Immune Targets Research Articles

Ocular Rosacea: An Updated Review.

Ocular rosacea is a chronic inflammatory disorder affecting the ocular surface, often associated with cutaneous rosacea. This review aims to explore its pathogenesis, treatment approaches, and future directions for management. A review of current literature on the pathophysiology, clinical features, and treatment strategies of ocular rosacea in adults and children (pediatric blepharokeratoconjunctivitis) was conducted. Emerging research on immune dysregulation, microbiome alterations, and potential therapeutic targets was analyzed. Ocular rosacea involves dysregulation of the immune and neurovascular systems, with toll-like receptor activation and complement system involvement leading to chronic ocular surface inflammation. Alterations in the ocular microbiome have been implicated in disease progression. Treatment strategies emphasize a stepwise approach, incorporating ocular and skin hygiene, lifestyle modifications, and pharmacological interventions. Recent advancements in understanding the disease mechanisms have led to the exploration of targeted therapies, including biologics and small-molecule inhibitors. Ocular rosacea remains challenging to diagnose and treat, particularly in children (pediatric blepharokeratoconjunctivitis), often leading to delayed intervention and poor outcomes. A multidisciplinary approach, including new therapeutic options, holds promise for improving patient care. Further research into the genetic and molecular basis of ocular rosacea may enable more personalized treatments.

Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5.

People living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND), even though combination antiretroviral therapy (cART) suppresses HIV replication. HIV-1 transactivator of transcription (HIV-1 Tat) contributes to the development of HAND through neuroinflammatory and neurotoxic mechanisms. C-C chemokine 5 receptor (CCR5) is important in immune cell targeting and is a co-receptor for HIV viral entry into CD4+ cells. Notably, CCR5 has been implicated in cognition unrelated to HIV infection. Inhibition of CCR5 has been shown to improve learning and memory. To test whether CCR5 is involved in cognitive changes in HAND, we used a non-infectious, transgenic model in which HIV-1 Tat is inducibly expressed. Well-powered cohorts of male and female mice were placed on a diet containing doxycycline to induce Tat expression for 8-wks. Males showed Tat-mediated deficits in the Barnes maze test of spatial learning and memory; females showed no impairments. Deficits in the males were fully reversed by the CCR5 antagonist, maraviroc (MVC). Tat-mediated deficits were not found in novel object recognition or contextual fear conditioning in either sex. Based on earlier work, we hypothesized that MVC might increase brain-derived neurotrophic factor (BDNF), which is essential in maintaining synaptodendritic function. MVC did increase the mBDNF to proBDNF ratio in males, perhaps contributing to improved cognition.

Illuminating the impact of CD38-induced adenosine formation in B-cell lymphoma

The expression of CD38 by cancer cells may mediate an immune-suppressive effect by producing Extracellular Adenosine (ADO) acting through G-protein-coupled cell surface receptors on cellular components and tumor cells. This can increase PD-1 expression and interaction with PD-L1, suppressing CD8 + cytotoxic T cells. This study examines the impact of heightened CD38 expression and extracellular ADO on various hematological and clinical parameters in patients with mature B-cell lymphoma, alongside their correlation with the soluble counterparts of the PD-1/PD-L1 axis. Our study was conducted on 90 patients, CD38-positive and CD38-negative (measured by flow cytometry), with mature B-cell lymphoma divided into CLL and B-NHL subtypes. Their serum ADO, soluble PD-1, and PD-L1 levels were measured using a sandwich ELISA. Our study revealed a positive correlation between CD38 expression, sADO, sPD-1, and sPD-L1 in mature B-cell lymphoma patients. CD38-positive patients had higher sADO, sPD-1, and sPD-L1 levels. Higher CD38 expression and extracellular ADO negatively affected HB level and PLT count and positively correlated with the higher risk stratification in mature B-cell lymphoma patients. This study explored the potential impact of CD38 expression and elevated extracellular ADO on B-cell lymphoma alongside their link with the PD-1/PD-L1 axis. Our findings underscore the influence of extracellular ADO on the neoplastic process of mature B-cell lymphoma. We also propose targeting the CD38-induced-ADO formation pathway, which could serve as a promising therapeutic immune target with multifaceted effects within mature B-cell neoplasms.

Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment

The tumor microenvironment (TME) plays a pivotal role in neoplastic initiation and progression. Epigenetic machinery, governing the expression of core oncogenes and tumor suppressor genes in transformed cells, significantly contributes to tumor development at both primary and distant sites. Recent studies have illuminated how epigenetic mechanisms integrate external cues and downstream signals, altering the phenotype of stromal cells and immune cells. This remolds the area surrounding tumor cells, ultimately fostering an immunosuppressive microenvironment. Therefore, correcting the TME by targeting the epigenetic modifications holds substantial promise for cancer treatment. This review synthesizes recent research that elucidates the impact of specific epigenetic regulations—ranging from DNA methylation to histone modifications and chromatin remodeling—on stromal and immune cells within the TME. Notably, we highlight their functional roles in either promoting or restricting tumor progression. We also discuss the potential applications of epigenetic agents for cancer treatment, envisaging their ability to normalize the ecosystem. This review aims to assist researchers in understanding the dynamic interplay between epigenetics and the TME, paving the way for better epigenetic therapy.

Immunomodulatory insights of monoterpene glycosides in endometriosis: immune infiltration and target pathways analysis

Endometriosis is a complex gynecological condition characterized by abnormal immune responses. This study aims to explore the immunomodulatory effects of monoterpene glycosides from Paeonia lactiflora on endometriosis. Using the ssGSEA algorithm, we assessed immune cell infiltration levels between normal and endometriosis groups. Key targets were identified through differential expression analysis of the GSE51981 dataset. Potential immunomodulatory targets of Paeonia lactiflora compounds were identified through Venn diagram analysis, followed by enrichment and machine learning analyses. A nomogram was developed for predicting endometriosis, while molecular docking explored compound-target interactions. Significant differences in immune cell infiltration were observed, with increased CD8 T cells, cytotoxic cells, and others in endometriosis. Differential expression analysis identified 43 potential targets. Enrichment analysis highlighted pathways involved in immune and inflammatory responses. Machine learning identified SSTR5, CASP3, FABP2, and SYK as critical targets, contributing to a nomogram that demonstrated good predictive performance for endometriosis risk. Molecular docking revealed strong interactions between Paeoniflorigenone and CASP3. Our findings suggest that monoterpene glycosides have therapeutic effects on endometriosis by modulating key immune-related targets and pathways, providing a basis for further investigation into Paeonia lactiflora’s potential as a treatment for this condition.

Immune targets for schistosomiasis control identified by a genome-wide association study of African snail vectors.

Schistosomiasis, a neglected tropical disease, is transmitted by freshwater snails. Interruption of transmission will require novel vector-focused interventions. We performed a genome-wide association study of African snails, Biomphalaria sudanica , exposed to Schistosoma mansoni in an endemic area of high transmission in Kenya. Two snail genomic regions, SudRes1 and SudRes2, were significantly associated with snail immunity to schistosomes. SudRes1 includes receptor-like protein tyrosine phosphatases while SudRes2 includes a class of leucine-rich repeat-containing G-protein coupled receptors, both comprising diverse extracellular binding domains suggestive of host-pathogen interaction. Resistant and susceptible haplotypes show numerous coding differences including presence/absence of entire genes. No loci previously tied to schistosome resistance in neotropical snail species showed any association with compatibility suggesting that loci involved in the resistance of African vectors are distinct. Snail ancestry was also strongly correlated with parasite compatibility. These results will inform future efforts to predict and manipulate immunity of a major schistosome vector.

Ultrasound-triggered drug-loaded nanobubbles for enhanced T cell recruitment in cancer chemoimmunotherapy.

Chemotherapy combined with immunotherapy is a highly promising approach for treating tumors. However, chemotherapeutic drugs often fail to accumulate effectively at the tumor site after systemic administration and they lack sufficient immunogenicity to activate adaptive immunity, making an effective T-cell immune response within the tumor microenvironmentdifficult to achieve. Here, this work developed drug-loaded nanobubbles (DTX-R837@NBs) that encapsulate the chemotherapy drug docetaxel and the immune adjuvant R837 via a thin-film hydration method. Ultrasound-targeted nanobubble destruction promoted drug accumulation within tumor tissues and damaged tumor cells through the cavitation effect, inducing immunogenic cell death and releasing damage-associated molecular patterns to augment dendritic cell maturation. Notably, DTX-R837@NBs exhibited excellent contrast-enhanced ultrasound imaging capabilities, enabling the seamless integration of diagnosis and treatment. In combination with immune checkpoint blockade targeting programmed cell death protein 1 (PD-1), the generated immunological responses attacked residual tumor cells and ameliorated the immunosuppressive tumor microenvironment, inhibiting distant tumor growth and metastasis. Moreover, this strategy exhibited robust immune memory effects, effectively protecting the host and preventing tumor recurrence upon rechallenge. Overall, ultrasound-mediated DTX-R837@NBs combined with anti-PD-1 immune checkpoint blockade therapy exhibits robust antitumor efficiency, represent a promising strategy for overcoming immunotherapy resistance in cold tumors, and warrant further investigation for clinical translation.

Discovery and exploration of adaptive immune response-related drug targets in diabetic retinopathy by Mendelian randomization

Discovery and exploration of adaptive immune response-related drug targets in diabetic retinopathy by Mendelian randomization

Immune Mechanisms and Treatment Targets in Rheumatoid Arthritis

Immune Mechanisms and Treatment Targets in Rheumatoid Arthritis

Tissue Determinants of Antiviral Immunity in the Liver.

The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.

A new strategy for drug delivery systems in oral diseases using stem cell-derived extracellular vesicles: review and new perspectives.

Extracellular vesicles (EVs) are membrane vesicles derived from cells and serve as an endogenous mechanism for intercellular communication. Since the discovery of their capacity to effectively transfer biological information, their potential as drug delivery vehicles has garnered significant scientific interest. Particularly, EVs derived from mesenchymal cells (MSC-EVs) have emerged as a highly promising method for drug delivery. They can transport bioactive molecules, such as nucleic acids, lipids, and proteins, and possess the ability to modulate immune responses, transmit information, and target specific cells. EVs offer several advantages over conventional drug delivery systems, including their capacity to traverse natural barriers, inherent cell targeting capabilities, and stability in circulation. Compared to their parent cells, EVs exhibit low immunogenicity, ease of storage and transport, and a reduced risk of tumorigenesis. The diagnosis and treatment of oral diseases often involve invasive measures, and MSC-EVs have demonstrated initial efficacy in oral disease treatment. This review explores the application of MSC-EVs in maxillofacial tissue regeneration, periodontitis, temporomandibular joint osteoarthritis, Sjögren's Syndrome, oral cancer, and other oral diseases. Additionally, it outlines potential future directions for the development of MSC-EVs. This review aims to provide a comprehensive understanding of MSC-EVs in oral disease treatment and to stimulate interest in their applications for targeted drug delivery.

Immune Checkpoint Inhibitors in Breast Cancer

The incidence of breast cancer has risen dramatically over the past few decades and has become the most common malignancy in women. By 2040, it is expected that there will be more than 3 million new cases of breast cancer and more than 1 million deaths per year. The incidence of breast cancer has risen dramatically over the past few decades and has become the most common malignancy in women. By 2040, it is expected that there will be more than 3 million new cases of breast cancer and more than 1 million deaths per year. Immune checkpoint therapeutics was significant technological breakthrough on cancer treatment programs. It uses the body’s immune system targets and eliminates cancer cells. This therapy maintains self-tolerance and modulates the immune response to minimize tissue damage during infection. This therapy inhibits immune checkpoints such as PD-1, PD-L1, and CTLA-4, which tumors exploit to evade immune detection. By blocking these pathways, immune checkpoint inhibitors can reactivate T cells, enabling them to recognize and attack breast cancer cells. This essay will explain how does checking for inhibitors help T cells recognize the breast tumor cells, and some drugs specialize in PD-1 and CTLA-4.

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.

Immunology and treatments of fatty liver disease.

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.

Complement C3d enables cell-mediated immunity capable of distinguishing spontaneously transformed from nontransformed cells

Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long noncoding (lnc) RNAs, to generate peptides for MHC-I presentation, and increase MHC-I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products that arise from noncanonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell-mediated immunity and sparing most nontransformed polyclonal B cells and PC with lower mutation loads. Malignant PC deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance.

Immune mechanisms and shared immune targets in neurodegenerative diseases.

The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.

Adenoviral Vectors for Gene Therapy of Hereditary Diseases.

Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, high capacity, and high transduction efficiency, which makes them actively used as oncolytic vectors and for creating vector vaccines. However, despite their numerous advantages, AdVs have not yet found their place in gene therapy for hereditary diseases. This review provides an overview of AdVs, their features, and clinical trials using them for gene replacement therapy in monogenic diseases and analyzes the reasons for the failures of these studies. Additionally, current research on the modification of AdVs to reduce immune responses and target delivery is discussed.

Metabolic inhibition induces pyroptosis in uveal melanoma.

Few treatment options are available for metastatic uveal melanoma (UM) patients. Although the bispecific tebentafusp is FDA-approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of UM. Treatment options that improve the recognition of UM by the immune system may be key to reducing disease burden. We investigated whether UM has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that UM expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8 (CASP1, 3, 4, and 8), and ninjurin1 (NINJ1). We induced cleavage of gasdermins in UM cell lines treated with metabolic inhibitors. In particular, the CPT1 inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage and the release of HMGB1 and IL-1β, indicating that the observed cleavage of gasdermins led to pyroptosis. Importantly, a gene-signature reflecting CPT1A activity correlated with poor prognosis in UM patients and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was GSDME-dependent, but GSDMD-independent and a pyroptosis gene-signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of UM patients. Together, these data show that metabolic inhibitors can induce pyroptosis in UM cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in metastatic UM patients. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.

Molecular Engineering of Ultrabright Biomimetic NanoGhost for Site-Selective Tumor Imaging and Biodistribution.

Optically active ultrabright imaging agents are shown to delineate tumor location with deep tissue visualization in pre noclinical tumor models. NanoGhosts (NGs) particles are reconstructed from the cell membrane and integrated with organic fluorophores to attain ultra-brightness for solid tumor imaging. Moreover, the integration of amphiphilic and lipophilic molecules reveals structural characteristics of NGs (≈70nm), which also alter their brightness. Upon intravenous administration (10 mgkg-1 single dose), these ultrabright NGs (778 MESF) enable the high-resolution of tumor site and real-time tracking of vital organs with high-contrast fluorescence signals. Engineered biomimetic NGs demonstrates better resolution and tissue penetration as compared to the clinically approved indocyanine green (ICG). High precision in tumor detection (0.5h) and strong tumor retention (24h which is further up to 30th day) without affecting healthy tissues ensure the future scope of NGs in early-stage cancer imaging. These findings suggest that these NGs mimic the biological characteristics of native cells, enabling them to evade immune clearance and target the solid tumor naturally.

Updates in novel immunotherapeutic strategies for relapsed/refractory AML.

Acute myeloid leukemia (AML) is a severe hematological malignancy with poor outcomes, particularly in older adults. Traditional treatment options like high-dose chemotherapy often lead to refractory or relapsed AML, with even worse outcomes. New therapies for relapsed and refractory AML are needed, and this review explores the most recent advancements in immunotherapy in AML. Checkpoint Inhibitors utilizing innate or adaptive immune targeting have shown potential to improve AML outcomes when combined with hypomethylating agents and chemotherapy. The use of adoptive cell therapy in AML demonstrates promising early data, however, there is a need for better target selection. Although early in development, both vaccine therapy as well as stimulator of interferon genes (STING) agonists have potential to enhance the innate immune response to overcome AML's immune evasion. Immunotherapy has become a promising approach for AML treatment, especially in refractory and relapsed AML, especially in patients who are not eligible for allogeneic stem cell transplants. Future research should focus on a deeper understanding of the immune microenvironment to identify the most critical targets for optimization, as well as personalized therapeutic combination strategies. Here we present a comprehensive overview of the recent developments in immunotherapy for relapsed and refractory AML.