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International Journal of Nanomedicine 2024This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have... (Review)
Review
This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have been extensively studied in various biomedical applications, their specific use in studying and addressing immunosuppression after stroke remains limited. Stroke-induced neuroinflammation is characterized by T-cell-mediated immunodepression, which leads to increased morbidity and mortality. Key observations related to immunodepression after stroke, including lymphopenia, T-cell dysfunction, regulatory T-cell imbalance, and cytokine dysregulation, are discussed. Nanomaterials, such as liposomes, micelles, polymeric nanoparticles, and dendrimers, offer advantages in the precise delivery of drugs to T cells, enabling enhanced targeting and controlled release of immunomodulatory agents. These nanomaterials have the potential to modulate T-cell function, promote neuroregeneration, and restore immune responses, providing new avenues for stroke treatment. However, challenges related to biocompatibility, stability, scalability, and clinical translation need to be addressed. Future research efforts should focus on comprehensive studies to validate the efficacy and safety of nanomaterial-based interventions targeting T cells in stroke-induced immunosuppression. Collaborative interdisciplinary approaches are necessary to advance the field and translate these innovative strategies into clinical practice, ultimately improving stroke outcomes and patient care.
Topics: Animals; Humans; Cytokines; Nanomedicine; Nanoparticles; Nanostructures; Stroke; T-Lymphocytes
PubMed: 38882535
DOI: 10.2147/IJN.S456632 -
Heliyon Jun 2024Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is...
Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is promising for advanced lung cancer treatment. However, the response rate requires being strengthened. This study aimed to determine whether the combination treatment of Qingfei mixture (QFM) and PD-1 inhibitor could improve the sensitivity of monoclonal antibody by regulating STAT1/IDO1-mediated tryptophan (Trp)-kynurenine (Kyn) pathway. The imaging system, immunofluorescence, hematoxylin-eosin staining, TUNEL, flow cytometry, HPLC, and ELISA were used to estimate the anti-tumor effects in LLC-luc tumor-bearing C57BL/6 mice treated with QFM, PD-1 inhibitor, 2-NP (enhancer of STAT1 transcription), and FICZ (AhR agonist) alone or in combination. IFN-γ-mediated A549 and LLC cells were treated with QFM-containing serum and fludarabine (FLU, STAT1 inhibitor), and cell viability, apoptosis, and Kyn content were then evaluated using CCK-8 assays, flow cytometry, and HPLC assays, respectively. Additionally, the expressions of STAT1, IDO1, AhR, NFATc1, TRIP12, PD-1, and PD-L1 were measured and . We found QFM increased the anti-cancer actions of PD-1 inhibitors by increasing the CD8IFNγ T cells infiltration and decreasing the ratio of Kyn/Trp. Besides, QFM-containing serum suppressed the proliferation and promoted apoptosis in A549 and LLC cells, meanwhile, FLU boosted the effects of QFM-containing serum. Moreover, the suppression of tumor growth in the combination therapy was attenuated in the mice receiving 2-NP or FICZ. The occurrence of the above results was accompanied by a decrease in STAT1, IDO1, AhR, PD-1, and PD-L1 expressions. Collectively, the findings suggested that QFM may increase the influences of PD-1 inhibitors at least partially by blocking the STAT1/IDO1-mediated tryptophan-kynurenine pathway in lung cancer.
PubMed: 38882349
DOI: 10.1016/j.heliyon.2024.e32260 -
JAAD International Jun 2024Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often...
BACKGROUND
Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often therapy-resistant.
OBJECTIVES
To compare the clinical, histological, and transcriptional features of irLP with spontaneous lichen planus (LP).
METHODS
Clinical and histological presentations of irLP and LP, as well as the gene expression profiles of irLP and LP lesional and healthy skin were assessed.
RESULTS
irLP differed considerably from LP with regard to the distribution pattern of skin lesions with irLP appearing mostly in an exanthematous form, whereas lesions were more localized in the LP group. Histologically, dermal lymphocyte infiltration was significantly lower in irLP compared with LP, whereas lymphocyte exocytosis and apoptotic keratinocytes were significantly higher in irLP. Gene expression analysis revealed irLP to have a more inflammatory profile with elevated levels and a possible role of phagosome signaling compared with LP.
LIMITATIONS
The study is descriptive and necessitates further investigation with larger cohorts and broader analyses.
CONCLUSION
irLP differs from spontaneous LP on the clinical, histopathological, and gene expression level. The inflammatory gene signature in irLP suggests that topical JAK inhibitors could be an effective treatment, targeting local skin inflammation without systemic immunosuppression.
PubMed: 38882039
DOI: 10.1016/j.jdin.2023.11.013 -
Scientific Reports Jun 2024This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of...
Dual T-cell depletion with individually tailored anti-thymocyte globulin and attenuated dose of post-transplant cyclophosphamide in haploidentical peripheral stem cell transplantation.
This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT.
Topics: Humans; Antilymphocyte Serum; Cyclophosphamide; Male; Female; Adult; Middle Aged; Graft vs Host Disease; Retrospective Studies; T-Lymphocytes; Lymphocyte Depletion; Transplantation, Haploidentical; Transplantation Conditioning; Young Adult; Peripheral Blood Stem Cell Transplantation; Adolescent; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Immunosuppressive Agents
PubMed: 38880835
DOI: 10.1038/s41598-024-64361-5 -
Biochemistry. Biokhimiia May 2024Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor.... (Review)
Review
Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and the most abundant population of immune cells infiltrating a tumor. TAMs can largely determine direction of anti-tumor immune response by promoting it or, conversely, contribute to formation of an immunosuppressive TME that allows tumors to evade immune control. Through interactions with tumor cells or other cells in the microenvironment and, as a result of action of anti-cancer therapy, macrophages can enter senescence. In this review, we have attempted to summarize information available in the literature on the role of senescent macrophages in tumors. With the recent development of senolytic therapeutic strategies aimed at removing senescent cells from an organism, it seems important to discuss functions of the senescent macrophages and potential role of the senolytic drugs in reprogramming TAMs to enhance anti-tumor immune response and improve efficacy of cancer treatment.
Topics: Tumor Microenvironment; Humans; Neoplasms; Tumor-Associated Macrophages; Cellular Senescence; Animals; Macrophages; Biomarkers, Tumor
PubMed: 38880645
DOI: 10.1134/S0006297924050055 -
Journal of Cranio-maxillo-facial... May 2024The aim of this study was to identify predictors of length of stay (LOS) after surgical therapy of maxillofacial abscess. Patients diagnosed with a maxillofacial abscess...
The aim of this study was to identify predictors of length of stay (LOS) after surgical therapy of maxillofacial abscess. Patients diagnosed with a maxillofacial abscess who underwent extraoral incision and drainage under general anesthesia between January 1st, 2012 and January 1st, 2022 were retrospectively reviewed Univariable and multivariable linear regressions were performed to identify the association between pre- and perioperative variables and the LOS. In total, 228 patients were included. In the forward stepwise multivariable analysis, all factors with a p-value <0.2 in the univariable model were included. Ultimately, six independent predictors of increased LOS were identified: female (coef. 0.14, 95% CI 0.03-0.25), immunosuppression (coef. 0.37, 95%CI 0.13-0.61), penicillin allergy (coef. 0.25, 95% CI 0.04-0.46), C-reactive protein (coef. 0.0008, 95% CI 0.0001-0.0014), multiple spaces involvement (coef. 0.36, 95% CI 0.13-0.59), and time to operation (coef. 0.005, 95% CI 0.002-0.008). In conclusion, our study provides new insights into predicting LOS for patients admitted with maxillofacial abscesses. The identification of these markers not only enhances the ability to forecast LOS, but also lays the groundwork for optimizing resource planning and potentially integrating them into a primary prevention algorithm.
PubMed: 38876956
DOI: 10.1016/j.jcms.2024.05.001 -
Immunobiology Jul 2024Recent evidence has shown that T cell exhaustion is implicated in Allergen-specific Immunotherapy (AIT). However, how T cell exhaustion plays a role in AIT is far from...
Recent evidence has shown that T cell exhaustion is implicated in Allergen-specific Immunotherapy (AIT). However, how T cell exhaustion plays a role in AIT is far from clear. Our study aimed to investigate T cell exhaustion associated with allergen exposure during AIT in mice. Ovalbumin (OVA) - sensitized C57BL/6J asthma mouse and AIT mouse models were constructed. Quantitative real-time PCR (qRTPCR) and flow cytometry were used to monitor the occurrence of local and systemic CD4 T cells and Th2T cells exhaustion in OVA-sensitized mice. The inhibitory surface marker programmed cell death protein 1 (PD-1) on CD4 T cells and Th2T cells was significantly upregulated in AIT mice compared with asthmatic and control mice. The level of PD-1 on the surface of CD4T cells of asthma mice was significantly higher than that of control mice. The inhibitory surface marker cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on CD4 T cells and Th2T cells showed no significant difference between the AIT, asthma and control mice. Collectively, our study indicated that the expression of PD-1 on CD4 T cells and Th2T cells was increased in AIT. Allergen exposure promotes the expression of PD-1 on the surface of CD4 T cells. T cell exhaustion plays an important role in AIT.
Topics: Animals; Programmed Cell Death 1 Receptor; Mice; CD4-Positive T-Lymphocytes; Asthma; Allergens; Desensitization, Immunologic; Th2 Cells; Mice, Inbred C57BL; Disease Models, Animal; Female; Biomarkers; Ovalbumin
PubMed: 38875763
DOI: 10.1016/j.imbio.2024.152824 -
Frontiers in Immunology 2024The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved...
The five-year survival rates for pancreatic ductal adenocarcinoma (PDAC) have scarcely improved over the last half-century. It is inherently resistant to FDA-approved immunotherapies, which have transformed the outlook for patients with other advanced solid tumours. Accumulating evidence relates this resistance to its hallmark immunosuppressive milieu, which instils progressive dysfunction among tumour-infiltrating effector T cells. This milieu is established at the inception of neoplasia by immunosuppressive cellular populations, including regulatory T cells (T), which accumulate in parallel with the progression to malignant PDAC. Thus, the therapeutic manipulation of T has captured significant scientific and commercial attention, bolstered by the discovery that an abundance of tumour-infiltrating T correlates with a poor prognosis in PDAC patients. Herein, we propose a mechanism for the resistance of PDAC to anti-PD-1 and CTLA-4 immunotherapies and re-assess the rationale for pursuing T-targeted therapies in light of recent studies that profiled the immune landscape of patient-derived tumour samples. We evaluate strategies that are emerging to limit T-mediated immunosuppression for the treatment of PDAC, and signpost early-stage trials that provide preliminary evidence of clinical activity. In this context, we find a compelling argument for investment in the ongoing development of T-targeted immunotherapies for PDAC.
Topics: Animals; Humans; Carcinoma, Pancreatic Ductal; Immune Checkpoint Inhibitors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Pancreatic Neoplasms; T-Lymphocytes, Regulatory; Tumor Microenvironment
PubMed: 38873607
DOI: 10.3389/fimmu.2024.1406250 -
Frontiers in Immunology 2024Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune...
INTRODUCTION
Autoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune dysregulation that may require long-lasting immunosuppression. Mycophenolate mofetil and sirolimus represent two well-tolerated options to treat these disorders, often as a steroid-sparing option. However, no data are available on the infection risk for patients undergoing long-lasting treatments.
PATIENTS AND METHODS
The rate of severe infective events was calculated in episodes per 100 persons/months at risk (p/m/r) documented by the analysis of hospitalization charts between January 2015 and July 2023 of patients treated with mycophenolate mofetil or sirolimus given for isolated AIC or AICs associated with autoimmune lymphoproliferative syndrome (ALPS)/ALPS-like syndromes in two large Italian pediatric hematology units.
RESULTS
From January 2015 to July 2023, 13 out of 96 patients treated with mycophenolate mofetil or sirolimus developed 16 severe infectious events requiring hospitalization. No patients died. Overall infection rate was 0.24 person/*100 months/risk (95% CI 0.09-0.3). Serious infectious events incidence was higher in patients with ALPS-like compared to others (0.42 versus 0.09; = 0.006) and lower in patients who underwent mycophenolate treatment alone compared to those who started sirolimus after mycophenolate failure (0.04 versus 0.29, = 0.03). Considering only patients who started treatment at the beginning of study period, overall cumulative hazard was 18.6% at 60 months (95% CI 3.4-31.4) with higher risk of infectious events after 5 years in ALPS-like patients (26.1%; 95% CI 3.2-43.5) compared to other AICs (4%; 95% CI 0-11.4; = 0.041).
DISCUSSION
To the best of our knowledge, this is the first study to describe the infectious risk related to mycophenolate and sirolimus chronic treatment in patients with AICs and immune dysregulation. Our data highlight that infection rate is very low and mainly related to the underlying hematological condition.
CONCLUSIONS
Mycophenolate and sirolimus represent a safe immunosuppressive therapy in AICs and immune dysregulation syndromes.
Topics: Humans; Mycophenolic Acid; Sirolimus; Female; Male; Child; Immunosuppressive Agents; Child, Preschool; Adolescent; Infant; Autoimmune Diseases; Infections; Risk Factors; Retrospective Studies; Incidence; Cytopenia
PubMed: 38873600
DOI: 10.3389/fimmu.2024.1415389 -
Stem Cell Research & Therapy Jun 2024Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with...
BACKGROUND
Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases.
METHODS
Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR.
RESULTS
The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process.
CONCLUSION
This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.
Topics: Animals; Colitis; Mice; Benzylamines; Male; Cyclams; Dextran Sulfate; Mice, Inbred C57BL; Tacrolimus; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Hematopoietic Stem Cells; Disease Models, Animal; Immunosuppression Therapy; Immunosuppressive Agents; Microspheres; Reactive Oxygen Species
PubMed: 38872206
DOI: 10.1186/s13287-024-03777-2