Strategies to overcome tumor microenvironment immunosuppressive effect on the functioning of CAR-T cells in high-grade glioma.

Despite significant progress in the treatment of some types of cancer, high-grade gliomas (HGGs) remain a significant clinical problem. In the case of glioblastoma (GBM), the most common solid tumor of the central nervous system in adults, the average survival time from diagnosis is only 15-18 months, despite the use of intensive multimodal therapy. Chimeric antigen receptor (CAR)-expressing T cells, which have already been approved by the Food and Drug Administration for use in the treatment of certain hematologic malignancies, are a new, promising therapeutic option. However, the efficacy of CAR-T cells in solid tumors is lower due to the immunosuppressive tumor microenvironment (TME). Reprogramming the immunosuppressive TME toward a pro-inflammatory phenotype therefore seems particularly important because it may allow for increasing the effectiveness of CAR-T cells in the therapy of solid tumors. The following literature review aims to present the results of preclinical studies showing the possibilities of improving the efficacy of CAR-T in the TME of GBM by reprogramming the TME toward a pro-inflammatory phenotype. It may be achievable thanks to the use of CAR-T in a synergistic therapy in combination with oncolytic viruses, radiotherapy, or epigenetic inhibitors, as well as by supporting CAR-T cells crossing of the blood-brain barrier, normalizing impaired angiogenesis in the TME, improving CAR-T effector functions by cytokine signaling or by blocking/knocking out T-cell inhibitors, and modulating the microRNA expression. The use of CAR-T cells modified in this way in synergistic therapy could lead to the longer survival of patients with HGG by inducing an endogenous anti-tumor response.

Infectious Disease Prophylaxis During and After Immunosuppressive Therapy.

Immune-mediated renal diseases are a diverse group of disorders caused by antibody, complement, or cell-mediated autosensitization. Although these diseases predispose to infection on their own, a growing array of traditional and newer, more targeted immunosuppressant medications are used to treat these diseases. By understanding their mechanisms of action and the infections associated with suppression of each arm of the immune system, nephrologists can better anticipate these risks and effectively prevent and recognize opportunistic infections. Focusing specifically on nonkidney transplant recipients, this review discusses the infections that can be associated with each of the commonly used immunosuppressants by nephrologists and suggest interventions to prevent infectious complications in patients with immune-mediated renal disease.

Vogt-Koyanagi-Harada Syndrome: A Case Report.

Vogt-Koyanagi-Harada disease (VKH) is a neurological disorder that impacts vision and hearing by causing the immune system to attack melanocytes. Symptoms of the condition include flu-like symptoms, eye pain, headache, and dizziness, which may progress to vitiligo and hearing impairment. The diagnostic criteria include ocular involvement, generalized choroiditis, tinnitus, meningitis, and skin depigmentation. The treatment includes corticosteroids and immunosuppressive drugs. VKH is believed to be an autoimmune condition, possibly triggered by hereditary factors and cross-reactivity with cytomegalovirus. VKH is common in East Asia and India and has a genetic link to certain alleles. Inflammation generated by Th1 in melanocytes results in the production of granulomas. An analysis of a 48-year-old female with VKH disease revealed symptoms of anterior uveitis and subsequent glaucoma. The treatment involved the administration of systemic steroids and intratympanic steroid injections. Biochemical indicators showed signs of inflammation. Timely identification and therapy are essential for managing VKH. Further research is necessary to enhance outcomes for patients with VKH disease.

Cardiac sarcoidosis treated with nonsteroidal immunosuppressive therapy.

Background: Nonsteroidal immunosuppressive therapy is a potential therapeutic strategy for cardiac sarcoidosis. However, it is not recommended as an established treatment option. This study aimed to demonstrate the clinical outcomes of patients with cardiac sarcoidosis using nonsteroidal immunosuppressants through the ILLUstration of the Management and PrognosIs of JapaNese PATiEnts with Cardiac Sarcoidosis multicenter retrospective registry. Methods: From a cohort of 512 patients, 426 who received corticosteroid therapy and 26 who received other immunosuppressive therapy were included for analysis. Clinical outcomes included all-cause death, fatal ventricular arrhythmic events (FVAE), and worsening heart failure with hospitalization. Results: Nonsteroidal immunosuppressants were used for retained fluorodeoxyglucose uptake in the heart (n = 14), corticosteroid side effects (n = 7), ventricular arrhythmia (n = 4), complete atrioventricular block (n = 2), worsened extracardiac sarcoidosis (n = 2), and other reasons (n = 2). They comprised of methotrexate (n = 20), cyclosporine (n = 2), cyclophosphamide (n = 2), and azathioprine (n = 3). After the addition of a nonsteroidal immunosuppressant, corticosteroids were reduced in 14 of 26 patients (5 [5-17] mg), although no patient discontinued corticosteroids. Of the 14 patients, decreased fluorodeoxyglucose uptake was observed in seven at follow-up. Clinical outcomes were observed in 11 patients (42.3 %). Detected events included all-cause death in five patients (19.2 %), FVAE in four (15.4 %), and worsening heart failure with hospitalization in five (19.2 %), with some overlap. Conclusions: Nonsteroidal immunosuppressive therapy may be a possible treatment option for patients who are not stabilized with corticosteroids alone or develop corticosteroid side effects.

Co-occurrence of oral pemphigus vulgaris and herpes simplex virus infection in a young patient with Crohn's disease: report of a rare case of oral lesions during anti-TFN alpha and immunomodulator therapy.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune disease that affects desmoglein-1 and desmoglein-3, leading to intraepithelial vesiculobullous lesions. In the oral mucosa, PV lesions can mimic other diseases such as mucous membrane pemphigoid, other forms of pemphigus, recurrent aphthous stomatitis, erythema multiforme, Stevens-Johnson syndrome, and virus-induced ulcers like herpes simplex virus (HSV), making diagnosis challenging. The co-occurrence of PV with Crohn's disease is rare and predominantly seen in younger patients. The therapeutic mainstay for both PV and Crohn's disease usually involves systemic corticosteroids combined with immunosuppressants and immunobiological drugs. Literature indicates that the use of these drugs, particularly TNF-alpha inhibitors, for managing autoimmune diseases like Crohn's can potentially induce other autoimmune diseases known as autoimmune-like syndromes, which include episodes of lupus-like syndrome and inflammatory neuropathies. There are few cases in the literature reporting the development of PV in individuals with CD undergoing infliximab therapy. CASE REPORT: A young female with severe Crohn's disease, treated with the TNF-alpha inhibitor infliximab, developed friable pseudomembranous oral ulcerations. Histopathological and immunofluorescence analyses confirmed these as PV. The treatment included clobetasol propionate and low-level photobiomodulation, which resulted in partial improvement. The patient later experienced severe intestinal bleeding, requiring intravenous hydrocortisone therapy, which improved both her systemic condition and oral lesions. Weeks later, new ulcerations caused by herpes virus and candidiasis were identified, leading to treatment with oral acyclovir, a 21-day regimen of oral nystatin rinse, and photodynamic therapy, ultimately healing the oral infections. To manage her condition, the gastroenterologists included methotrexate (25 mg) in her regimen to reduce the immunogenicity of infliximab and minimize corticosteroid use, as the patient was in remission for Crohn's disease, and the oral PV lesions were under control. CONCLUSION: Young patients with Crohn's disease should be referred to an oral medicine specialist for comorbidity investigation, as oral PV and opportunistic infections can arise during immunosuppressive therapy. The use of TNF-alpha inhibitors in patients treated for inflammatory bowel disease, such as Crohn's, should be carefully evaluated for potential side effects, including oral PV.

Atypical posterior reversible encephalopathy syndrome: A lentiform fork sign following transplantation.

Key Clinical Message: Posterior Reversible Encephalopathy Syndrome, typically characterized by parieto-occipital vasogenic edema, can present atypically, as a bilateral symmetrical vasogenic edema in the basal ganglia, featuring the called "lentiform fork sign." Prompt recognition of such variations is crucial for accurate diagnosis and tailored management, highlighting the complexity of this syndrome's manifestations. Abstract: Posterior Reversible Encephalopathy Syndrome (PRES) manifests as transient neurological symptoms and cerebral edema, commonly associated with immunosuppressive drugs (ISDs) in transplant recipients. ISDs can lead to endothelial dysfunction and compromise the blood-brain barrier. Typically, PRES exhibits identifiable MRI patterns, often demonstrating vasogenic edema in the bilateral parieto-occipital white matter. Identifying unique presentations, such as the recently observed "lentiform fork sign," commonly seen in uremic encephalopathy, emphasizes this syndrome's broad spectrum manifestations. A 19-year-old male, who underwent bilateral lung and liver transplantation, experienced a bilateral tonic-clonic seizure of unknown onset 47 days post-surgery. MRI findings revealed an unconventional PRES pattern, featuring the "lentiform fork sign" as bilateral symmetrical vasogenic edema in the basal ganglia, surrounded by a hyperintense rim outlining the lentiform nucleus bilaterally. Subsequent management, including ISD modification and magnesium supplementation, resulted in clinical and neuroimaging resolution. An almost complete clinical and radiological resolution was achieved after 14 days. The occurrence of PRES in transplant recipients highlights the intricate interplay among ISDs, physiological factors, and cerebrovascular dynamics, potentially involving direct neurovascular endothelial toxicity and disruption of the blood-brain barrier. Neuroimaging plays a pivotal role in diagnosis. The distinctive "lentiform fork sign" was observed in this patient despite the absence of typical metabolic disturbances. Management strategies usually involve reducing hypertension, discontinuing ISDs, correcting electrolyte imbalances, and initiating antiseizure drugs if necessary. Identifying the presence of the "lentiform fork sign" alongside typical PRES edema in a patient lacking renal failure emphasizes that this manifestation is not solely indicative of uremic encephalopathy. Instead, it might represent the final common pathway resulting from alterations in the blood-brain barrier integrity within the deep white matter. Understanding such atypical imaging manifestations could significantly aid earlier and more precise diagnosis, influencing appropriate management decisions.

Contemporary Immunosuppression Management and 1-Year Outcomes in Dual Organ Heart Transplantation.

BACKGROUND: There have been limited reports on immunosuppression strategies and outcomes in dual organ heart transplant populations, primarily from before the 2018 United Network for Organ Sharing (UNOS) heart allocation policy change. Recent data suggested that outcomes with heart-lung and heart-liver transplants remained comparable in the new allocation era, yet heart-kidney recipients have worse 1-year survival. METHODS: This single-center retrospective study evaluated adult heart-kidney, heart-liver, and heart-lung transplant recipients from September 2019 to May 2023. Immunosuppression regimen, infectious complications, and graft outcomes were collected for 12 months. RESULTS: A total of 36 patients (kidney n = 20, liver n = 9, and lung n = 7) were included in this study. Basiliximab was the most commonly employed induction strategy across the organ groups (12/20 in kidney, 4/9 in liver, and 7/7 in lung). All patients were on triple immunosuppression at 12 months posttransplant with prednisone wean achieved in one heart-liver recipient. Infection complications were frequently reported (95% kidney, 75% liver, 100% lung group). One patient went back to dialysis due to focal segmental glomerulosclerosis. One chronic lung allograft dysfunction was reported, but no other severe biopsy-proven rejection or retransplant was reported. The 1-year survival was 85% (17/20) in heart-kidney, 78% (7/9) in heart-liver, and 86% (6/7) in heart-lung recipients. CONCLUSION: This study summarized real-world immunosuppression strategies and outcomes in dual organ heart transplant recipients.

Leucosceptrane sesterterpenoids from Tibetan Leucosceptrum canum and their immunosuppressive activity.

Phytochemical investigation on the leaves of Tibetan Leucosceptrum canum, a Chinese medicinal herb, led to the isolation of seven new leucosceptrane sesterterpenoids (1-7) and five known analogs (8-12). Comprehensive spectroscopic analysis (including 1D and 2D NMR, and HRMS), quantum chemistry computations, and single crystal X-ray crystallographic analysis were applied to elucidate their structures. Compounds 1-3 and 6 were the first examples of the leucosceptrane sesterterpenoids with rare C-2 oxidation. Compound 2 exhibited immunosuppressive activities via suppressing the secretion of cytokines IL-6 and TNF-α in LPS-induced macrophages RAW264.7 with IC50 values of 13.39 and 19.34 µM, respectively.

A battle between two biological singularities: Immune response vs. cancer.

In a post-growth multicellular organism, the phenomenon in which a small number of rare cells can be the starting point for inducing a dramatic change in the entire system is considered a "biological singularity." The immune response and cancer can be regarded as singularity phenomena in mammals, but their nature is fundamentally different. The immune response is considered a "programmed" singularity, whereas cancer is an "unprogrammed" singularity. These two systems perpetually engage in a cycle of attack and defense within the organism. The outcome is depending on the wining system, which determines whether the individual experiences a state resembling light or darkness. However, the overall mechanism of the competition remains unclear and is expected to be elucidated with future innovations in bioimaging technologies. Immune checkpoint blockade therapy is a means by which the two singularity balances can be artificially manipulated; therefore, mechanistic insight is necessary for cancer treatment strategies. Altogether, these findings provide a different perspective crucial for understanding the behavior of dynamic cell populations in multicellular organisms.

Hepatitis B virus infection, infertility, and assisted reproduction. / ä¹™è‚ã€ä¸å­•ä¸è‚²ä¸Žè¾ åŠ©ç”Ÿæ®–.

BACKGROUND: Hepatitis B virus (HBV) is one of the most widespread viruses worldwide and a major cause of hepatitis, cirrhosis, and hepatocellular carcinoma. Previous studies have revealed the impacts of HBV infection on fertility. An increasing number of infertile couples with chronic hepatitis B (CHB) virus infection choose assisted reproductive technology (ART) to meet their fertility needs. Despite the high prevalence of HBV, the effects of HBV infection on assisted reproduction treatment remain limited and contradictory. OBJECTIVE: The aim of this study was to provide a comprehensive overview of the effect of HBV infection on fertility and discuss its effects on pregnancy outcomes, vertical transmission, pregnancy complications, and viral activity during ART treatment. METHODS: We conducted a literature search in PubMed for studies on HBV infection and ART published from 1996 to 2022. RESULTS: HBV infection negatively affected fertility in both males and females. Existing research shows that HBV infection may increase the risk of pregnancy complications in couples undergoing assisted reproduction treatment. The impact of HBV infection on the pregnancy outcomes of ART is still controversial. Current evidence does not support that ART increases the risk of vertical transmission of HBV, while relevant studies are limited. With the development of ART, the risk of HBV reactivation (HBVr) is increasing, especially due to the wide application of immunosuppressive therapy. CONCLUSIONS: Regular HBV infection screening and HBVr risk stratification and management are essential to prevent HBVr during ART. The determination of optimal strategy and timing of prophylactic anti-HBV therapy during ART still needs further investigation.

Multi-Metallic Nanosheets Reshaping Immunosuppressive Tumor Microenvironment through Augmenting cGAS-STING Innate Activation and Adaptive Immune Responses for Cancer Immunotherapy.

The highly immunosuppressive tumor microenvironment (TME) restricts the efficient activation of immune responses. To restore the surveillance of the immune system for robust activation, vast efforts are devoted to normalizing the TME. Here, a manganese-doped layered double hydroxide (Mn-LDH) is developed for potent anti-tumor immunity by reversing TME. Mn-LDH is synthesized via a one-step hydrothermal method. In addition to the inherent proton neutralization capacity of LDH, the introduction of manganese oxide endows LDH with an additional ability to produce oxygen. Mn-LDH effectively releases Mn2+ and Mg2+ upon exposure to TME with high levels of H+ and H2O2, which activates synthase-stimulator of interferon genes pathway and maintains the cytotoxicity of CD8+ T cells respectively, achieving a cascade-like role in innate and adaptive immunity. The locally administered Mn-LDH facilitated a "hot" network consisting of mature dendritic cells, M1-phenotype macrophages, as well as cytotoxic and helper T cells, significantly inhibiting the growth of primary and distal tumors. Moreover, the photothermal conversion capacity of Mn-LDH sparks more robust therapeutic effects in large established tumor models with a single administration and irradiation. Overall, this study guides the rational design of TME-modulating immunotherapeutics for robust immune activation, providing a clinical candidate for next-generation cancer immunotherapy.

Long-Term Observation of Prognostic Factors and Clinical Outcome of Vernal Keratoconjunctivitis in Childhood.

Purpose: Vernal keratoconjunctivitis (VKC) is a refractory ocular allergic disorder that mainly affects boys. Long-term follow-up has been rarely reported for VKC. We investigated the long-term clinical outcome of VKC to identify relevant clinical features of prognostic value based on follow-up for a median of 70 months. Methods: In total, 45 consecutive patients clinically diagnosed with VKC aged 4 to 12 years at onset at the Department of Ophthalmology of Fukuoka University Hospital were included. Patients were treated with immunosuppressive eye drops without simultaneous corticosteroid eye drops, except for the occurrence of exacerbations. Collated variables were gender, age at onset, clinical score of ocular lesions (conjunctival giant papillae, limbal edema and corneal epithelial lesions) at the first visit, and clinical score of atopic dermatitis (AD) at baseline. Cumulative cure rate was estimated using Kaplan-Meier method. A binomial logistic predictive model was used to determine the most reliable clinical predictors of VKC outcome. Results: The observation period ranged from 24 to 188 months, with median of 70 months. Among the 45 cases enrolled, all non-cured cases (14 cases) observed clinically were complicated by AD. Cumulative cure rate was 74.5% and 84.9% at eight- and ten-year follow-up, respectively. Ten-year cumulative cure rates of cases with and without AD were 50.5% and 100%, respectively, and a significant difference was found between these cumulative cure curves. Binomial regression analysis revealed that AD and gender were significantly related to worse outcome, and this binomial regression model had high sensitivity and specificity. Conclusion: This study demonstrated that th eclinical outcomeof VKC might be predicted by several factors that can beobtained in the early clinical phase. Information on the long-term prognosis of VKC patients might play an important role for precision medicine for VKC in childhood.

Magnolol's Therapeutic Efficacy and Immunomodulatory Effects in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) presents a significant health challenge, requiring effective treatments. Magnolol, a compound with potential anticancer properties, warrants investigation in OSCC treatment. Here, we aimed to assess the efficacy of magnolol in inhibiting progression of OSCC and to explore the underlying mechanisms of its action. MATERIALS AND METHODS: We evaluated the effect of magnolol on tumor progression using the MOC1-bearing orthotopic model. We examined its impact on pathology and toxicity through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and biochemical analysis. We also investigated the immunoregulatory effects of magnolol in the MOC1-bearing model using flow cytometry. RESULTS: At high doses, magnolol significantly reduced tumor volume (p<0.0001 for comparisons between treated with magnolol and untreated groups) and weight loss by 70% in vivo. It also induced caspase-dependent apoptosis, evidenced by 2.42-, 2-, and 2.2-fold increases in the expression of caspase-3, -8, and -9, respectively, in mouse tumors treated with high 60 mg/kg of magnolol compared to untreated (p<0.0001 for all comparisons). Magnolol demonstrated no toxicity, maintaining body weight and normal biochemical parameters, including liver and kidney function. Pathological evaluations showed no adverse effects on organs in all treatment groups. Moreover, high doses of magnolol enhanced natural killer cells (by 3%), dendritic cells (20-25%), and cytotoxic T cells (20-40%) while reducing myeloid-derived suppressor cells and regulatory T cells by 1.5 times. CONCLUSION: Magnolol demonstrates potential as a therapeutic agent for OSCC, offering antitumor efficacy and immunomodulatory benefits.

4th booster-dose SARS-CoV-2 heterologous and homologous vaccination in rheumatological patients.

Objective: to evaluate the immune response to the SARS-CoV-2 vaccines in adults with immune-mediated rheumatic diseases (IMRDs) in comparison to healthy individuals, observed 1-20 weeks following the fourth vaccine dose. Additionally, to evaluate the impact of immunosuppressive therapies, vaccination schedules, the time interval between vaccination and sample collection on the vaccine's immune response. Methods: We designed a longitudinal observational study conducted at the rheumatology department of Hospital de Copiapó. Neutralizing antibodies (Nabs) titers against the Wuhan and Omicron variant were analyzed between 1-20 weeks after administration of the fourth dose of the SARS-CoV-2 vaccine to 341 participants (218 IMRD patients and 123 healthy controls). 218 IMRD patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), systemic vasculitis (VS) and systemic scleroderma (SS) were analyzed. Results: Performing a comparison between the variants, Wuhan vs Omicron, we noticed that there were significant differences (p<0.05) in the level of the ID50, both for healthy controls and for patients with IMRDs. The humoral response of patients with IMRDs is significantly lower compared to healthy controls for the Omicron variant of SARS-CoV-2 (p = 0.0015). The humoral response of patients with IMRDs decreases significantly when the time interval between vaccination and sample collection is greater than 35 days. This difference was observed in the response, both for the Wuhan variant and for the Omicron variant. Conclusion: The IMRDs patients, the humoral response variation in the SARS-CoV-2 vaccine depends on doses and type of vaccine administered, the humoral response times and the treatment that these patients are receiving.

Armored bicistronic CAR T cells with dominant-negative TGF-ß receptor II to overcome resistance in glioblastoma.

Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor ß (TGF-ß) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-ß-mediated suppressive activity, we combined a dominant-negative TGF-ß receptor II (dnTGFßRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFßRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFßRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-ß concentration in a TGF-ß-rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGFßRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.

A validated UPLC-MS/MS method for the quantification of immunosuppressive drugs in peripheral blood mononuclear cells using liquid-liquid extraction with low temperature purification without complex pretreatment steps.

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0-128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2-20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

Delayed peak antibody titers after the second dose of SARS-CoV-2 vaccine in solid organ transplant recipients: Prospective cohort study.

Poor post-vaccination production of antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a concern among solid organ transplant (SOT) recipients. Furthermore, the timing and kinetics of antibody titers after the second vaccine dose are unknown. We conducted a multicenter prospective observational study that included 614 SOT recipients: 460 kidney, 53 heart, 50 liver, 20 lung, and 31 simultaneous pancreas-kidney (SPK). The participants received two doses of the mRNA vaccine (Pfizer BNT162b2 or Moderna mRNA-1273), as indicated. Serum samples were collected before the first and second vaccinations and at 1, 3, and 6 months after the second vaccine dose, which were then assessed for SARS-CoV-2 antibodies. The overall seropositivity rate was 43% at 1 month after administration of the second vaccine dose; it gradually increased to 68% at 3 months after second dose administration and to 70% at 6 months. In addition, recipient of kidney, lung or SPK transplants had lower antibody titers at the 3- and 6-month time points than did the other recipients. SOT recipients acquired SARS-CoV-2 S-IgG antibodies slowly, and the peak titer differed significantly from that of the general population.

Successful maintenance therapy with tocilizumab for severe acute liver failure associated with adult-onset still's disease.

Elevated liver enzymes are commonly observed among adult-onset Still's disease (AOSD), but severe acute liver failure is extremely rare. Although severe acute liver failure associated with AOSD poses a life-threatening condition, the appropriate treatment is unclear. Some case reports have demonstrated the efficacy of high-dose prednisolone (PSL) and cyclosporin A (CyA), although the adverse effects of CyA led certain patients to cease its use. Therefore, an alternative treatment option is crucial, and thus far, there have been no reports of tocilizumab (TCZ) being used for this severe phenotype. Here, we report the first case of successful treatment using TCZ as maintenance therapy for severe ALF associated with AOSD. Following initial treatment with high-dose PSL and CyA, our case was switched to TCZ due to CyA-related side effects including alopecia and tremors. Our case highlights TCZ as a potential option for maintenance therapy of this severe condition.

Unveiling Immunological Signatures and Predictors of Response to Immunosuppressive Therapy in Acquired Aplastic Anaemia".

Acquired Aplastic Anaemia (AA) often results from immune destruction of hematopoietic stem and progenitor cells. However, only 60-70% of patients with AA respond to immunosuppressive therapy (IST). There is lack of strong predictive marker for response to IST which can help therapy. Our study sought to pinpoint unique immune markers in AA patients and validate established predictors for response to IST. We enrolled 51 severe AA patients and analyzed 57 immunological parameters via flow cytometry. Additionally, we measured paroxysmal nocturnal hemoglobinuria (PNH) clone, telomere length, and thrombopoietin (TPO) levels prior to IST. After a 6-months follow-up, response was observed. Patients with AA had a distinct immunological signature characterized by absolute lymphopenia, skewed CD4/CD8 ratio with expansion of CD8 T cells with activated and senescent phenotype. Treg counts were reduced, while proportion of Treg A and B was comparable to controls. Treatment response was correlated with elevated Absolute Neutrophil Count (ANC), Absolute Reticulocyte Count (ARC), and reduced CD57+ CD8+ naive cells and B cell % before therapy. However, predictors like TPO, telomere length, and PNH did not emerge as indicators of treatment response. Identifying predictors for treatment response in AA is challenging due to abnormal haematopoiesis, genetic mutations, and treatment variables.

Neuropsychiatric manifestations of anti-N-methyl-D-aspartate receptor encephalitis in a 14-year-old female: A case report.

Key Clinical Message: This case underscores the critical importance of timely recognition and management of NMDAR encephalitis in adolescents to mitigate potential long-term sequelae. If a pediatric patient presents with suspected viral encephalitis, autoimmune etiology must be excluded via cerebrospinal fluid antibody assay to guide appropriate immunosuppressive therapy, and improve patient outcomes. Abstract: Autoimmune encephalitis particularly involving the n-methyl-d-aspartate receptor (NMDAR) is recognized as a rare cause of acute encephalopathy in pediatric patients. The following case is of a 14-year-old female diagnosed with anti-NMDAR encephalitis who initially presented with fever, episodic convulsions, and loss of consciousness. She subsequently developed right-sided body weakness, expressive aphasia, and visual hallucinations. Clinical examination revealed prominent neuropsychiatric manifestations such as altered sensorium, motor deficits, hallucinations, and visual disturbances. Cerebello-bulbar signs were not appreciable in this particular case. She was treated for viral encephalitis but showed no improvement. Laboratory investigations revealed the presence of NMDAR antibodies in the cerebrospinal fluid confirming the diagnosis of autoimmune etiology. The patient demonstrated notable improvement following immunosuppressive treatment.