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1.
Indian J Hematol Blood Transfus ; 40(2): 335-339, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38708152

RESUMEN

To assess the incidence of anti-HLA donor-specific antibodies and the effectiveness of desensitization strategy in children who underwent haploidentical HSCT at our hospital. A retrospective review, management and outcomes of children with positive anti-HLA DSA who underwent haploidentical HSCT at our hospital from 2020 to 2022. Three patients with Thalassemia major were treated with 2 cycles of pretransplant immune suppression (PTIS) comprising Fludarabine and Dexamethasone in addition to desensitization. Five out of the 26 children who underwent haploidentical HSCT had positive anti-HLA DSA. Post desensitization, three out of the 5 children engrafted with sustained full donor chimerism, 1 patient developed primary graft rejection, while 1 patient died. It is feasible to desensitize children with high anti-HLA donor specific antibodies undergoing haploidentical HSCT to improve outcomes.

2.
Adv Healthc Mater ; : e2401270, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38801164

RESUMEN

Current immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll-like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid-derived suppressor cells (MDSCs) and tumor-associated M2 macrophages, and boost dendritic cell (DC)-based T-cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two-step activation strategy via Antibody-Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti-SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody-mediated endocytosis. ATICC blocks the CD47-SIRPα ("don't eat me" signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs, and increases cross-presentation by DCs, resulting in antigen-specific CD8+ T-cell generation in tumor-draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen-specific CD8+ T cells, and antibody-dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities.

3.
J Transl Med ; 22(1): 452, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38741166

RESUMEN

Extracellular vesicles (EVs) are lipid bilayer structures released by all cells and widely distributed in all biological fluids. EVs are implicated in diverse physiopathological processes by orchestrating cell-cell communication. Colorectal cancer (CRC) is one of the most common cancers worldwide, with metastasis being the leading cause of mortality in CRC patients. EVs contribute significantly to the advancement and spread of CRC by transferring their cargo, which includes lipids, proteins, RNAs, and DNAs, to neighboring or distant cells. Besides, they can serve as non-invasive diagnostic and prognostic biomarkers for early detection of CRC or be harnessed as effective carriers for delivering therapeutic agents. Autophagy is an essential cellular process that serves to remove damaged proteins and organelles by lysosomal degradation to maintain cellular homeostasis. Autophagy and EV release are coordinately activated in tumor cells and share common factors and regulatory mechanisms. Although the significance of autophagy and EVs in cancer is well established, the exact mechanism of their interplay in tumor development is obscure. This review focuses on examining the specific functions of EVs in various aspects of CRC, including progression, metastasis, immune regulation, and therapy resistance. Further, we overview emerging discoveries relevant to autophagy and EVs crosstalk in CRC.


Asunto(s)
Autofagia , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Vesículas Extracelulares , Metástasis de la Neoplasia , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/inmunología , Vesículas Extracelulares/metabolismo , Animales , Terapia de Inmunosupresión
4.
Transplant Cell Ther ; 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38740138

RESUMEN

BACKGROUND: Allogeneic stem cell transplantation (alloSCT) offers curative potential for older patients with myeloid malignancies. We evaluated the efficacy and safety of alloSCT using post-transplantation cyclophosphamide (PTCy) in combination with a very short duration of immune suppression (IS) in this population. METHODS: We retrospectively analyzed 92 consecutive patients aged 65 years and older who underwent an alloSCT for myeloid malignancies between February 2018 and December 2022 at our institution. Data on patient characteristics, treatment modalities, and outcomes were collected. RESULTS: Ninety-two patients received an alloSCT with PTCy-based GVHD prophylaxis. The majority had minimal comorbidities and were diagnosed with acute myeloid leukemia (AML). Patients mostly received conditioning regimens with low to intermediate TCI scores. In 43% of patients, IS could be permanently stopped at day +90, resulting in a median time of IS of 2.93 months in high-risk patients. At a median follow-up of 21.3 months, the 1- and 2-year overall survival rates were 89% and 87%, respectively. Relapse-free survival rates were 88% and 84% at 1 and 2 years, respectively. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while transplant-related mortality (TRM) estimates were 9% at both time points. Acute GVHD grade 3-4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year graft versus host and relapse free survival (GRFS) of 74% and 70%, respectively. CONCLUSION: AlloSCT using PTCy in combination with a short duration of IS in older patients with myeloid malignancies demonstrates favorable survival outcomes due to low relapse rates and a low TRM. The low incidence of relapse and acceptable rates of graft-versus-host disease suggest the efficacy and safety of this approach. Further studies are warranted to validate these findings and optimize transplant strategies for older patients with myeloid malignancies.

5.
Acta Pharm Sin B ; 14(5): 1951-1964, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38799637

RESUMEN

Adenosine (Ado) is significantly elevated in the tumor microenvironment (TME) compared to normal tissues. It binds to adenosine receptors (AdoRs), suppressing tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors on dendritic cells (DCs) and macrophages, inhibiting antigen presentation. It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor (TCR) binding and signal transduction. Ado also inhibits chemokine secretion and KCa3.1 channel activity, impeding effector T cell trafficking and infiltration into the tumor site. Furthermore, Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion, upregulating immune checkpoint proteins, and enhancing immune-suppressive cell activity. Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies. Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

6.
Am J Cancer Res ; 14(4): 1850-1865, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38726266

RESUMEN

Chronic inflammation associated with lung cancers contributes to immunosuppressive tumor microenvironments, reducing CD8+ T-cell function and leading to poor patient outcomes. A disintegrin and metalloprotease domain 9 (ADAM9) promotes cancer progression. Here, we aim to elucidate the role of ADAM9 in the immunosuppressive tumor microenvironment. A bioinformatic analysis of TIMER2.0 was used to investigate the correlation of ADAM9 and to infiltrate immune cells in the human lung cancer database and mouse lung tumor samples. Flow cytometry, immunohistochemistry, and RNA sequencing (RNA-seq) were performed to investigate the ADAM9-mediated immunosuppressive microenvironment. The coculture system of lung cancer cells with immune cells, cytokine array assays, and proteomic approach was used to investigate the mechanism. By analyzing the human LUAD database and the mouse lung cancer models, we showed that ADAM9 was associated with the immunosuppressive microenvironment. Additionally, ADAM9 released IL6 protein from cancer cells to inhibit IL12p40 secretion from dendritic cells, therefore leading to dendritic cell dysfunction and further affecting T-cell functions. Proteomic analysis indicated that ADAM9 promoted cholesterol biosynthesis and increased IL6-STAT3 signaling. Mechanistically, ADAM9 reduced the protein stability of LDLR, resulting in reduced cholesterol uptake and induced cholesterol biosynthesis. Moreover, LDLR reduction enhanced IL6-STAT3 activation. We reveal that ADAM9 has a novel biological function that drives the immunosuppressive tumor microenvironment by linking lung cancer's metabolic and signaling axes. Thus, by targeting ADAM9 an innovative and promising therapeutic opportunity was indicated for regulating the immunosuppression of lung cancer.

7.
Front Cell Dev Biol ; 12: 1387198, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38726320

RESUMEN

Tumor-associated endothelial cells (TECs) are crucial mediators of immune surveillance and immune escape in the tumor microenvironment (TME). TECs driven by angiogenic growth factors form an abnormal vasculature which deploys molecular machinery to selectively promote the function and recruitment of immunosuppressive cells while simultaneously blocking the entry and function of anti-tumor immune cells. TECs also utilize a similar set of signaling regulators to promote the metastasis of tumor cells. Meanwhile, the tumor-infiltrating immune cells further induce the TEC anergy by secreting pro-angiogenic factors and prevents further immune cell penetration into the TME. Understanding the complex interactions between TECs and immune cells will be needed to successfully treat cancer patients with combined therapy to achieve vasculature normalization while augmenting antitumor immunity. In this review, we will discuss what is known about the signaling crosstalk between TECs and tumor-infiltrating immune cells to reveal insights and strategies for therapeutic targeting.

8.
Heliyon ; 10(9): e29795, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38765174

RESUMEN

This research investigated the impacts of lycium barbarum polysaccharide (LBP) on the digestive function, intestinal mucosal barrier function, inflammatory response, and myosin light chain kinase (MLCK) signaling pathway in immunosuppressed mice. 70 mg/kg cyclophosphamide was injected into abdomen for the preparation of immune suppression model. Healthy BALB/c mice served as control for the analysis of the differences in gastrointestinal motility and absorptive capacity, intestinal mucosal barrier function, the phagocytic ability of abdominal macrophages, serum immune factor and inflammatory factor levels, and the activation status of the MLCK signaling pathway after continuous gavage with 100 mg/kg LBP. Results revealed a decrease in d-xylose content, phagocytic rate, index of abdominal macrophages, and spleen index in the serum and urine of model mice compared to those of controls. In addition, levels of IgA, IgG, IgM, IL-6 (interleukin-6), IL-12, and interferon-γ (IFN-γ) decreased, while MLCK and myosin light chain (MLC) levels rose (P < 0.01). Versus those in Model group, urine d-xylose content, phagocytic rate, index of abdominal macrophages, spleen index, and the levels of IgA, IgG, IgM, IL-6, IL-12, and IFN-γ of mice undergoing the gavage with LBP increased, while MLCK and p-MLC levels declined (P < 0.05). In conclusion, LBP improved digestive absorption and immune function of immunosuppressed mice and regulated intestinal mucosal barrier immune system by inhibiting MLCK signaling pathway activation.

9.
Biomedicines ; 12(4)2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38672174

RESUMEN

The presence of an immunosuppressive tumour microenvironment in oesophageal adenocarcinoma (OAC) is a major contributor to poor responses. Novel treatment strategies are required to supplement current regimens and improve patient survival. This study examined the immunomodulatory effects that radiation therapy and chemokine receptor antagonism impose on T cell phenotypes in OAC with a primary goal of identifying potential therapeutic targets to combine with radiation to improve anti-tumour responses. Compared with healthy controls, anti-tumour T cell function was impaired in OAC patients, demonstrated by lower IFN-γ production by CD4+ T helper cells and lower CD8+ T cell cytotoxic potential. Such diminished T cell effector functions were enhanced following treatment with clinically relevant doses of irradiation. Interestingly, CCR5+ T cells were significantly more abundant in OAC patient blood compared with healthy controls, and CCR5 surface expression by T cells was further enhanced by clinically relevant doses of irradiation. Moreover, irradiation enhanced T cell migration towards OAC patient-derived tumour-conditioned media (TCM). In vitro treatment with the CCR5 antagonist Maraviroc enhanced IFN-γ production by CD4+ T cells and increased the migration of irradiated CD8+ T cells towards irradiated TCM, suggesting its synergistic therapeutic potential in combination with irradiation. Overall, this study highlights the immunostimulatory properties of radiation in promoting anti-tumour T cell responses in OAC and increasing T cell migration towards chemotactic cues in the tumour. Importantly, the CCR5 antagonist Maraviroc holds promise to be repurposed in combination with radiotherapy to promote anti-tumour T cell responses in OAC.

10.
Cell Metab ; 36(5): 984-999.e8, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38642552

RESUMEN

The relevance of biopterin metabolism in resistance to immune checkpoint blockade (ICB) therapy remains unknown. We demonstrate that the deficiency of quinoid dihydropteridine reductase (QDPR), a critical enzyme regulating biopterin metabolism, causes metabolite dihydrobiopterin (BH2) accumulation and decreases the ratio of tetrahydrobiopterin (BH4) to BH2 in pancreatic ductal adenocarcinomas (PDACs). The reduced BH4/BH2 ratio leads to an increase in reactive oxygen species (ROS) generation and a decrease in the distribution of H3K27me3 at CXCL1 promoter. Consequently, myeloid-derived suppressor cells are recruited to tumor microenvironment via CXCR2 causing resistance to ICB therapy. We discovered that BH4 supplementation is capable to restore the BH4/BH2 ratio, enhance anti-tumor immunity, and overcome ICB resistance in QDPR-deficient PDACs. Tumors with lower QDPR expression show decreased responsiveness to ICB therapy. These findings offer a novel strategy for selecting patient and combining therapies to improve the effectiveness of ICB therapy in PDAC.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/metabolismo , Humanos , Animales , Ratones , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Microambiente Tumoral , Línea Celular Tumoral , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones Endogámicos C57BL , Biopterinas/análogos & derivados , Biopterinas/metabolismo , Femenino , Masculino , Especies Reactivas de Oxígeno/metabolismo
11.
Artículo en Inglés | MEDLINE | ID: mdl-38589986

RESUMEN

BACKGROUND: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells among others. MSC have been isolated from different tumors and they favor tumor cell growth, however, their role in pituitary tumors (PT) remains unknown. Herein we report the presence of MSCs in 2 ACTH-secreting PT causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF) and 2 non tumoral pituitary glands (MS). METHODS: We have analyzed their transcriptomic profiles by RNAseq and compared MSC in terms of their immunosuppressive effects against lymphoid T cell and macrophage populations by means of co-cultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSC derived from non-tumoral pituitaries and MSC derived from PT. Two distinct subpopulations of MSC, one displaying immunosuppressive properties and the other with increased pro-proliferative capabilities, regardless of their origin. MSC derived from ACTH- and nonfunctioning PT, but not those derived from non-tumoral glands significantly inhibited the proliferation of activated T cells, favored the generation of Tregs and promote M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony stimulating factor (M-CSF) and IL-10. Importantly, MSC derived from ACTH-PT showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least two MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSC may have important implications in PT growth.

12.
Clin Ter ; 175(2): 95-100, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38571465

RESUMEN

Abstract: The Influenza A H1N1 subtype can present with a wide spectrum of severity, from mild symptoms of influenza to severe respiratory distress. The morbidity and mortality connected to influenza are mostly associated with secondary bacterial infections. The influenza syndrome alone can cause a massive release of cytokines with dysregulation of the immune system, and it can act in synergy with other bacteria which can enhance cytokines secretion. This article deals with a case of severe pneumonia of H1N1 in a 17-year-old woman with bacterial superinfection with Staphylococcus aureus characterized by a high level of interleukine-6 (105900 pg/mL) and the appearance of severe leukopenia with immuno-suppression, such that HIV infection and hematological diseases were included in the initial differential diagnosis. After death, the autopsy confirmed the presence of severe pneumonia, in addition to an hepatic steatosis in absence of other risk factors. This case reports the rapid and lethal course of influenza A /H1N1 in a young and healthy subject without comorbidities, in an age group in which mortality is about 0.3 deaths per 100,000. The case underlines the importance of quickly diagnosis of viral infections and the differential diagnoses with other immunosuppressive diseases, which can be fatal even in adolescent and healthy subjects.


Asunto(s)
Infecciones por VIH , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Neumonía , Sepsis , Femenino , Adolescente , Humanos , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Sepsis/complicaciones , Autopsia , Neumonía/complicaciones , Citocinas
13.
Mol Ther Methods Clin Dev ; 32(1): 101216, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38440160

RESUMEN

Adeno-associated virus (AAV) vectors are used for correcting multiple genetic disorders. Although the goal is to achieve lifelong correction with a single vector administration, the ability to redose would enable the extension of therapy in cases in which initial gene transfer is insufficient to achieve a lasting cure, episomal vector forms are lost in growing organs of pediatric patients, or transgene expression is diminished over time. However, AAV typically induces potent and long-lasting neutralizing antibodies (NAbs) against capsid that prevents re-administration. To prevent NAb formation in hepatic AAV8 gene transfer, we developed a transient B cell-targeting protocol using a combination of monoclonal Ab therapy against CD20 (for B cell depletion) and BAFF (to slow B cell repopulation). Initiation of immunosuppression before (rather than at the time of) vector administration and prolonged anti-BAFF treatment prevented immune responses against the transgene product and abrogated prolonged IgM formation. As a result, vector re-administration after immune reconstitution was highly effective. Interestingly, re-administration before the immune system had fully recovered achieved further elevated levels of transgene expression. Finally, this immunosuppression protocol reduced Ig-mediated AAV uptake by immune cell types with implications to reduce the risk of immunotoxicities in human gene therapy with AAV.

14.
BMC Cancer ; 24(1): 328, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38468240

RESUMEN

The sialic acid binding Ig like lectin 15 (Siglec-15) was previously identified as tumor immune suppressor gene in some human cancers with elusive molecular mechanism to be elucidated. The continuous focus on both clinical and basic biology of bladder cancer leads us to characterize aberrant abundance of BACH1-IT2 associating with stabilization of Siglec-15, which eventually contributes to local immune suppressive microenvironment and therefore tumor advance. This effect was evidently mediated by miR-4786-5p. BACH1-IT2 functions in this scenario as microRNA sponge, and competitively conceals miR-4786 and up-regulates cancer cell surface Siglec-15. The BACH1-IT2-miR-4786-Siglec-15 axis significantly influences activation of immune cell co-culture. In summary, our data highlights the critical involvements of BACH1-IT2 and miR-4786 in immune evasion in bladder cancer, which hints the potential for both therapeutic and prognostic exploitation.


Asunto(s)
MicroARNs , Neoplasias de la Vejiga Urinaria , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Microambiente Tumoral/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética
15.
Indian J Otolaryngol Head Neck Surg ; 76(1): 683-686, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38440515

RESUMEN

Kimura disease is an idiopathic chronic inflammatory disorder, that usually affects the head and neck sites. The use of steroid for its management has been long reviewed in literature alongside immune suppression, but there are only few studies that compare the efficacy of steroid as a single modality treatment for the same. A middle-aged patient, hailing from southern state of India, presented to our outpatient clinic with right sided facial swelling for 2 years. Patient was diagnosed as a case of kimura disease of head and neck with cytological analysis and other investigations. Patient was managed medically with low dose oral corticosteroids and followed up for 6 months. This is a retrospective analysis of the efficacy of this single modality treatment. Patients with Kimura disease with no renal involvement, low dose oral corticosteroids can be tried as a single modality treatment, provided there are no contra indications for the same. Although long term follow up is essential to look for recurrence rates and associated long term benefits for the same.

16.
Cell Rep ; 43(3): 113934, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38461416

RESUMEN

Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.


Asunto(s)
Colitis , Neutrófilos , Animales , Ratones , Mielopoyesis , Colitis/inducido químicamente , Médula Ósea
17.
J Dairy Sci ; 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38428491

RESUMEN

Cows in early lactation (EL) are purportedly immune suppressed, which renders them more susceptible to disease. Thus, the study objective was to compare key biomarkers of immune activation from i.v. lipopolysaccharide (LPS) between EL and mid-lactation (ML) cows. Multiparous EL (20 ± 2 DIM; n = 11) and ML (131 ± 31 DIM; n = 12) cows were enrolled in a 2 × 2 factorial design and assigned to 1 of 2 treatments by lactation stage (LS): (1) EL (EL-LPS; n = 6) or ML (ML-LPS; n = 6) cows administered a single LPS bolus from Escherichia coli O55:B5 (0.09 µg/kg of body weight), or (2) pair-fed (PF) EL (EL-PF; n = 5) or ML (ML-PF; n = 6) cows administered i.v. saline. After LPS administration, cows were intensely evaluated for 3 d to analyze their response and recovery to LPS. Rectal temperature increased in LPS relative to PF cows (1.1°C in the first 9 h), and the response was more severe in EL-LPS relative to ML-LPS cows (2.3 vs. 1.3°C increase at 4 h post-LPS; respectively). Respiration rate increased only in EL-LPS cows (47% relative to ML-LPS in the first h post-LPS). Circulating tumor necrosis factor-α, IL-6, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1ß, and IFN-γ-inducible protein-10 increased within the first 6 h after LPS and these changes were exacerbated in EL-LPS relative to ML-LPS cows (6.3-, 4.8-fold, 57%, 93%, 10%, and 61% respectively). All cows administered LPS had decreased circulating iCa relative to PF cows (34% at the 6 h nadir), but the hypocalcemia was more severe in EL-LPS than ML-LPS cows (14% at 6 h nadir). In response to LPS, neutrophils decreased regardless of LS, then increased into neutrophilia by 24 h in all LPS relative to PF cows (2-fold); however, the neutrophilic phase was augmented in EL- compared with ML-LPS cows (63% from 24 to 72 h). Lymphocytes and monocytes rapidly decreased then gradually returned to baseline in LPS cows regardless of LS; however, monocytes were increased (57%) at 72 h in EL-LPS relative to ML-LPS cows. Platelets were reduced (46%) in LPS relative to PF cows throughout the 3-d following LPS, and from 24 to 48 h, platelets were further decreased (41%) in EL-LPS compared with ML-LPS. During the 3-d following LPS, serum amyloid A (SAA), LPS-binding protein (LBP), and haptoglobin (Hp) increased in LPS compared with PF groups (9-fold, 72%, and 153-fold, respectively), and the LBP and Hp responses were more exaggerated in EL-LPS than ML-LPS cows (85 and 79%, respectively) whereas the SAA response did not differ by LS. Thus, our data indicates that EL immune function does not appear "suppressed," and in fact many aspects of the immune response are seemingly functionally robust.

18.
Inflammation ; 2024 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-38429403

RESUMEN

Sepsis is a severe and life-threatening disease caused by infection, characterized by a dysregulated immune response. Unfortunately, effective treatment strategies for sepsis are still lacking. The intricate interplay between metabolism and the immune system limits the treatment options for sepsis. During sepsis, there is a profound shift in cellular energy metabolism, which triggers a metabolic reprogramming of immune cells. This metabolic alteration impairs immune responses, giving rise to excessive inflammation and immune suppression. Recent research has demonstrated that UCP2 not only serves as a critical target in sepsis but also functions as a key metabolic switch involved in immune cell-mediated inflammatory responses. However, the regulatory mechanisms underlying this modulation are complex. This article focuses on UCP2 as a target and discusses metabolic reprogramming during sepsis and the complex regulatory mechanisms between different stages of inflammation. Our research indicates that overexpression of UCP2 reduces the Warburg effect, restores mitochondrial function, and improves the prognosis of sepsis. This discovery aims to provide a promising approach to address the significant challenges associated with metabolic dysfunction and immune paralysis.

19.
Hum Gene Ther ; 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38450566

RESUMEN

Adeno-associated virus (AAV) gene therapy is making rapid strides owing to its wide range of therapeutic applications. However, development of serious immune responses to the capsid antigen or the therapeutic transgene product hinders its full clinical impact. Immune suppressive (IS) drug treatments have been used in various clinical trials to prevent the deleterious effects of cytotoxic T cells to the viral vector or transgene, although there is no consensus on the best treatment regimen, dosage, or schedule. Regulatory T cells (Tregs) are crucial for maintaining tolerance against self or nonself antigens. Of importance, Tregs also play an important role in dampening immune responses to AAV gene therapy, including tolerance induction to the transgene product. Approaches to harness the tolerogenic effect of Tregs include the use of selective IS drugs that expand existing Tregs, and skew activated conventional T cells into antigen-specific peripherally induced Tregs. In addition, Tregs can be expanded ex vivo and delivered as cellular therapy. Furthermore, receptor engineering can be used to increase the potency and specificity of Tregs allowing for suppression at lower doses and reducing the risk of disrupting protective immunity. Because immune-mediated toxicities to AAV vectors are a concern in the clinic, strategies that can enhance or preserve Treg function should be considered to improve both the safety and efficacy of AAV gene therapy.

20.
Front Immunol ; 15: 1356651, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38469300

RESUMEN

Cryptococcus neoformans and C. gattii, the etiologic agents of cryptococcosis, cause over 100,000 deaths worldwide every year, yet no cryptococcal vaccine has progressed to clinical trials. In preclinical studies, mice vaccinated with an attenuated strain of C. neoformans deleted of three cryptococcal chitin deacetylases (Cn-cda1Δ2Δ3Δ) were protected against a lethal challenge with C. neoformans strain KN99. While Cn-cda1Δ2Δ3Δ extended the survival of mice infected with C. gattii strain R265 compared to unvaccinated groups, we were unable to demonstrate fungal clearance as robust as that seen following KN99 challenge. In stark contrast to vaccinated mice challenged with KN99, we also found that R265-challenged mice failed to induce the production of protection-associated cytokines and chemokines in the lungs. To investigate deficiencies in the vaccine response to R265 infection, we developed a KN99-R265 coinfection model. In unvaccinated mice, the strains behaved in a manner which mirrored single infections, wherein only KN99 disseminated to the brain and spleen. We expanded the coinfection model to Cn-cda1Δ2Δ3Δ-vaccinated mice. Fungal burden, cytokine production, and immune cell infiltration in the lungs of vaccinated, coinfected mice were indicative of immune evasion by C. gattii R265 as the presence of R265 neither compromised the immunophenotype established in response to KN99 nor inhibited clearance of KN99. Collectively, these data indicate that R265 does not dampen a protective vaccine response, but rather suggest that R265 remains largely undetected by the immune system.


Asunto(s)
Coinfección , Criptococosis , Cryptococcus gattii , Cryptococcus neoformans , Vacunas , Ratones , Animales , Evasión Inmune
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