review
Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to harness immune cells: monoclonal antibodies against tumor antigens, immune checkpoint inhibitors, vaccination, adoptive cell therapies (e.g., CAR-T cells) and cytokine administration. In the last decades, it is emerging that the chemokine system represents a potential target for immunotherapy. Chemokines, a large family of cytokines with chemotactic activity, and their cognate receptors are expressed by both cancer and stromal cells. Their altered expression in malignancies dictates leukocyte recruitment and activation, angiogenesis, cancer cell proliferation, and metastasis in all the stages of the disease. Here, we review first attempts to inhibit the chemokine system in cancer as a monotherapy or in combination with canonical or immuno-mediated therapies. We also provide recent findings about the role in cancer of atypical chemokine receptors that could become future targets for immunotherapy.
Topics: Antibodies, Monoclonal, Humanized; Benzylamines; Chemokines, CC; Chemokines, CXC; Cyclams; Heterocyclic Compounds; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Receptors, CCR; Receptors, CXCR
PubMed: 30894861
DOI: 10.3389/fimmu.2019.00379 -
Proceedings of the National Academy of... Nov 2020Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in...
Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
Topics: Aged; Benzylamines; Carcinoma, Pancreatic Ductal; Chemokine CXCL12; Colorectal Neoplasms; Cyclams; Female; Heterocyclic Compounds; Humans; Immunity; Immunotherapy; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Receptors, CCR2; Receptors, CXCR3; Receptors, CXCR4; Receptors, CXCR5; Receptors, CXCR6; Receptors, Interleukin-8A; Signal Transduction; Tumor Microenvironment
PubMed: 33127761
DOI: 10.1073/pnas.2013644117 -
CNS Neuroscience & Therapeutics Sep 2019Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test...
BACKGROUND
Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test whether the CXCL12/CXCR4 signaling pathway contributes to the pathogenesis of neuropathic pain after spinal nerve ligation (SNL) via central sensitization mechanisms.
METHODS
Neuropathic pain was induced and assessed in a SNL rat model. The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot. The effects of CXCL12 rat peptide, CXCL12 neutralizing antibody, CXCR4 antagonist, and astrocyte metabolic inhibitor on pain hypersensitivity were explored by behavioral tests in naive or SNL rats. We measured the expression level of c-Fos and CGRP to evaluate the sensitization of neurons by RT-PCR. The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba-1. The mRNA levels of the pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and Connexin 30, Connexin 43, EAAT 1, EAAT 2 were also detected by RT-PCR.
RESULTS
First, we found that the expression of CXCL12 and CXCR4 was upregulated after SNL. CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL. Moreover, intrathecal administration of rat peptide, CXCL12, induced hypersensitivity in naive rats, which was partly reversed by fluorocitrate. In addition, the CXCL12 rat peptide increased mRNA levels of c-Fos, GFAP, and iba-1. A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model. Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain, and reduced the expression of GFAP and iba-1 in the spinal dorsal horn. Finally, repeated intrathecal administration of the CXCR4 antagonist, AMD3100, significantly suppressed the initiation and duration of neuropathic pain. The mRNA levels of c-Fos, CGRP, GFAP, iba-1, and pro-inflammatory cytokines, also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100, while EAAT 1 and EAAT 2 mRNAs were increased.
CONCLUSION
We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms. Importantly, intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain.
Topics: Animals; Benzylamines; Central Nervous System Sensitization; Chemokine CXCL12; Cyclams; Heterocyclic Compounds; Ligation; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Receptors, CXCR4; Signal Transduction; Spinal Cord; Spinal Nerves
PubMed: 30955244
DOI: 10.1111/cns.13128 -
Cell Death & Disease Aug 2021Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well...
Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein-protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.
Topics: Animals; Atrial Fibrillation; Benzylamines; Case-Control Studies; Chemokine CXCL12; Computational Biology; Cyclams; Databases, Genetic; Disease Models, Animal; Electrocardiography; Fibrosis; Gene Expression Profiling; Gene Ontology; Gene Regulatory Networks; Heart Atria; Humans; Inflammation; Macrophages; Mice, Inbred C57BL; Phosphorylation; Receptors, CXCR4; Signal Transduction; T-Lymphocytes; Vascular Remodeling; Mice
PubMed: 34453039
DOI: 10.1038/s41419-021-04109-5 -
ACS Nano Jun 2022Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor...
Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4 monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Chemokine CXCL12; Glioblastoma; Glioma; Immunotherapy; Nanoparticles; Receptors, CXCR4; Signal Transduction; Tumor Microenvironment
PubMed: 35616289
DOI: 10.1021/acsnano.1c07492 -
Transplantation and Cellular Therapy Mar 2023For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT)....
Stem Cell Mobilization Yields with Daratumumab- and Lenalidomide-Containing Quadruplet Induction Therapy in Newly Diagnosed Multiple Myeloma: Findings from the MASTER and GRIFFIN Trials.
For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT. Therefore, we assessed stem cell mobilization in patients following frontline induction therapy in the MASTER and GRIFFIN phase 2 clinical studies by examining stem cell mobilization yields, apheresis attempts, and engraftment outcomes for patients from each study. Adult transplantation-eligible patients with NDMM received induction therapy consisting of daratumumab plus carfilzomib/lenalidomide/dexamethasone (D-KRd) for four 28-day cycles in the single-arm MASTER trial or lenalidomide/bortezomib/dexamethasone (RVd) with or without daratumumab (D) for four 21-day cycles in the randomized GRIFFIN trial, followed by stem cell mobilization and ASCT in both studies. Institutional practice differed regarding plerixafor use for stem cell mobilization; the strategies were upfront (ie, planned plerixafor use) or rescue (ie, plerixafor use only after mobilization parameters indicated failure with granulocyte colony-stimulating factor [G-CSF] alone). Descriptive analyses were used to summarize patient characteristics, stem cell mobilization yields, and engraftment outcomes. In MASTER, 116 D-KRd recipients underwent stem cell mobilization and collection at a median of 24 days after completing induction therapy. In GRIFFIN, 175 patients (D-RVd, n = 95; RVd, n = 80) underwent mobilization at a median of 27 days after completing D-RVd induction therapy and 24 days after completing RVd induction therapy. Among those who underwent mobilization and collection, 7% (8 of 116) of D-KRd recipients, 2% (2 of 95) of D-RVd recipients, and 6% (5 of 80) of RVd recipients did not meet the center-specific minimally required CD34 cell yield in the first mobilization attempt; however, nearly all collected sufficient stem cells for ASCT on remobilization. Among patients who underwent mobilization, plerixafor use, either upfront or as a rescue strategy, was higher in patients receiving D-KRd (97%; 112 of 116) and D-RVd (72%; 68 of 95) compared with those receiving RVd (55%; 44 of 80). The median total CD34 cell collection was 6.0 × 10/kg (range, 2.2 to 13.9 × 10/kg) after D-KRd induction, 8.3 × 10/kg (range, 2.6 to 33.0 × 10/kg) after D-RVd induction, and 9.4 × 10/kg (range, 4.1 to 28.7 × 10/kg) after RVd induction; the median days for collection were 2, 2, and 1, respectively. Among patients who underwent mobilization, 98% (114 of 116) of D-KRd patients, 99% (94 of 95) of D-RVd patients, and 98% (78 of 80) of RVd patients underwent ASCT using median CD34 cell doses of 3.2 × 10/kg, 4.2 × 10/kg, and 4.8 × 10/kg, respectively. The median time to neutrophil recovery was 12 days in all 3 treatment groups across the 2 trials. Because both trials used different criteria to define platelet recovery, data on platelet engraftment using the same criteria are not available. Four cycles of daratumumab- and lenalidomide-based quadruplet induction therapy had a minimal impact on stem cell mobilization and allowed predictable stem cell harvesting and engraftment in all patients who underwent ASCT. Upfront plerixafor strategy may be considered, but many patients were successfully collected with the use of G-CSF alone or rescue plerixafor.
Topics: Adult; Humans; Multiple Myeloma; Lenalidomide; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Induction Chemotherapy; Heterocyclic Compounds; Transplantation, Autologous; Bortezomib; Dexamethasone; Granulocyte Colony-Stimulating Factor
PubMed: 36494017
DOI: 10.1016/j.jtct.2022.11.029 -
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