Journal of cellular immunology最新文献

Introduction: Renal Cell Carcinoma (RCC) is among the most frequently diagnosed malignancies in both genders with over 81,000 estimated cases in 2024. Despite increasing incidence of renal cell carcinomas <4 cm, up to 1/3 of patients diagnosed with RCC exhibit metastatic disease (mRCC) at time of diagnosis. Cytoreductive nephrectomy (CN), a procedure which encompasses the surgical removal of the primary tumor in patients with metastatic disease, was offered upfront as standard of care during the cytokine era; however, as systemic treatment has evolved, the role of CN in mRCC patients has become less clear.

Purpose of review: We sought to review the evolution of CN in mRCC patients from historical treatments through current standard of care considering ongoing clinical trials and perioperative considerations for CN in patients treated with tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI).

Conclusion: CN following immunotherapy is safe and beneficial in appropriately selected patients. The choice to perform CN in patients with mRCC amidst an ever-changing treatment landscape is nuanced. Clinical trial enrollment is critical to refine selection criteria and timing of CN. As treatment options continue to progress, shared decision-making and multidisciplinary collaboration remain paramount in selecting the optimal treatment course for each patient.

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, crucial in the innate immune response, is linked to various human diseases. However, the effect of endogenous metabolites, like 4-hydroxynonenal (HNE), on NLRP3 inflammasome activity remains underexplored. Recent research highlights HNE's inhibitory role in NLRP3 inflammasome activation, shedding light on its potential as an endogenous regulator of inflammatory responses. Studies demonstrate that HNE blocks NLRP3 inflammasome-mediated pyroptosis and IL-1β secretion. Additionally, covalent targeting emerges as a common mechanism for inhibiting NLRP3 inflammasome assembly, offering promising avenues for therapeutic intervention. Further investigation is needed to understand the impact of endogenous HNE on NLRP3 inflammasome activation, especially in settings where lipid peroxidation byproducts like HNE are produced. Understanding the intricate interplay between HNE and the NLRP3 inflammasome holds significant potential for unraveling novel therapeutic strategies for inflammatory disorders.

Neutrophil elastase (ELANE) mutations are the most common cause of cyclic (CyN) and congenital neutropenia (SCN), two autosomal dominant disorders causing recurrent infections due to impaired neutrophil production. Granulocyte colony-stimulating factor (G-CSF) corrects neutropenia but has adverse effects, including bone pain and in some cases, an increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML). Hematopoietic stem cell transplantation is an alternative but is limited by its complications and donor availability. Alternative therapies are needed, particularly for patients with poor responses to G-CSF and those at higher risk of MDS/AML. We previously reported that cell-permeable neutrophil elastase (NE) inhibitors are a potential treatment for ELANE neutropenia, based on studies using HL-60 cells. Our hypothesis was that mutant NE was not properly stored to the neutrophil granules and thereby caused cytoplasmic damage, activation of apoptotic pathways and neutropenia. We have extended this work using CD34⁺ cells from patients with ELANE mutations and several selective NE inhibitors, i.e., MK0339, sivelestat, BAY-678, and GW311616, as well as the DDP1 inhibitor, brensocatib. Only MK0339 restored neutrophil differentiation with an increase in the proportion of neutrophil marker-positive cells (CD66b⁺/CD14⁺ and CD11b⁺/CD15⁺). In contrast, other NE inhibitors, i.e., sivelestat, BAY-678, and GW311616 and the DPP1 inhibitor, brensocatib, showed no effect on neutrophil differentiation. Molecular docking studies showed that MK0339 binds to an alternative site on the NE protein compared to other inhibitors with greater inhibitor-NE protein stability, suggesting a unique mechanism of action and supporting further investigation of MK0339 as a therapy for ELANE associated neutropenia.

Chimeric antigen receptor (CAR)-T cell therapy has shown potential in improving outcomes for individuals with hematological malignancies. However, achieving long-term full remission for blood cancer remains challenging due to severe life-threatening toxicities such as limited anti-tumor efficacy, antigen escape, trafficking restrictions, and limited tumor invasion. Furthermore, the interactions between CAR-T cells and their host tumor microenvironments have a significant impact on CAR-T function. To overcome these considerable hurdles, fresh methodologies and approaches are needed to produce more powerful CAR-T cells with greater anti-tumor activity and less toxicity. Despite advances in CAR-T research, microbial resistance remains a significant obstacle. In this review, we discuss and describe the basics of CAR-T structures, generations, challenges, and potential risks of infections in CAR-T cell therapy.

Background: Chikungunya virus (CHIKV) is an alphavirus spread by mosquitos that causes arthralgias and arthritis that may last for years. The objective of this study was to describe the arthritis progression and T cell immunology over a two-year period.

Methods: A cohort of 40 cases of serologically confirmed CHIKV from Magdalena and Atlántico, Colombia were followed in 2019 and again in 2021. Arthritis disease severity, disability, pain, stiffness, physical function, mobility, fatigue, anxiety, sleep disturbances and depression were assessed. Serum cytokines and T-cell subsets were measured and tested for change. Correlations within each of the 2 time periods for laboratory parameters were also examined.

Results: Although, arthritis disease severity, as measured by the Disease Activity Score-28 (DAS-28) did not change significantly over a two-year period, a new metric- the Chikungunya Disease Activity Score (CHIK-DAS)- was more sensitive to detect changes in disease severity than the Disease Activity Score-28 (DAS-28) and showed some improvement in average disease severity from moderate to mild over two years. Cases were characterized by moderate disability, pain, and stiffness with mild alterations of physical function, mobility, fatigue, anxiety, sleep disturbances and depression that did not change significantly over time. Small joints including the fingers and wrists were most affected without significant change over time. The percentage of effector T cells (Teffs) and regulatory T cells (Tregs) of CD4⁺ T cells both decreased over time. Teff percentages decreased more significantly resulting in a halving of the Teff/Treg ratio two years later. Furthermore, markers of Treg immunosuppressive function such as CTLA4, Helios, CD28, CD45RA and 41bb decreased over time. Cytokines did not change significantly over time.

Conclusions: The presented data suggest that arthritis persists almost seven years after chikungunya infection in some patients with waning Teff and Treg numbers and activation markers over time. Treg activation may be a promising therapeutic target for further investigation.

Polyamines are small organic molecules ubiquitously present in all living organisms and function as crucial regulators of biological processes ranging from fundamental cellular metabolism to immune regulation. Dysregulation of polyamine metabolism has been implicated in numerous diseases, including neurodegenerative disorders, inflammatory conditions, autoimmune diseases, and cancer. This review provides an overview of pathophysiology of these conditions, highlighting polyamines' role in immunometabolic alterations in the context of immune regulation. Exploring the intricate mechanisms of polyamine metabolism holds promise for advancing our understanding of disease processes and developing potential innovative therapeutic interventions.