Immunomodulatory Strategies Research Articles

The role of N6-methyladenosine (m6A) mRNA modifications in herpesvirus infections.

Herpesviruses, a family of large enveloped DNA viruses, establish persistent infections in a wide range of hosts. This characteristic requires an intricate network of interactions with their hosts and host cells. In recent years, the interplay between herpesviruses and the epitranscriptome-chemical modifications in transcripts that may affect mRNA biology and fate-has emerged as a novel aspect of herpesvirus-host interactions. In particular, herpesviruses display different mechanisms to modulate and usurp the most abundant mRNA modification, N6-methyladenosine or m6A. Some herpesviruses interfere with m6A methylation of transcripts, while others enhance or take advantage of m6A methylation of viral and/or cellular transcripts. In many cases, herpesviruses appear to modulate the m6A methylation process to suppress the antiviral host response. This review highlights the strategies used by members of the different herpesvirus subfamilies to manipulate host m6A mediators and how these contribute to virus replication and the antiviral host response. Research aimed at deciphering the interaction of herpesviruses with the m6A epitranscriptome not only may lead to new avenues in the design of antiviral and immunomodulatory strategies, but also provides new insights in the regulation and the role of m6A transcript methylation in general.

Triple-negative breast cancer modifies the systemic immune landscape and alters neutrophil functionality

Cancer disrupts intratumoral innate-adaptive immune crosstalk, but how the systemic immune landscape evolves during breast cancer progression remains unclear. We profiled circulating immune cells in stage I–III and stage IV triple-negative breast cancer (TNBC) patients and healthy donors (HDs). Metastatic TNBC (mTNBC) patients had reduced T cells, dendritic cells, and differentiated B cells compared to non-metastatic TNBC patients and HDs, partly linked to prior chemotherapy. Vδ1 γδ T cells from mTNBC patients produced more IL17 than those from HDs. Chemotherapy-naïve mTNBC patients showed increased classical monocytes and neutrophils. Transcriptional, proteomic, and functional analyses revealed that neutrophils in mTNBC exhibited enhanced migratory capacity, elevated granule proteins, and higher ROS production. Some immune changes, such as reduced non-switched B cells and heightened neutrophil migration, were evident in earlier TNBC stages. This study comprehensively maps systemic immunity in TNBC, guiding future research on patient stratification and immunomodulation strategies.

Enhancing the Implant Osteointegration via Supramolecular Co-Assembly Coating with Early Immunomodulation and Cell Colonization.

Osteointegration, the effective coupling between an implant and bone tissue, is a highly intricate biological process. The initial stages of bone-related immunomodulation and cellular colonization play crucial roles, but have received limited attention. Herein, a novel supramolecular co-assembled coating of strontium (Sr)-doped metal polyphenol networks (MPN) modified with c(RGDfc) is developed and well-characterized, for eliciting an early immunomodulation and cellular colonization. The results showed that the (Sr-MPN)@RGD coating significantly regulated the polarization of macrophages to the M2 phenotype by controllable release of Sr, and promote the initial adhesion of bone marrow mesenchymal stem cells (BMSCs) by RGD presented on MPN. Notably, the (Sr-MPN)@RGD attenuated osteoclast differentiation and oxidative stress as well as enhanced osteoblast differentiation and angiogenesis due to macrophage polarization toward M2 phenotype, which in turn has a profound effect on neighboring cells through paracrine signaling. In vivo results showed that the (Sr-MPN)@RGD coating manifested superior osseointegration and bone maturation to the bare Ti-rod or Ti-rod coated with MPN and Sr-MPN. This work contributed to the design of multifunctional implant coatings that address the complex biological process of osteointegration from the perspective of orchestrating stem cell recruitment with immunomodulatory strategies.

Tumor-Associated Macrophages Nano-Reprogrammers Induce "Gear Effect" to Empower Glioblastoma Immunotherapy.

Glioblastoma (GBM), the most malignant brain tumor with high prevalence, remains highly resistant to the existing immunotherapies due to the significant immunosuppression within tumor microenvironment (TME), predominantly manipulated by M2-phenotypic tumor-associated macrophages (M2-TAMs). Here in this work, an M2-TAMs targeted nano-reprogrammers, MG5-S-IMDQ, is established by decorating the mannose molecule as the targeting moiety as well as the toll-like receptor (TLR) 7/8 agonist, imidazoquinoline (IMDQ) on the dendrimeric nanoscaffold. MG5-S-IMDQ demonstrated an excellent capacity of penetrating the blood-brain barrier (BBB) as well as selectively targeting M2-TAMs in the GBM microenvironment, leading to a phenotype transformation and function restoration of TAMs shown as heightened phagocytic activity toward tumor cells, enhanced cytotoxic effects, and improved tumor antigen cross-presentation capability. In the meantime, by induction of a function-oriented "gear effect", MG5-S-IMDQ treatment extended its impact systemically by enhancing the infiltration of type I conventional dendritic cells (cDC1s) into the tumor sites and bolstering adaptive immune responses. In sum, by precisely working on M2-TAMs as a unique target in tumor situ, the nano-reprogrammers successfully established a robust immune network that worked synergistically to combat tumors. This facile nanoplatform-based immunomodulatory strategy, serving as a powerful and convenient immune monotherapy or as a complementary treatment alongside other therapies like surgery, provided deep insights for advancing translational study in GBM.

Substrate curvature influences cytoskeletal rearrangement and modulates macrophage phenotype.

Inflammation is a vital immune response, tightly orchestrated through both biochemical and biophysical cues. Dysregulated inflammation contributes to chronic diseases, highlighting the need for novel therapies that modulate immune responses with minimal side effects. While several biochemical pathways of inflammation are well understood, the influence of physical properties such as substrate curvature on immune cell behavior remains underexplored. This study investigates how substrate curvature impacts macrophage cytoskeletal dynamics, gene expression, and immunophenotype through mechanosensitive pathways. Gelatin-based microgels with tunable surface curvatures were fabricated via water-in-oil emulsification and crosslinked with genipin. Microgels were sorted into three size ranges, yielding high (40-50 µm), intermediate (150-250 µm), and low (350-400 µm) curvature profiles. Macrophages were seeded onto these microgels, and cytoskeletal dynamics were examined using confocal microscopy, SEM, and actin-specific staining. Gene expression of pro- and anti-inflammatory markers was quantified using qPCR. The role of actin polymerization was assessed using Latrunculin-A (Lat-A) treatment. Macrophages adhered effectively to both high- and low-curvature microgels, displaying curvature-dependent morphological changes. Confocal imaging revealed that macrophages on low-curvature microgels exhibited significantly higher F-actin density than those on high-curvature microgels. Correspondingly, qPCR analysis showed upregulation of pro-inflammatory markers (e.g., Tnf, Nos2) in high-curvature conditions, while anti-inflammatory markers (e.g., Arg1) were elevated in low-curvature conditions. Lat-A treatment reduced F-actin density and modulated gene expression patterns, confirming the cytoskeletal regulation of macrophage phenotype. These findings demonstrate that substrate curvature influences macrophage behavior by modulating cytoskeletal dynamics and associated immunophenotypic markers through actin-mediated transcriptional pathways. By controlling curvature, therapeutic biomaterials may direct immune responses, offering a new avenue for treating inflammatory diseases. This mechanobiological approach presents a promising strategy for precision immunomodulation in regenerative medicine.

Neuro-immune regulation in allergic Diseases: Role of neuropeptides.

The role of neuro-immune interaction in allergic diseases, a group of common immune system diseases, has garnered increasing attention. Neuropeptides, as a crucial component of neuro-immune crosstalk with local neuroendocrine and signaling functions, play a significant role that must not be overlooked. Neuropeptides are released by neurons and even some immune cells, and mediate neuro-immune crosstalk by activating relevant specific receptors on immune cells. Recent studies have found that neuropeptides have a certain regulatory effect on allergic diseases, which could be beneficial or detrimental for the development of allergic diseases. Nevertheless, the precise mechanism of neuropeptides in allergic diseases remains unclear, particularly in the context of food allergy where their role is poorly understood. This review summarized the interplay between neuropeptides and different immune cells, as well as their current research progress in several common allergic diseases: atopic dermatitis, allergic asthma, and food allergy. It is evident that neuropeptides such as substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuromedin U, exert important regulatory effects on allergic diseases, yet further investigation is required to fully elucidate their mechanisms of action, which may contribute to better understanding of the onset and progression of allergic diseases and finding better immunomodulatory strategies.

Neuroinflammatory Loop in Schizophrenia, Is There a Relationship with Symptoms or Cognition Decline?

Schizophrenia (SZ), a complex psychiatric disorder of neurodevelopment, is characterised by a range of symptoms, including hallucinations, delusions, social isolation and cognitive deterioration. One of the hypotheses that underlie SZ is related to inflammatory events which could be partly responsible for symptoms. However, it is unknown how inflammatory molecules can contribute to cognitive decline in SZ. This review summarises and exposes the possible contribution of the imbalance between pro-inflammatory and anti-inflammatory interleukins like IL-1beta, IL-4 and TNFalfa among others on cognitive impairment. We discuss how this inflammatory imbalance affects microglia and astrocytes inducing the disruption of the blood-brain barrier (BBB) in SZ, which could impact the prefrontal cortex or associative areas involved in executive functions such as planning and working tasks. We also highlight that inflammatory molecules generated by intestinal microbiota alterations, due to dysfunctional microbial colonisers or the use of some anti-psychotics, could impact the central nervous system. Finally, the question arises as to whether it is possible to modulate or correct the inflammatory imbalance that characterises SZ, and if an immunomodulatory strategy can be incorporated into conventional clinical treatments, either alone or in complement, to be applied in specific phases, such as prodromal or in the first-episode psychosis.

Advancements and Challenges in Immune Protection Strategies for Islet Transplantation.

Pancreatic islet transplantation is a crucial treatment for managing type 1 diabetes (T1D) in clinical settings. However, the limited availability of human cadaveric islet donors and the need for ongoing administration of immunosuppressive agents post-transplantation hinder the widespread use of this treatment. Stem cell-derived islet organoids have emerged as an effective alternative to primary human islets. Nevertheless, implementing this cell replacement therapy still requires chronic immune suppression, which may result in life-long side effects. To address these challenges, innovations such as encapsulation devices, universal stem cells, and immunomodulatory strategies are being developed to mitigate immune rejection and prolong the function of the transplant. This review outlines the contemporary challenges in pancreatic β cell therapy, particularly immune rejection, and recent progress in immune-isolation devices, hypoimmunogenic stem cells, and immune regulation of transplants. A comprehensive evaluation of the advantages and limitations of these approaches will contribute to improved future clinical investigations. With these promising advancements, the application of pancreatic β cell therapy holds the potential to effectively treat T1D and benefit a larger population of T1D patients.

Curing cryptoglandular anal fistulas-Is it possible without surgery?

Empirical reviews suggested that cryptoglandular anal fistulas require surgical resolution. However, some reports have indicated the possibility of nonsurgical and conservative treatment, which is discussed in this review. This review explores the potential of nonsurgical approaches for curing anal fistulas through bacterial inhibition and immunomodulation. The longstanding cryptoglandular theory has been a subject of controversy, prompting the reevaluation of conventional surgical interventions for anal fistulas. The review was conducted through database searches, including Medline, EMBASE, PubMed, and the Cochrane Library. Emerging evidence suggests that targeting the anaerobic environments present in anal fistulas and perianal abscesses and eradicating bacteria and their by-products may be critical for successful treatment. Immunomodulatory strategies show promise as a potential avenue for the nonsurgical management of anal fistulas. Ongoing developments in pharmacological research offer opportunities for alternative treatment options, shedding light on the prospects of noninvasive anal fistula management.

Exercise-induced upregulation of TRIM9 attenuates neuroinflammation in Alzheimer's disease-like rat.

Exercise exerts protective effects against Alzheimer's disease (AD). However, the factors and mechanisms underlying these effects remain largely unknown. This study aims to elucidate the molecular mechanisms by which exercise exerts its protective effects against AD. Male 7-week-old Sprague-Dawley rats were randomly allocated to four groups (n=10 per group): control (CON), exercise control (EXE), sedentary AD model induced by intracerebroventricular streptozotocin (STZ) injection, and AD model with treadmill exercise (EXE+STZ). The exercise groups underwent a 13-week treadmill exercise. An intracerebroventricular injection of STZ was used to induce a rat model of AD. The Barnes maze task was employed as an assessment of spatial learning and memory. Hippocampal tissues from three rats per group was collected for proteomic analysis. Immunofluorescence staining, western blot analysis and polymerase chain reaction were performed for the evaluation of Aβ production, tau hyperphosphorylation, differential protein and corresponding signaling pathway. Treadmill exercise could significantly improve STZ-induced cognitive dysfunction and provide neuroprotection by reducing Aβ deposition and tau hyperphosphorylation. Proteomic analysis and further studies demonstrated that treadmill training could significantly increase the expression of tripartite motif-containing 9 (TRIM9). Subsequent research indicated that the upregulation of TRIM9 maybe due, in part,to the inhibition of the NF-κB pathway, thereby reducing the pro-inflammatory factor, and exerting an anti-inflammatory effect. Treadmill exercise attenuates cognitive decline in AD models by upregulating TRIM9 expression, which in turn inhibits NF-κB-mediated neuroinflammation. These findings suggest that TRIM9 may serve as a potential therapeutic target for immunomodulatory strategies against AD.

Microbial Dynamics in COVID-19: Unraveling the Impact of Human Microbiome on Disease Susceptibility and Therapeutic Strategies.

This review explores the bidirectional relationship between the human microbiome and SARS-CoV-2 infection, elucidating its implications for COVID-19 susceptibility, severity, and therapeutic strategies. Metagenomic analyses reveal notable alterations in microbiome composition associated with SARS-CoV-2 infection, impacting disease severity and clinical outcomes. Dysbiosis within the respiratory, gastrointestinal, oral, and skin microbiomes exacerbates COVID-19 pathology through immune dysregulation and inflammatory pathways. Understanding these microbial shifts is pivotal for devising targeted therapeutic interventions. Notably, co-infection of oral pathogens with SARS-CoV-2 worsens lung pathology, while gut microbiome dysbiosis influences viral susceptibility and severity. Potential therapeutic approaches targeting the microbiome include probiotics, antimicrobial agents, and immunomodulatory strategies. This review underscores the importance of elucidating host-microbiota interactions to advance precision medicine and public health initiatives in combating COVID-19 and other infectious diseases.

Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation.

Challenges of Multidrug-Resistant Tuberculosis Meningitis: Current Treatments and the Role of Glutathione as an Adjunct Therapy.

Multidrug-resistant tuberculosis (MDR-TB) poses a significant global health threat, especially when it involves the central nervous system (CNS). Tuberculous meningitis (TBM), a severe manifestation of TB, is linked to high mortality rates and long-term neurological complications, further exacerbated by drug resistance and immune evasion mechanisms employed by Mycobacterium tuberculosis (Mtb). Although pulmonary TB remains the primary focus of research, MDR-TBM introduces unique challenges in diagnosis, treatment, and patient outcomes. The effectiveness of current treatments is frequently compromised by poor CNS penetration of anti-TB drugs and the necessity for prolonged therapy, which often involves considerable toxicity. This review explores the potential of cytokine-based adjunct immunotherapies for MDR-TBM, addressing the challenges of balancing pro-inflammatory and anti-inflammatory signals within the CNS. A central focus is the prospective role of glutathione, not only in reducing oxidative stress but also in enhancing host immune defenses against Mtb's immune evasion strategies. Furthermore, the development of vaccines aimed at upregulating glutathione synthesis in macrophages represents a promising strategy to bolster the immune response and improve treatment outcomes. By integrating glutathione and innovative vaccine approaches into MDR-TBM management, this review proposes a comprehensive strategy that targets Mtb directly while supporting immune modulation, with the potential to enhance patient outcomes and reduce treatment related adverse effects. We underscore the urgent need for further research into adjunctive therapies and immunomodulatory strategies to more effectively combat MDR-TBM.

Copper chelation redirects neutrophil function to enhance anti-GD2 antibody therapy in neuroblastoma

Anti-disialoganglioside (GD2) antibody therapy has provided clinical benefit to patients with neuroblastoma however efficacy is likely impaired by the immunosuppressive tumor microenvironment. We have previously defined a link between intratumoral copper levels and immune evasion. Here, we report that adjuvant copper chelation potentiates anti-GD2 antibody therapy to confer durable tumor control in immunocompetent models of neuroblastoma. Mechanistic studies reveal copper chelation creates an immune-primed tumor microenvironment through enhanced infiltration and activity of Fc-receptor-bearing cells, specifically neutrophils which are emerging as key effectors of antibody therapy. Moreover, we report copper sequestration by neuroblastoma attenuates neutrophil function which can be successfully reversed using copper chelation to increase pro-inflammatory effector functions. Importantly, we repurpose the clinically approved copper chelating agent Cuprior as a non-toxic, efficacious immunomodulatory strategy. Collectively, our findings provide evidence for the clinical testing of Cuprior as an adjuvant to enhance the activity of anti-GD2 antibody therapy and improve outcomes for patients with neuroblastoma.

Severe SARS-CoV-2 infection is associated with increased risk of De novo HLA antibody production in lung transplant recipients: Single-center study.

The COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients (LTR). Respiratory viral infections may be associated with de-novo HLA donor-specific antibody (DSA) production and impact lung transplant outcomes. Since one of the immunomodulation strategies post-SARS-CoV-2 infection in LTR include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo DSA production in LTR. We performed a retrospective chart review of 63 consecutive LTR diagnosed with COVID-19 to investigate this concern. COVID-19 disease severity was divided into 3 groups: mild, moderate, and severe. Mild disease was defined as patients with COVID-19 diagnosis who were stable enough to be treated as out-patients. Moderate disease was defined as patients who required admission to the hospital and were on less than 10 l of oxygen at rest. Severe disease was identified as patients who required hospitalization and were on more than 10 l of oxygen with or without mechanical ventilation or extra corporal membrane oxygenation (ECMO). Groups were compared using the Kruskal-Wallis test. A total of 11, 43, and 9 LTR were diagnosed with mild, moderate, and severe COVID-19 respectively. We observed no significant differences in the CPRA pre-COVID-19 compared to 1 and 6 months post-COVID-19 diagnosis in 6/11 (54.5 %), 18/43 (41.8 %), and 6/9 (66.9 %) LTR with mild (p = 0.66), moderate (p = 0.74), and severe (p = 0.22) COVID-19 respectively. HLA class I and II DSA were detected pre-COVID-19 diagnosis and persisted with no significant differences in the median MFI levels at 1 and 6 months post-COVID-19 diagnosis in 2/11 (p = 0.93), 7/43 (p = 0.71), and 0/9 LTR with mild, moderate, and severe COVID-19 respectively. De-novo HLA DSA were detected within 6 months post-COVID-19 diagnosis in 0/11 (0 %), 1/43 (2.3 %), and 3/9 (33.3 %%) LTR with mild, moderate, and severe COVID-19 respectively (p = 0.001). Severe COVID-19 may be associated with increased risk of de novo HLA DSA production resulting in allograft dysfunction.

Altered Immune Cell Profiles in the Follicular Fluid of Patients with Poor Ovarian Response According to the POSEIDON Criteria.

This study aims to investigate alterations in immune cell counts within preovulatory follicles of patients with poor ovarian response (POR) during assisted reproductive technology (ART), classified according to the POSEIDON criteria. This single-centre cross-sectional study included 543 women undergoing IVF/ICSI treatment, selected based on specific inclusion and exclusion criteria: 292 with normal ovarian response and 251 with poor response. Follicular fluid (FF) was collected on the day of oocyte retrieval and analysed by flow cytometry to determine the proportions of macrophages (Mφs), M1 and M2 Mφs, T cells (CD4 and CD8 T cells), dendritic cells (DCs), including type 1 conventional dendritic cells (cDC1) and type 2 conventional dendritic cells (cDC2), and neutrophils. Multivariable logistic regression assessed the relationship between immune cell counts and POR, Pearson correlation determined associations with the number of retrieved oocytes, and receiver operating characteristic (ROC) curves evaluated the predictive power of immune cell counts for POR. Immune cells accounted for 52.57% (±23.90%) of the total cell population in the follicular microenvironment, which was approximately equal to that of granulosa cells, with Mφs being the most abundant, followed sequentially by T cells, DCs, and neutrophils. In patients with POR, overall Mφs infiltration in the follicular microenvironment decreased, whereas M1 and M2 polarization increased. T cell infiltration increased, with a decrease in the CD4/CD8 ratio. Both cDC1 and cDC2 were significantly elevated. Moreover, multivariable logistic regression revealed that the total macrophage count, CD4 T cell count, and cDC2 count were independent predictors of POR. Notably, cDC2 showed the largest area under the ROC curve, suggesting its strong potential as a biomarker for predicting POR. The proportion of immune cells in preovulatory follicles were significantly altered in patients with POR. These findings suggest that immune cell dynamics in the follicular microenvironment may play a crucial role in determining ovarian response and prognosis, indicating that targeted immunomodulatory strategies could be considered in future therapeutic approaches.

New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells

Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.

Anti-CD19 CAR-T cells are effective in severe idiopathic Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoantibody-mediated disease of the neuromuscular junction characterized by muscular weakness. Autoantibodies to presynaptic P/Q-type voltage-gated calcium channels (VGCCs) induce defective neuromuscular function. In severe cases, current immunosuppressive and immunomodulatory treatment strategies are often insufficient. First reports show beneficial effects of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy in patients with autoantibody-mediated myasthenia gravis. We report a patient with isolated idiopathic LEMS treated with autologous anti-CD19-CAR-T cells. In this patient, CAR-T infusion leads to expansion of predominantly CD4+ CAR-T cells with a terminally differentiated effector memory cells re-expressing CD45RA (TEMRA)-like phenotype indicating cytotoxic capabilities and subsequent B cell depletion. VGCC antibody titers decrease, resulting in a clinical improvement of LEMS symptoms, e.g., 8-fold increase in walking distance. The patient does not show relevant side effects except for cytokine release syndrome grade 2 and intermittent neutropenia suggesting that anti-CD19 CAR-T cell therapy may be a treatment option in patients with LEMS.

Human macrophage polarisation and regulation of angiogenesis and osteogenesis is dependent on culture extracellular matrix and dimensionality

The immune system plays a crucial role in tissue repair and regeneration. Macrophages have been identified as master regulators of the early immune response and healing outcome, by orchestrating the temporal nature of the initial inflammation phase and coordinating the fate of stem/progenitor cells involved in regeneration. However, traditional in-vitro models for the study of macrophages often fail to fully replicate the complexity of the in-vivo microenvironment, therefore generating models which do not fully capture the extensive spectrum of macrophage behaviour seen in native tissues. To this end, we used a hematoma-mimetic 3D fibrin matrix characteristic of early injured tissues to generate a 3D in-vitro model mirroring the local macrophage microenvironment. Leveraging this framework, we demonstrated significant effects of extracellular matrix and dimensionality on macrophage basal signalling and polarisation, achieving more pronounced regenerative phenotypes upon stimulation with the M2a polarisation factors compared to traditional 2D tissue culture conditions. Moreover, this enhanced physiological macrophage behaviour corresponded to increased coordination of angiogenesis and osteogenesis, better mirroring the healing processes seen in-vivo. Taken together, this study demonstrates the critical importance of integrating tissue composition and 3D architecture when investigating the macrophage behaviour in-vitro, establishing a powerful tool that overcomes known limitations associated with traditional 2D culture on plastic, and can be used to identify and validate novel immunomodulation strategies to enhance tissue regeneration.

Current Scenario and Future Perspectives of Porcine Corneal Xenotransplantation.

Corneal diseases represent a significant cause of blindness worldwide, with corneal transplantation being an effective treatment to prevent vision loss. Despite substantial advances in transplantation techniques, the demand for donor corneas exceeds the available supply, particularly in developing countries. Cornea xenotransplantation has emerged as a promising strategy to address the worldwide scarcity, notably using porcine corneas. In addition to the inherent immune privilege of the cornea, the low cost of porcine breeding and the anatomical and physiological similarities between humans and pigs have made porcine corneas a viable alternative. Nonetheless, ethical concerns, specifically the risk of xenozoonotic transmission and the necessity for stringent biosafety measures, remain significant obstacles. Moreover, the success of xenotransplantation is compromised by innate and adaptive immune responses, which requires meticulous consideration and further studies. Despite these challenges, recent breakthroughs have further contributed to reducing immunogenicity while preserving the corneal architecture. Advances in genetic engineering, such as the use of CRISPR-Cas9 to eliminate critical porcine antigens, have shown promise for mitigating immune reactions. Additionally, new immunosuppressive protocols, such as have techniques like decellularization and the use of porcine-derived acellular matrices, have greatly increased graft survival in preclinical models. Future research must focus on refining immunomodulatory strategies and improving graft preparation techniques to ensure the long-term survival and safety of porcine corneal xenotransplantation in clinical trials in humans.