RESUMEN

Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1ß, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.

Asunto(s)

Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Células Dendríticas , Rechazo de Injerto , Trasplante de Corazón , Inmunidad Innata , Inflamación , Animales , Rechazo de Injerto/inmunología , Ratones , Células Dendríticas/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Inflamación/inmunología , Inmunidad Innata/inmunología , Ratones Endogámicos C57BL , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Células T de Memoria/inmunología , Ratones Noqueados , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Citocinas/metabolismo , Citocinas/inmunología

RESUMEN

During coronary artery bypass grafting (CABG), the surgical procedure, particularly the manipulation of the major arteries of the heart, induces a significant inflammatory state that may compromise platelet function to the extent that platelet transfusion is required. Given stored platelets as a major source of biological mediators, this study investigates the effects of platelet transfusion on the major pro-aggregatory, pro-inflammatory and immunomodulatory markers of platelets. Platelets from 20 patients, 10 who received platelet transfusion and 10 without, were subjected to flow cytometery where P-selectin and CD40 ligand (CD40L) expressions and PAC-1 binding (activation-specific anti GPIIb/GPIIIa antibody) analysed at five-time points of 24 h before surgery, immediately, 2 h, 24 h and 1 week after surgery. Analysis of intra-platelet transforming growth factor-beta-1 (TGF-ß1) was also conducted using western blotting. Patients with platelet transfusion showed increased levels of P-selectin, CD40L and intra-platelet TGF-ß1 2-h after surgery compared to those without transfusion (p < 0.05). PAC-1 binding was increased 24 h after surgery in transfused patients (p < 0.05). Given the significant post-transfusion elevation of platelet TGF-ß1, P-sel/CD40L reduction in transfused patients a week after was of much interest. This study showed for the first time the significant effects of platelet transfusion on the pro-inflammatory, pro-aggeregatory and immunomodulatory state of platelets in CABG patients, which manifested with immediate, midterm and delayed consequences. While the increased pro-inflammatory conditions manifested as an immediate effect of platelet transfusion, the pro-aggregatory circumstances emerged 24 h post-transfusion. A week after surgery, attenuations of pro-inflammatory markers of platelets in transfused patients were shown, which might be due to the immunomodulatory effects of TGF-ß1.

Asunto(s)

Plaquetas , Ligando de CD40 , Puente de Arteria Coronaria , Selectina-P , Transfusión de Plaquetas , Humanos , Puente de Arteria Coronaria/efectos adversos , Plaquetas/metabolismo , Masculino , Femenino , Selectina-P/sangre , Selectina-P/metabolismo , Persona de Mediana Edad , Ligando de CD40/sangre , Ligando de CD40/metabolismo , Anciano , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/metabolismo , Inflamación/sangre , Agregación Plaquetaria

RESUMEN

Cancer remains a significant challenge in medicine due to its complexity and heterogeneity. Biomarkers have emerged as vital tools for cancer research and clinical practice, facilitating early detection, prognosis assessment, and treatment monitoring. Among these, CD40 ligand (CD40L) has gained attention for its role in immune response modulation. Soluble CD40 ligand (sCD40L) has shown promise as a potential biomarker in cancer diagnosis and progression, reflecting interactions between immune cells and the tumor microenvironment. This review explores the intricate relationship between sCD40L and cancer, highlighting its diagnostic and prognostic potential. It discusses biomarker discovery, emphasizing the need for reliable markers in oncology, and elucidates the roles of CD40L in inflammatory responses and interactions with tumor cells. Additionally, it examines sCD40L as a biomarker, detailing its significance across various cancer types and clinical applications. Moreover, the review focuses on therapeutic interventions targeting CD40L in malignancies, providing insights into cellular and gene therapy approaches and recombinant protein-based strategies. The clinical effectiveness of CD40L-targeted therapy is evaluated, underscoring the need for further research to unlock the full potential of this signaling pathway in cancer management.

Asunto(s)

Biomarcadores de Tumor , Ligando de CD40 , Neoplasias , Humanos , Ligando de CD40/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/inmunología , Biomarcadores de Tumor/metabolismo , Animales , Pronóstico , Microambiente Tumoral/inmunología

RESUMEN

Discovered 30 years ago, CD40L antagonists are proving to be powerful autoimmune drugs.

Asunto(s)

Enfermedades Autoinmunes , Autoinmunidad , Ligando de CD40 , Animales , Humanos , Ratones , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Autoinmunidad/efectos de los fármacos , Ligando de CD40/antagonistas & inhibidores

RESUMEN

Memory B cells (mBCs) are characterized by their long-term stability, fast reactivation, and capability to rapidly differentiate into antibody-secreting cells (ASCs). However, the role of T cells in the differentiation of mBCs, in contrast to naive B cells, remains to be delineated. We study the role of T cells in mBC responses, using CD40L stimulation and autologous T-B co-cultures. Our results showed that increased CD40L levels led to a selective increased proliferation of IgM+ mBC, which did not class-switched, resulting in higher frequencies of IgM+ ASCs and a lower frequency of IgG+ ASCs. The IgG+/IgA+ mBCs were unaffected. We further compared the transcription of immune-related genes in IgM+ and IgG+ pre-plasmablasts cultured at high (500 ng/mL) and low (50 ng/mL) CD40L levels. In response to increased CD40L levels, both populations exhibited a core response to genes related to activation (TRAF1, AKT3, CD69, and CD80). However, they differed in genes related to cytokine/chemokine/homing interactions (CCL3/4/17, LTA, NKX2-3, BCL2 and IL21R) and cell-cell interactions (HLADR, CD40, and ICOSL), which were largely confined to IgG+ cells. Our findings revealed that in co-cultures with a high T-ratio, the response was similar to that found in cultures with high CD40L levels. These results suggest that IgG+ mBCs have a greater capacity for proliferation and T cell interaction, and weaker migration capabilities, leading to a preference for an IgG response over IgM in the short term. This adaptable response could fine-tune the memory repertoire with different functions of IgG versus IgM mBCs.

Asunto(s)

Ligando de CD40 , Inmunoglobulina G , Inmunoglobulina M , Células B de Memoria , Linfocitos T , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Humanos , Inmunoglobulina M/inmunología , Inmunoglobulina M/metabolismo , Inmunoglobulina G/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células B de Memoria/inmunología , Células B de Memoria/metabolismo , Comunicación Celular/inmunología , Técnicas de Cocultivo , Memoria Inmunológica , Activación de Linfocitos/inmunología , Células Cultivadas , Diferenciación Celular/inmunología , Proliferación Celular

RESUMEN

Hypertension causes platelet activation and adhesion in the brain resulting in glial activation and neuroinflammation. Further, activation of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR) axis of central Renin-Angiotensin System (RAS), is known to reduce glial activation and neuroinflammation, thereby exhibiting anti-hypertensive and anti-neuroinflammatory properties. Therefore, in the present study, the role of ACE2/Ang (1-7)/MasR axis was studied on platelet-induced glial activation and neuroinflammation using Diminazene Aceturate (DIZE), an ACE2 activator, in astrocytes and microglial cells as well as in rat model of hypertension. We found that the ACE2 activator DIZE, independently of its BP-lowering properties, efficiently prevented hypertension-induced glial activation, neuroinflammation, and platelet CD40-CD40L signaling via upregulation of ACE2/Ang (1-7)/MasR axis. Further, DIZE decreased platelet deposition in the brain by reducing the expression of adhesion molecules on the brain endothelium. Activation of ACE2 also reduced hypertension-induced endothelial dysfunction by increasing eNOS bioavailability. Interestingly, platelets isolated from hypertensive rats or activated with ADP had significantly increased sCD40L levels and induced significantly more glial activation than platelets from DIZE treated group. Therefore, injection of DIZE pre-treated ADP-activated platelets into normotensive rats strongly reduced glial activation compared to ADP-treated platelets. Moreover, CD40L-induced glial activation, CD40 expression, and NFкB-NLRP3 inflammatory signaling are reversed by DIZE. Furthermore, the beneficial effects of ACE2 activation, DIZE was found to be significantly blocked by MLN4760 (ACE2 inhibitor) as well as A779 (MasR antagonist) treatments. Hence, our study demonstrated that ACE2 activation reduced the platelet CD40-CD40L induced glial activation and neuroinflammation, hence imparted neuroprotection.

Asunto(s)

Enzima Convertidora de Angiotensina 2 , Ligando de CD40 , Diminazeno , Modelos Animales de Enfermedad , Hipertensión , Peptidil-Dipeptidasa A , Transducción de Señal , Animales , Diminazeno/análogos & derivados , Diminazeno/farmacología , Diminazeno/uso terapéutico , Enzima Convertidora de Angiotensina 2/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Ligando de CD40/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Ratas , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Proto-Oncogenes Mas , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Fragmentos de Péptidos , Angiotensina I , Células Cultivadas , Microglía/efectos de los fármacos , Microglía/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Antígenos CD40/metabolismo , Humanos , Activación Plaquetaria/efectos de los fármacos , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico

RESUMEN

Several in vitro models have been developed to mimic chronic lymphocytic leukemia (CLL) proliferation in immune niches; however, they typically do not induce robust proliferation. We prepared a novel model based on mimicking T-cell signals in vitro and in patient-derived xenografts (PDXs). Six supportive cell lines were prepared by engineering HS5 stromal cells with stable expression of human CD40L, IL4, IL21, and their combinations. Co-culture with HS5 expressing CD40L and IL4 in combination led to mild CLL cell proliferation (median 7% at day 7), while the HS5 expressing CD40L, IL4, and IL21 led to unprecedented proliferation rate (median 44%). The co-cultures mimicked the gene expression fingerprint of lymph node CLL cells (MYC, NFκB, and E2F signatures) and revealed novel vulnerabilities in CLL-T-cell-induced proliferation. Drug testing in co-cultures revealed for the first time that pan-RAF inhibitors fully block CLL proliferation. The co-culture model can be downscaled to five microliter volume for large drug screening purposes or upscaled to CLL PDXs by HS5-CD40L-IL4 ± IL21 co-transplantation. Co-transplanting NSG mice with purified CLL cells and HS5-CD40L-IL4 or HS5-CD40L-IL4-IL21 cells on collagen-based scaffold led to 47% or 82% engraftment efficacy, respectively, with ~20% of PDXs being clonally related to CLL, potentially overcoming the need to co-transplant autologous T-cells in PDXs.

Asunto(s)

Ligando de CD40 , Proliferación Celular , Técnicas de Cocultivo , Leucemia Linfocítica Crónica de Células B , Células del Estroma , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Animales , Ratones , Células del Estroma/metabolismo , Células del Estroma/patología , Ligando de CD40/metabolismo , Ligando de CD40/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Interleucinas/genética , Interleucinas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología

RESUMEN

Dendritic cells (DCs) have been intensively studied in correlation to tumor immunology and for the development DC-based cancer vaccines. Here, we present the significance of the temporal aspect of DC maturation for the most essential subsequent timepoint, namely at interaction with responding T cells or after CD40-Ligand restimulation. Mostly, DC maturation is still being achieved by activation processes which lasts 24 h to 48 h. We hypothesized this amount of time is excessive from a biological standpoint and could be the underlying cause for functional exhaustion. Indeed, shorter maturation periods resulted in extensive capacity of monocyte-derived DCs to produce inflammatory cytokines after re-stimulation with CD40-Ligand. This effect was most evident for the primary type 1 polarizing cytokine, IL-12p70. This capacity reached peak at 6 h and dropped sharply with longer exposure to initial maturation stimuli (up to 48 h). The 6 h maturation protocol reflected superiority in subsequent functionality tests. Namely, DCs displayed twice the allostimulatory capacity of 24 h- and 48 h-matured DCs. Similarly, type 1 T cell response measured by IFN-γ production was 3-fold higher when CD4+ T cells had been stimulated with shortly matured DC and over 8-fold greater in case of CD8+ T cells, compared to longer matured DCs. The extent of melanoma-specific CD8+ cytotoxic T cell induction was also greater in case of 6 h DC maturation. The major limitation of the study is that it lacks in vivo evidence, which we aim to examine in the future. Our findings show an unexpectedly significant impact of temporal exposure to activation signals for subsequent DC functionality, which we believe can be readily integrated into existing knowledge on in vitro/ex vivo DC manipulation for various uses. We also believe this has important implications for DC vaccine design for future clinical trials.

Asunto(s)

Diferenciación Celular , Citocinas , Células Dendríticas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Citocinas/metabolismo , Factores de Tiempo , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Ligando de CD40/metabolismo , Linfocitos T CD8-positivos/inmunología

RESUMEN

When the membrane protein CD40 ligand (CD40L) on activated T cells binds the receptor CD40 on B-cells, it provides a co-stimulatory signal for B cell activation. Dysregulation of the CD40L:CD40 axis is associated with inflammatory and autoimmune diseases. The presence of soluble CD40L (sCD40L) in plasma is implicated in several diseases, from cardiovascular and autoimmune diseases to different types of cancer, and sCD40L has been suggested as a valuable marker of disease. If sCD40L is to be used as a biomarker, being able to precisely measure and quantify the levels of sCD40L in human blood samples is of utmost importance. We demonstrate the development of a sandwich-type time-resolved immunofluorometric assay for quantification of sCD40L in plasma or serum samples. For this, we generate 29 monoclonal anti-CD40L antibodies, and from these, we select the optimal combination of capture antibody and detection antibody. A number of variables were tested: the influence of the type of sample (comparing 3 different blood collection tubes for serum sampling and 4 different types of tubes for plasma sampling), the influence of freeze-thaw cycles, the influence of sampling time during night and day, and the influence of centrifugation of the samples. We found a very similar level of sCD40L in paired EDTA plasma and serum samples. Out of 100 healthy blood donor samples 61 had a level of sCD40L below the detection level of the assay, whereas the remaining 39 samples had ranging levels of sCD40L from 1.14 to 33.14 ng/mL. In summary, we present a time-resolved immunofluorometric assay based on paired monoclonal antibodies, ensuring high specificity, sensitivity, and homogeneity. The Eu3+-based assay additionally provides consistent assay readouts due to the extended decay time not seen in standard enzyme-linked immunosorbent assays. The assay paves the way for specific and consistent quantification of sCD40L in human plasma and serum samples.

Asunto(s)

Ligando de CD40 , Humanos , Ligando de CD40/sangre , Biomarcadores/sangre , Anticuerpos Monoclonales/inmunología , Fluoroinmunoensayo/métodos , Reproducibilidad de los Resultados

RESUMEN

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

Asunto(s)

Ligando de CD40 , Síndrome de Sjögren , Humanos , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/tratamiento farmacológico , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/inmunología , Método Doble Ciego , Femenino , Persona de Mediana Edad , Masculino , Adulto , Anciano , Resultado del Tratamiento

RESUMEN

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Asunto(s)

Linfocitos T CD4-Positivos , Ligando de CD40 , Pulmón , Células B de Memoria , Streptococcus pneumoniae , Animales , Ratones , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Quimiocina CXCL13/metabolismo , Modelos Animales de Enfermedad , Memoria Inmunológica , Pulmón/inmunología , Células B de Memoria/inmunología , Células B de Memoria/metabolismo , Ratones Endogámicos C57BL , Infecciones Neumocócicas/inmunología , Transducción de Señal , Streptococcus pneumoniae/inmunología

RESUMEN

Soluble components secreted by Tfh cells are critical for the germinal center responses. In this study, we investigated whether Tfh cells could regulate the B-cell response by releasing small extracellular vesicles (sEVs). Our results showed that Tfh cells promote B-cell differentiation and antibody production through sEVs and that CD40L plays a crucial role in Tfh-sEVs function. In addition, increased Tfh-sEVs were found in mice with collagen-induced arthritis (CIA). Adoptive transfer of Tfh cells significantly exacerbated the severity of CIA; however, the effect of Tfh cells on exacerbating the CIA process was significantly diminished after inhibiting sEVs secretion. Moreover, the levels of plasma Tfh-like-sEVs and CD40L expression on Tfh-like-sEVs in RA patients were significantly higher than those in healthy subjects. In summary, Tfh cell-derived sEVs can enhance the B-cell response, and exacerbate the procession of autoimmune arthritis.

Asunto(s)

Artritis Experimental , Linfocitos B , Vesículas Extracelulares , Células T Auxiliares Foliculares , Animales , Artritis Experimental/inmunología , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , Humanos , Células T Auxiliares Foliculares/inmunología , Masculino , Artritis Reumatoide/inmunología , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Traslado Adoptivo , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Índice de Severidad de la Enfermedad , Femenino

RESUMEN

INTRODUCTION: Here, we explored methods to generate anti-tumor bone marrow-derived macrophages (BMDM) and how delivery of the BMDM at early tumor sites could impact disease progression. METHODS: BMDM treated with IFN-γ, sCD40L, poly(I:C), and a combination of the three were assessed. RESULTS: Treatment with sCD40L had no significant impact on the BMDM. Treating BMDM with IFN-γ impacted IL-1ß, MHC Class II, and CD80 expression. While poly(I:C) treatment had a greater impact on the BMDM than IFN-γ when assessed by the in vitro assays, the BMDM treated with poly (I:C) had mixed results in vivo where they decreased growth of the EMT6 tumor, did not impact growth of the 168 tumor, and enhanced growth of the 4T1 tumor. The combination of poly(I:C), IFN-γ, and sCD40L had the greatest impact on the BMDM in vitro and in vivo. Treatment with all three agonists resulted in increased IL-1ß, TNF-α, and IL-12 expression, decreased expression of arginase and mrc, increased phagocytic activity, nitrite production, and MHC Class II and CD80 expression, and significantly impacted growth of the EMT6 and 168 murine mammary carcinoma models. DISCUSSION: Collectively, these data show that treating BMDM with poly(I:C), IFN-γ, and sCD40L generates BMDM with more consistent anti-tumor activity than BMDM generated with the individual agonists.

Asunto(s)

Ligando de CD40 , Interferón gamma , Macrófagos , Poli I-C , Animales , Femenino , Ratones , Antígeno B7-1/metabolismo , Ligando de CD40/farmacología , Línea Celular Tumoral , Citocinas/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Interferón gamma/metabolismo , Interferón gamma/farmacología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Ratones Endogámicos BALB C , Poli I-C/farmacología

RESUMEN

X-linked hyper-immunoglobulin M (X-HIGM) syndrome and autosomal recessive hyper-immunoglobulin E syndrome (HIES) are rare inborn errors of immunity characterized by recurrent infections due to immune system impairment. In this study, we identified a novel hemizygous CD40 ligand (CD40L) mutation and compound heterozygous dedicator of cytokinesis-8 (DOCK8) mutations in two Han Chinese families with X-HIGM and HIES, respectively. We aimed to investigate the association between their genotypes and phenotypes. Genomic DNA was extracted from peripheral blood samples obtained from the families. Whole exome sequencing and Sanger sequencing were performed to identify and verify pathogenic variants in the two families. Clinical analyses of the probands were also performed. A novel hemizygous mutation of CD40L in exon 2 (c.257delA) was identified in the first proband, resulting in the substitution of glycine with glutamic acid at codon 86 of the protein. This leads to premature termination of translation at downstream codon 9 (p.E86Gfs*9). Sanger sequencing confirmed that the variant was inherited from the mother. The second proband carried two novel compound heterozygous mutations in DOCK8: one at exon 14 (c.1546C > G) inherited from the father, and the other at intron 41 (c.5355 + 6C > T; splicing) inherited from the mother. This study enhances our understanding of the pathogenetic mutation spectrum of CD40L and DOCK8 genes, facilitating the prenatal diagnosis of X-HIGM and HIES and enabling timely treatment of patients.

Asunto(s)

Ligando de CD40 , Factores de Intercambio de Guanina Nucleótido , Heterocigoto , Mutación , Linaje , Niño , Preescolar , Femenino , Humanos , Masculino , Pueblo Asiatico/genética , Ligando de CD40/genética , China , Pueblos del Este de Asia , Secuenciación del Exoma , Factores de Intercambio de Guanina Nucleótido/genética , Síndrome de Inmunodeficiencia con Hiper-IgM Tipo 1/genética , Síndrome de Job/genética

RESUMEN

The interaction between CD40 and CD40 ligand (CD40L) a crucial co-stimulatory signal for activating adaptive immune cells, has a noteworthy role in atherosclerosis. It is well-known that atherosclerosis is linked to immune inflammation in blood vessels. In atherosclerotic lesions, there is a multitude of proinflammatory cytokines, adhesion molecules, and collagen, as well as smooth muscle cells, macrophages, and T lymphocytes, particularly the binding of CD40 and CD40L. Therefore, research on inhibiting the CD40-CD40L system to prevent atherosclerosis has been ongoing for more than 30 years. However, it's essential to note that long-term direct suppression of CD40 or CD40L could potentially result in immunosuppression, emphasizing the critical role of the CD40-CD40L system in atherosclerosis. Thus, specifically targeting the CD40-CD40L interaction on particular cell types or their downstream signaling pathways may be a robust strategy for mitigating atherosclerosis, reducing potential side effects. This review aims to summarize the potential utility of the CD40-CD40L system as a viable therapeutic target for atherosclerosis.

Asunto(s)

Aterosclerosis , Ligando de CD40 , Humanos , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/metabolismo , Ligando de CD40/antagonistas & inhibidores , Ligando de CD40/metabolismo , Citocinas/metabolismo , Interleucina-2/metabolismo , Macrófagos/metabolismo

RESUMEN

CD40 and its ligand have been recently implicated in the pathogenesis of cardiovascular disease (CVD). This meta-analysis examined the effect of bariatric surgery in reducing circulating CD40L levels. A systematic review was performed using Embase, Google Scholar, PubMed, Scopus, and Web of Science. The meta-analysis was provided by Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was detected by a random-effects meta-analysis and the leave-one-out approach. Random-effects meta-analysis of 7 studies including 191 subjects showed a significant reduction in CD40L after bariatric surgery (standardized mean difference (SMD), - 0.531; 95% CI, - 0.981, - 0.082; p = 0.021; I2, 87.00). Circulating levels of CD40L are decreased after bariatric surgery which may represent a mechanism for improvement of metabolic profile.

Asunto(s)

Cirugía Bariátrica , Enfermedades Cardiovasculares , Obesidad Mórbida , Humanos , Ligando de CD40 , Obesidad Mórbida/cirugía , Factores de Riesgo , Factores de Riesgo de Enfermedad Cardiaca

RESUMEN

CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the CD40 ligand (CD40L) plays an essential function in signaling, and the CD40/CD40L complex works as an immune checkpoint molecule. CD40 has become a therapeutic target, and a variety of agonistic/antagonistic anti-CD40 monoclonal antibodies (mAbs) have been developed. To better understand the mode of action of anti-CD40 mAbs, we determined the X-ray crystal structures of dacetuzumab (agonist) and bleselumab (antagonist) in complex with the extracellular domain of human CD40, respectively. The structure reveals that dacetuzumab binds to CD40 on the top of cysteine-rich domain 1 (CRD1), which is the domain most distant from the cell surface, and it does not compete with CD40L binding. The binding interface of bleselumab spread between CRD2 and CRD1, overlapping with the binding surface of the ligand. Our results offer important insights for future structural and functional studies of CD40 and provide clues to understanding the mechanism of biological response. These data can be applied to developing new strategies for designing antibodies with more therapeutic efficacy.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Antígenos CD40 , Humanos , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/inmunología , Sitios de Unión , Antígenos CD40/química , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Ligando de CD40/química , Ligando de CD40/metabolismo , Ligando de CD40/inmunología , Cristalografía por Rayos X , Modelos Moleculares , Unión Proteica , Conformación Proteica

Asunto(s)

Ligando de CD40 , Trasplante de Órganos , Humanos , Ligando de CD40/inmunología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología

RESUMEN

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

Asunto(s)

Supervivencia de Injerto , Riñón , Animales , Humanos , Porcinos , Trasplante Heterólogo/métodos , Xenoinjertos , Terapia de Inmunosupresión/métodos , Ligando de CD40 , Antígenos CD40 , Rechazo de Injerto

RESUMEN

This study demonstrates the effect of nitrogen doping on the surface state densities (Nss) of monolayer MoS2 and its effect on the responsivity and the response time of the photodetector. Our experimental results shows that by doping monolayer MoS2 by nitrogen, the surface state (Nss) increases thereby increasing responsivity. The mathematical model included in the paper supports the relation of photocurrent gain and its dependency on trap level which states that the increasing the trap density increases the photocurrent gain and the same is observed experimentally. The experimental results at room temperature revealed that nitrogen doped MoS2 have a high NSS of 1.63 X 1013 states/m2/eV compared to undoped MoS2 of 4.2 x 1012 states/m2/eV. The increase in Nss in turn is the cause for rise in trap states which eventually increases the value of photo responsivity from 65.12 A/W (undoped MoS2) to 606.3 A/W (nitrogen doped MoS2). The response time calculated for undoped MoS2 was 0.85 sec and for doped MoS2 was 0.35 sec. Finally, to verify the dependence of surface states on the responsivity, the surface states were varied by varying temperature and it was observed that upon increment in temperature, the surface states decreases which causes the responsivity values also to decrease.

Asunto(s)

Ligando de CD40 , Molibdeno , Ingeniería , Nitrógeno , Tiempo de Reacción