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1.
Front Immunol ; 15: 1382977, 2024.
Article in English | MEDLINE | ID: mdl-38799465

ABSTRACT

CD38 antigen is a glycoprotein that found on the surface of several immune cells, and this property makes its monoclonal antibodies have the effect of targeted elimination of immune cells. Therefore, the CD38 monoclonal antibody (such as daratumumab, Isatuximab) becomes a new treatment option for membranous nephropathy, lupus nephritis, renal transplantation, and other refractory kidney diseases. This review summarizes the application of CD38 monoclonal antibodies in different kidney diseases and highlights future prospects.


Subject(s)
ADP-ribosyl Cyclase 1 , Antibodies, Monoclonal , Kidney Diseases , Humans , ADP-ribosyl Cyclase 1/immunology , ADP-ribosyl Cyclase 1/antagonists & inhibitors , ADP-ribosyl Cyclase 1/metabolism , Antibodies, Monoclonal/therapeutic use , Kidney Diseases/immunology , Animals , Membrane Glycoproteins/immunology , Membrane Glycoproteins/antagonists & inhibitors , Kidney Transplantation , Antibodies, Monoclonal, Humanized/therapeutic use
2.
Clin Lab ; 70(5)2024 May 01.
Article in English | MEDLINE | ID: mdl-38747919

ABSTRACT

BACKGROUND: For many years it has been postulated that the immune system controls the progress of multiple myeloma (MM). However, the phenotypes of T cells in MM remain to be elucidated. In this study, we compared the phenotypes of T cells, which were obtained from the peripheral blood, in MM patients with those in healthy donors (HD). The expression of CCR7, CD57, CD28, HLA-DR, CD38, CD45RA, and CD45RO were assessed on T cells from MM patients and HDs using multicolor flow cytometry (MFC). METHODS: For this study, 17 newly diagnosed MM patients were selected, and 20 healthy people were selected as a control group. MFC was used to detect the markers on T cells. RESULTS: We detected significant increases in the expression levels of HLA-DR, CD38, and CD57on CD8+ T cells, significant decreases in the expression levels of CD28 and CD45RA on CD8+ T cells, and a decrease of CD4+ effec-tor T cells in MM patients, compared to the HD group. CONCLUSIONS: Our study shows that the accumulation of peripheral CD8+CD57+T cells, CD8+CD38high T cells, and CD8+HLA-DR+CD38high T cells is reflective of an ongoing antitumor T cell response and a progressive immune dysfunction in MM. During chemotherapy, the recovery of immune function can be monitored by detecting the proportion of activated molecules of T lymphocytes.


Subject(s)
ADP-ribosyl Cyclase 1 , CD28 Antigens , Flow Cytometry , HLA-DR Antigens , Leukocyte Common Antigens , Multiple Myeloma , Humans , Multiple Myeloma/immunology , CD28 Antigens/immunology , CD28 Antigens/metabolism , ADP-ribosyl Cyclase 1/metabolism , HLA-DR Antigens/immunology , HLA-DR Antigens/metabolism , HLA-DR Antigens/blood , Leukocyte Common Antigens/metabolism , Male , Middle Aged , Female , Aged , CD57 Antigens/metabolism , Case-Control Studies , Immunophenotyping/methods , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Adult , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Membrane Glycoproteins/immunology
3.
Cells ; 13(10)2024 May 20.
Article in English | MEDLINE | ID: mdl-38786100

ABSTRACT

Current treatment strategies for multiple myeloma (MM) are highly effective, but most patients develop relapsed/refractory disease (RRMM). The anti-CD38/CD3xCD28 trispecific antibody SAR442257 targets CD38 and CD28 on MM cells and co-stimulates CD3 and CD28 on T cells (TCs). We evaluated different key aspects such as MM cells and T cells avidity interaction, tumor killing, and biomarkers for drug potency in three distinct cohorts of RRMM patients. We found that a significantly higher proportion of RRMM patients (86%) exhibited aberrant co-expression of CD28 compared to newly diagnosed MM (NDMM) patients (19%). Furthermore, SAR442257 mediated significantly higher TC activation, resulting in enhanced MM killing compared to bispecific functional knockout controls for all relapse cohorts (Pearson's r = 0.7). Finally, patients refractory to anti-CD38 therapy had higher levels of TGF-ß (up to 20-fold) compared to other cohorts. This can limit the activity of SAR442257. Vactoserib, a TGF-ß inhibitor, was able to mitigate this effect and restore sensitivity to SAR442257 in these experiments. In conclusion, SAR442257 has high potential for enhancing TC cytotoxicity by co-targeting CD38 and CD28 on MM and CD3/CD28 on T cells.


Subject(s)
ADP-ribosyl Cyclase 1 , Multiple Myeloma , T-Lymphocytes , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multiple Myeloma/immunology , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/antagonists & inhibitors , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/drug effects , CD3 Complex/metabolism , CD28 Antigens/metabolism , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , Cell Line, Tumor , Recurrence
4.
Int J Mol Sci ; 25(9)2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38731936

ABSTRACT

Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients' samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs.


Subject(s)
ADP-ribosyl Cyclase 1 , Antibodies, Monoclonal , Multiple Myeloma , NK Cell Lectin-Like Receptor Subfamily K , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Humans , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/antagonists & inhibitors , Animals , Antibodies, Monoclonal/pharmacology , Mice , Cell Line, Tumor , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Xenograft Model Antitumor Assays , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Membrane Glycoproteins/metabolism , Drug Synergism , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class I/genetics , Up-Regulation/drug effects
5.
Anticancer Res ; 44(6): 2747-2753, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38821591

ABSTRACT

BACKGROUND/AIM: The relevance of cytogenetic markers as prognostic risk factors has been demonstrated in a vast number of studies, with many prognostication tools utilizing these factors to determine treatment approaches. Patients aged above 60 years represent an important subgroup of acute myeloid leukemia (AML) patients, especially because they usually exhibit a poorer cytogenetic landscape and are less suitable for intensive treatments. The importance of evaluating prognostic parameters in AML, especially in low-income countries, prompted an investigation into CD38 expression and its effects. PATIENTS AND METHODS: Medical records of AML patients aged above 60 years from three hospitals in Brazil's northwest region were analyzed. A total of 67 patients were evaluated in terms of overall survival and factors predicting worse outcomes. The risk stratification was performed based on the European LeukemiaNet 2022 guidelines. The analysis of immunophenotyping markers was conducted using multi-parametric flow cytometry. RESULTS: The overall survival of CD38-positive AML patients was higher than that of patients with CD38-negative AML, with survival rates of 15.6 months versus 4 months, respectively (p-value=0.026). The impact of CD38 positivity was relevant also in multivariable Cox proportional hazards regression, demonstrating a positive effect on overall survival, with a hazard ratio of 0.33 (95%CI=0.13-0.79; p-value=0.014). CONCLUSION: Expression of CD38 in patients with AML was associated with better overall survival and serves as a relevant predictor of improved outcome in patients aged above 60 years.


Subject(s)
ADP-ribosyl Cyclase 1 , Biomarkers, Tumor , Immunophenotyping , Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/mortality , Aged , ADP-ribosyl Cyclase 1/metabolism , Female , Male , Prognosis , Middle Aged , Biomarkers, Tumor/genetics , Aged, 80 and over , Membrane Glycoproteins/metabolism
6.
Invest Ophthalmol Vis Sci ; 65(5): 36, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38776115

ABSTRACT

Purpose: The purpose of this study was to investigate the protective effect of CD38 deletion on retinal ganglion cells (RGCs) in a mouse retinal ischemia/reperfusion (I/R) model and an optic nerve crush (ONC) model, and to elucidate the underlying molecular mechanisms. Methods: Retinal I/R and ONC models were constructed in mice. PCR was used to identify the deletion of CD38 gene in mice, hematoxylin and eosin (H&E) staining was used to evaluate the changes in retinal morphology, and electroretinogram (ERG) was used to evaluate the changes in retinal function. The survival of RGCs and activation of retinal macroglia were evaluated by immunofluorescence staining. The expression of Sirt1, CD38, Ac-p65, Ac-p53, TNF-α, IL-1ß, and Caspase3 proteins in the retina was further evaluated by protein imprinting. Results: In retinal I/R and ONC models, CD38 deficiency reduced the loss of RGCs and activation of macroglia and protected the retinal function. CD38 deficiency increased the concentration of NAD+, reduced the degree of acetylation of NF-κB p65 and p53, and reduced expression of the downstream inflammatory cytokines TNFα, IL-1ß, and apoptotic protein Caspase3 in the retina in the ONC model. Intraperitoneal injection of the Sirt1 inhibitor EX-527 partially counteracted the effects of CD38 deficiency, suggesting that CD38 deficiency acts at least in part through the NAD+/Sirt1 pathway. Conclusions: CD38 plays an important role in the pathogenesis of retinal I/R and ONC injury. CD38 deletion protects RGCs by attenuating inflammatory responses and apoptosis through the NAD+/Sirt1 pathway.


Subject(s)
ADP-ribosyl Cyclase 1 , Disease Models, Animal , Mice, Inbred C57BL , NAD , Optic Nerve Injuries , Reperfusion Injury , Retinal Ganglion Cells , Sirtuin 1 , Animals , Sirtuin 1/metabolism , Sirtuin 1/genetics , Retinal Ganglion Cells/pathology , Retinal Ganglion Cells/metabolism , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/genetics , Reperfusion Injury/metabolism , Reperfusion Injury/prevention & control , Mice , NAD/metabolism , Optic Nerve Injuries/metabolism , Electroretinography , Nerve Crush , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Male , Signal Transduction/physiology
7.
Scand J Immunol ; 99(6): e13364, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38720521

ABSTRACT

Mucosal-associated invariant T-cells (MAIT) are unconventional T-cells with cytotoxic and pro-inflammatory properties. Previous research has reported contradictory findings on their role in cancerogenesis with data being even scarcer in haematological malignancies. Here, we report the results of a systematic analysis of MAIT cells in treatment-naïve patients with a broad range of haematological malignancies. We analysed peripheral blood of 204 patients and 50 healthy subjects. The pool of haematological patients had a statistically significant lower both the absolute value (median values, 0.01 × 109/L vs. 0.05 × 109/L) of MAIT cells and their percentage (median values 0.94% vs. 2.56%) among T-cells compared to the control group. Separate analysis showed that the decrease in the absolute number of MAIT cells is significant in patients with acute myeloid leukaemia, myeloproliferative neoplasms, plasma cell myeloma, B-cell non-Hodgkin lymphomas, otherwise not specified, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma compared to the control population. Furthermore, in haematological malignancies, MAIT cells overexpress PD-1 (average values, 51.7% vs. 6.7%), HLA-DR (average values, 40.2% vs. 7%), CD38 (average values, 25.9% vs. 4.9%) and CD69 (average values, 40.2% vs. 9.2%). Similar results were obtained when comparing patients with individual malignancies to the control population. Our data show that the depletion of circulating MAIT cells is a common observation in a broad spectrum of haematological malignancies. In addition to their reduced numbers, MAIT cells acquire an activated/exhausted phenotype.


Subject(s)
Hematologic Neoplasms , Mucosal-Associated Invariant T Cells , Programmed Cell Death 1 Receptor , Humans , Mucosal-Associated Invariant T Cells/immunology , Hematologic Neoplasms/immunology , Male , Female , Middle Aged , Aged , Adult , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Antigens, CD/metabolism , Aged, 80 and over , Antigens, Differentiation, T-Lymphocyte/metabolism , Lymphocyte Count , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/immunology , Immunophenotyping , Young Adult , Membrane Glycoproteins/immunology , Lectins, C-Type
8.
Front Immunol ; 15: 1346178, 2024.
Article in English | MEDLINE | ID: mdl-38680487

ABSTRACT

Introduction: Natural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy. Methods: We conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses. Results and Discussion: Our analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks post-administration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies.


Subject(s)
ADP-ribosyl Cyclase 1 , Immune Checkpoint Inhibitors , Humans , ADP-ribosyl Cyclase 1/antagonists & inhibitors , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/immunology , Immune Checkpoint Inhibitors/therapeutic use , Lymphoma, Extranodal NK-T-Cell/therapy , Lymphoma, Extranodal NK-T-Cell/immunology , Lymphoma, Extranodal NK-T-Cell/drug therapy , Membrane Glycoproteins/antagonists & inhibitors , Male , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Middle Aged , Female , Treatment Outcome
9.
EBioMedicine ; 103: 105098, 2024 May.
Article in English | MEDLINE | ID: mdl-38608514

ABSTRACT

BACKGROUND: The widespread involvement of tumor-infiltrating B cells highlights their potential role in tumor behavior. However, B cell heterogeneity in PDAC remains unexplored. Studying TIL-Bs in PDAC aims to identify new treatment strategies. METHODS: We performed single-cell RNA sequencing to study the heterogeneity of B cells in PDAC. The prognostic and immunologic value of the identified CD38+ B cells was explored in FUSCC (n = 147) and TCGA (n = 176) cohorts. Flow cytometry was conducted to characterize the relationship between CD38+ B cells and other immune cells, as well as their phenotypic features. In vitro and in vivo experiments were performed to assess the putative effect of CD38+ B cells on antitumor immunity. FINDINGS: The presence of CD38+ B cells in PDAC was associated with unfavorable clinicopathological features and poorer overall survival (p < 0.001). Increased infiltration of CD38+ B cells was accompanied by reduced natural killer (NK) cells (p = 0.021) and increased regulatory T cells (p = 0.016). Molecular profiling revealed high expression of IL-10, IL-35, TGF-ß, GZMB, TIM-1, CD5 and CD21, confirming their putative regulatory B cell-like features. Co-culture experiments demonstrated suppression of NK cell cytotoxicity by CD38+ B cell-derived IL-10 (p < 0.001). Finally, in vivo experiments suggested adoptive transfer of CD38+ B cells reduced antitumor immunity and administration of a CD38 inhibitor hampered tumor growth (p < 0.001). INTERPRETATION: We discovered regulatory B cell-like CD38+ B cell infiltration as an independent prognostic factor in PDAC. The use of CD38 inhibitor may provide new possibilities for PDAC immunotherapy. FUNDING: This study was supported by the National Natural Science Foundation of China (U21A20374), Shanghai Municipal Science and Technology Major Project (21JC1401500), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Special Project for Clinical Research in the Health Industry of the Shanghai Health Commission (No. 20204Y0265) and Natural Science Foundation of Shanghai (23ZR1479300).


Subject(s)
ADP-ribosyl Cyclase 1 , Carcinoma, Pancreatic Ductal , Humans , ADP-ribosyl Cyclase 1/metabolism , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/therapy , Animals , Mice , Prognosis , Antigens, CD19/metabolism , Antigens, CD19/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/mortality , Female , Male , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Cell Line, Tumor , Tumor Microenvironment/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Middle Aged , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Immunosuppression Therapy
10.
Int J Mol Sci ; 25(8)2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38673941

ABSTRACT

Abdominal aortic aneurysm (AAA) is a serious vascular disease which is associated with vascular remodeling. CD38 is a main NAD+-consuming enzyme in mammals, and our previous results showed that CD38 plays the important roles in many cardiovascular diseases. However, the role of CD38 in AAA has not been explored. Here, we report that smooth-muscle-cell-specific deletion of CD38 (CD38SKO) significantly reduced the morbidity of AngII-induced AAA in CD38SKOApoe-/- mice, which was accompanied with a increases in the aortic diameter, medial thickness, collagen deposition, and elastin degradation of aortas. In addition, CD38SKO significantly suppressed the AngII-induced decreases in α-SMA, SM22α, and MYH11 expression; the increase in Vimentin expression in VSMCs; and the increase in VCAM-1 expression in smooth muscle cells and macrophage infiltration. Furthermore, we demonstrated that the role of CD38SKO in attenuating AAA was associated with the activation of sirtuin signaling pathways. Therefore, we concluded that CD38 plays a pivotal role in AngII-induced AAA through promoting vascular remodeling, suggesting that CD38 may serve as a potential therapeutic target for the prevention of AAA.


Subject(s)
ADP-ribosyl Cyclase 1 , Angiotensin II , Aortic Aneurysm, Abdominal , Mice, Knockout , Myocytes, Smooth Muscle , Vascular Remodeling , Animals , Male , Mice , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/genetics , Aortic Aneurysm, Abdominal/chemically induced , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/pathology , Disease Models, Animal , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Mice, Inbred C57BL , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Myosin Heavy Chains/metabolism , Myosin Heavy Chains/genetics , Signal Transduction , Vascular Remodeling/genetics
11.
Cell Rep ; 43(5): 114102, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38636518

ABSTRACT

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.


Subject(s)
ADP-ribosyl Cyclase 1 , Cellular Senescence , Cholesterol , Liver X Receptors , Macrophages , Mice, Inbred C57BL , NAD , NAD/metabolism , Animals , Liver X Receptors/metabolism , Macrophages/metabolism , Cellular Senescence/drug effects , Cholesterol/metabolism , ADP-ribosyl Cyclase 1/metabolism , ADP-ribosyl Cyclase 1/genetics , Mice , Humans , Macular Degeneration/metabolism , Macular Degeneration/pathology , Lysosomes/metabolism , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Male
12.
Inflamm Res ; 73(5): 739-751, 2024 May.
Article in English | MEDLINE | ID: mdl-38493256

ABSTRACT

OBJECTIVES: Cellular NAD+ declines in inflammatory states associated with increased activity of the leukocyte-expressed NADase CD38. In this study, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. METHODS: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals and used the air pouch gouty inflammation model. RESULTS: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1ß and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 activity in macrophages. BMDM RNA-seq analysis of differentially expressed genes (DEGs) revealed CD38 to control multiple MSU crystal-modulated inflammation pathways. Top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-κB activation when it is overexpressed. CONCLUSIONS: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.


Subject(s)
ADP-ribosyl Cyclase 1 , Inflammation , Macrophages , Mice, Inbred C57BL , Mice, Knockout , NAD , Uric Acid , Animals , ADP-ribosyl Cyclase 1/genetics , ADP-ribosyl Cyclase 1/metabolism , Macrophages/drug effects , Macrophages/metabolism , Inflammation/drug therapy , Mice , NAD/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Male , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Cells, Cultured , Arthritis, Gouty/drug therapy , Arthritis, Gouty/metabolism , Arthritis, Gouty/genetics , Inflammasomes/metabolism , Inflammasomes/drug effects
13.
PLoS Biol ; 22(2): e3002517, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38422172

ABSTRACT

A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs. The state of dormancy protects the HSC pool from exhaustion throughout life; however, excessive dormancy may prevent an efficient response to hematological stresses. Despite the significance of dHSCs, the mechanisms maintaining their dormancy remain elusive. Here, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. We demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing the release of Ca2+ from the endoplasmic reticulum (ER). Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57Kip2 to drive HSC dormancy. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+/c-Fos/p57Kip2 axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease.


Subject(s)
ADP-ribosyl Cyclase 1 , Cyclic ADP-Ribose , Animals , Humans , Mice , Calcium/metabolism , Cyclic ADP-Ribose/metabolism , Hematopoietic Stem Cells , ADP-ribosyl Cyclase 1/metabolism , Cyclin-Dependent Kinase Inhibitor p57/metabolism
14.
Adv Sci (Weinh) ; 11(16): e2308617, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38421139

ABSTRACT

The limited availability of molecularly targeted low-molecular-weight imaging agents for monitoring multiple myeloma (MM)-targeted therapies has been a significant challenge in the field. In response, a first-in-class peptide-based radiotracer, [68Ga]Ga-AJ206, is developed that can be seamlessly integrated into the standard clinical workflow and is specifically designed to noninvasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). A bicyclic peptide, AJ206, is synthesized and exhibits high affinity to CD38 (KD: 19.1 ± 0.99 × 10-9 m) by surface plasmon resonance. Further, [68Ga]Ga-AJ206-PET shows high contrast within 60 min and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detects CD38 expression in cell line-derived xenografts, patient-derived xenografts (PDXs), and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantifies CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following all-trans retinoic acid (ATRA) therapy. In conclusion, [68Ga]Ga-AJ206 exhibits the salient features required for clinical translation, providing CD38-specific high-contrast images in multiple models of MM. [68Ga]Ga-AJ206-PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement.


Subject(s)
ADP-ribosyl Cyclase 1 , Gallium Radioisotopes , Multiple Myeloma , Positron-Emission Tomography , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Multiple Myeloma/diagnostic imaging , Animals , ADP-ribosyl Cyclase 1/metabolism , Mice , Humans , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Disease Models, Animal , Peptides/metabolism , Membrane Glycoproteins/metabolism , Cell Line, Tumor
15.
Blood ; 143(16): 1599-1615, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38394668

ABSTRACT

ABSTRACT: Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-γ-induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-γ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.


Subject(s)
Interferon-gamma , Leukemia, Myeloid, Acute , T-Lymphocytes , Animals , Humans , Mice , ADP-ribosyl Cyclase 1/immunology , ADP-ribosyl Cyclase 1/metabolism , Antigens, CD34/metabolism , Cell Line, Tumor , Hematopoietic Stem Cells/metabolism , Interferon-gamma/drug effects , Interferon-gamma/metabolism , Leukemia, Myeloid, Acute/metabolism , Neoplastic Stem Cells/metabolism , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Lymphocyte Activation/drug effects
16.
Cancer Biol Ther ; 25(1): 2314322, 2024 12 31.
Article in English | MEDLINE | ID: mdl-38361357

ABSTRACT

Multiple myeloma (MM) is an incurable malignancy of the B-cell lineage. Remarkable progress has been made in the treatment of MM with anti-CD38 monoclonal antibodies such as daratumumab and isatuximab, which can kill MM cells by inducing complement-dependent cytotoxicity (CDC). We showed that the CDC efficacy of daratumumab and isatuximab is limited by membrane complement inhibitors, including CD46 and CD59, which are upregulated in MM cells. We recently developed a small recombinant protein, Ad35K++, which is capable of transiently removing CD46 from the cell surface. We also produced a peptide inhibitor of CD59 (rILYd4). In this study, we tested Ad35K++ and rILYd4 in combination with daratumumab and isatuximab in MM cells as well as in cells from two other B-cell malignancies. We showed that Ad35K++ and rILYd4 increased CDC triggered by daratumumab and isatuximab. The combination of both inhibitors had an additive effect in vitro in primary MM cells as well as in vivo in a mouse xenograft model of MM. Daratumumab and isatuximab treatment of MM lines (without Ad35K++ or rILYd4) resulted in the upregulation of CD46/CD59 and/or survival of CD46high/CD59high MM cells that escaped the second round of daratumumab and isatuximab treatment. The escape in the second treatment cycle was prevented by the pretreatment of cells with Ad35K++. Overall, our data demonstrate that Ad35K++ and rILYd4 are efficient co-therapeutics of daratumumab and isatuximab, specifically in multi-cycle treatment regimens, and could be used to improve treatment of multiple myeloma.


Subject(s)
Antineoplastic Agents , Multiple Myeloma , Humans , Mice , Animals , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , ADP-ribosyl Cyclase 1/metabolism , CD59 Antigens/therapeutic use , Membrane Cofactor Protein/metabolism
17.
Cardiovasc Res ; 120(3): 286-300, 2024 03 14.
Article in English | MEDLINE | ID: mdl-38271281

ABSTRACT

AIMS: Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. METHODS AND RESULTS: Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. CONCLUSION: NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.


Subject(s)
NAD+ Nucleosidase , NAD , Mice , Animals , NAD+ Nucleosidase/metabolism , ADP-ribosyl Cyclase 1/genetics , ADP-ribosyl Cyclase 1/metabolism , NAD/metabolism , Cardiotoxicity , Mice, Transgenic , Doxorubicin/toxicity , Inflammation , Mammals/metabolism
18.
Hum Mol Genet ; 33(7): 594-611, 2024 Mar 20.
Article in English | MEDLINE | ID: mdl-38181046

ABSTRACT

Duchenne muscular dystrophy (DMD) is a lethal degenerative muscle wasting disease caused by the loss of the structural protein dystrophin with secondary pathological manifestations including metabolic dysfunction, mood and behavioral disorders. In the mildly affected mdx mouse model of DMD, brief scruff stress causes inactivity, while more severe subordination stress results in lethality. Here, we investigated the kynurenine pathway of tryptophan degradation and the nicotinamide adenine dinucleotide (NAD+) metabolic pathway in mdx mice and their involvement as possible mediators of mdx stress-related pathology. We identified downregulation of the kynurenic acid shunt, a neuroprotective branch of the kynurenine pathway, in mdx skeletal muscle associated with attenuated peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) transcriptional regulatory activity. Restoring the kynurenic acid shunt by skeletal muscle-specific PGC-1α overexpression in mdx mice did not prevent scruff -induced inactivity, nor did abrogating extrahepatic kynurenine pathway activity by genetic deletion of the pathway rate-limiting enzyme, indoleamine oxygenase 1. We further show that reduced NAD+ production in mdx skeletal muscle after subordination stress exposure corresponded with elevated levels of NAD+ catabolites produced by ectoenzyme cluster of differentiation 38 (CD38) that have been implicated in lethal mdx response to pharmacological ß-adrenergic receptor agonism. However, genetic CD38 ablation did not prevent mdx scruff-induced inactivity. Our data do not support a direct contribution by the kynurenine pathway or CD38 metabolic dysfunction to the exaggerated stress response of mdx mice.


Subject(s)
ADP-ribosyl Cyclase 1 , Indoleamine-Pyrrole 2,3,-Dioxygenase , Membrane Glycoproteins , Muscular Dystrophy, Duchenne , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Animals , Mice , Disease Models, Animal , Kynurenic Acid/metabolism , Kynurenine/metabolism , Mice, Inbred mdx , Muscle, Skeletal/metabolism , Muscular Dystrophy, Duchenne/pathology , NAD/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Membrane Glycoproteins/metabolism , ADP-ribosyl Cyclase 1/metabolism
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