Search Results (343)

Background: Immunological monitoring in multiple sclerosis (MS) patients treated with disease-modifying drugs may help predict infectious complications and guide treatment. The main objective of this study was to evaluate whether anti-CD20 treatments in MS patients induce immunodeficiency and whether certain immunological parameters can predict the risk of infection and response to treatment. Methods: This retrospective, observational, single-centre study included MS patients who started treatment with ocrelizumab or rituximab and received follow-up in the Neuroimmunology Unit of our centre between January 2017 and January 2023. The study was conducted in collaboration with the Immunology Department of this hospital. Results: Fifty-five patients were included, with a mean age of 47 years and a follow-up period of 24 months. Analyses of lymphocyte subpopulations (T, B, NK) and immunoglobulin levels (IgG, IgA, IgM) were performed before treatment and at 6-, 12- and 24-month follow-ups. In addition, we carried out an exhaustive study of B cells in the baseline analysis. Sixty-four percent of patients presented infections, mostly due to COVID-19. Three patients developed cryptogenic organising pneumonia. IgG hypogammaglobulinemia was the main risk factor for developing infections. Patients with infections had fewer mature memory B cells and a lower percentage of NK cells. Furthermore, a lower proportion of naïve and mature memory B cells was associated with inflammatory activity and disease progression, respectively. The absence of CD20 depletion during follow-up was associated with clinical worsening. Conclusions: Baseline immunophenotype and immunological monitoring can help predict the risk of infections and the efficacy of anti-CD20 therapy in MS patients. Full article

Multiple myeloma (MM) is a clonal malignancy of terminally differentiated plasma cells characterized by bone marrow infiltration and excessive production of monoclonal immunoglobulins, leading to end-organ damage such as osteolytic bone lesions. Despite substantial therapeutic progress achieved with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, multiple myeloma remains incurable, and outcomes for triple-class-refractory patients remain dismal, with median survival below one year. Bispecific T cell engaging antibodies (TCEs) have recently emerged as a promising immunotherapeutic approach capable of redirecting cytotoxic T cells to eliminate malignant plasma cells. These engineered antibodies simultaneously engage CD3 on T cells and a tumor-associated antigen such as B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor homolog 5 (FcRH5), thereby forming an immune synapse that triggers T cell activation, cytokine secretion, and perforin–granzyme-mediated apoptosis of the targeted B cell. This review summarizes the molecular design, mechanism of action, and clinical development of TCEs in MM, encompassing early bi-specific T cell engagers (BiTE) constructs such as AMG 420 and next-generation IgG-like molecules including teclistamab. Pivotal clinical trials have demonstrated overall response rates between 43% and 73%, accompanied by durable remissions and manageable safety profiles. Future directions include earlier-line integration, synergistic combinations with immunomodulatory or costimulatory agents, and the development of trispecific formats to overcome antigen escape and T cell exhaustion. Collectively, TCEs represent a paradigm shift toward durable, immune-mediated disease control in multiple myeloma. Full article

Background: Neurofilament light chain (NfL) is a well-established biomarker of neuroaxonal damage, detectable in serum through immunoassays. Its potential relevance in psychiatric conditions, including anorexia nervosa (AN), is currently under investigation. This study aims to quantify serum NfL levels in individuals with AN, evaluate their correlation with autoantibodies detection, and critically examine the specificity of NfL as a biomarker in this context. Methods: A total of 100 participants were enrolled, comprising 50 individuals diagnosed with AN and 50 age-matched, normal-weight controls. Serum concentrations of NfL and immunoglobulin G (IgG) antibodies reactive to hypothalamic antigens were measured using validated immunoassay techniques. Results: Serum NfL concentrations were markedly higher in the AN group compared to healthy controls. Interestingly, NfL levels tended to decrease with longer disease duration and with the recovery of body mass index (BMI), indicating a possible association between clinical improvement and reduced neuroaxonal damage. Furthermore, the results confirmed the presence of anti-hypothalamic autoantibodies and revealed a positive correlation between their levels and serum NfL concentrations. Conclusions: Clinical remission in AN appears to be linked to a decrease in both markers neuronal damage and hypothalamic autoimmunity. However, as elevated serum NfL is observed across a spectrum of neurological and psychiatric disorders, its specificity as a biomarker for AN should be further investigated. While NfL may reflect neuroaxonal injury in AN, its interpretation should be contextualized within a broader clinical and immunological framework. Full article

Background: Physiologically based pharmacokinetic (PBPK) modeling is applied to address clinical pharmacology issues including dose selection and exposure assessments for special populations (e.g., pediatrics, and renally or hepatically impaired patients). The objective of this study was to evaluate the predictive performance of a PBPK model for dosing assessment of intravenous immunoglobulin (IVIG) and anti-D immunoglobulin (anti-D Ig) products in pregnant women. Methods: A minimal PBPK (mPBPK) model that incorporates pregnancy-specific physiological parameters and allometric scaling approaches was developed and evaluated for predicting the exposure of IVIG and anti-D Ig in pregnant women. The concentration versus time data were obtained from the published literature. Results: The IVIG (n = 22) and anti-D Ig (n = 29) concentrations were predicted using the mPBPK model with an average fold error of 1.17 and 1.22, respectively. A total of 100% and 95% of IVIG concentrations were predicted within the 0.5–2-fold and 0.5–1.5-fold prediction error ranges, respectively. For anti-D Ig, predictions fell within the 0.5–2-fold and 0.5–1.5-fold ranges for 93% and 76% concentrations, respectively. A mPBPK model-based simulation following administration of 0.5 g/kg IVIG in 100 virtual nonpregnant and pregnant subjects revealed that the maximum plasma concentration (Cmax) was 15% lower and trough concentration (Ctrough) was 8% lower during the third trimester of pregnancy compared to nonpregnant subjects. In contrast, with flat dosing, Cmax and Ctrough were 32% and 26% lower in pregnant subjects, respectively. Overall, the model demonstrated reasonable predictive performance, and bodyweight-based dosing regimen is an acceptable approach that results in minimal change in exposure of IVIG in pregnant women. Full article

Background/Objectives: Following the global spread of SARS-CoV-2, there was an urgent need for vaccine development to support immune protection. This study aimed to evaluate the impact of active and hybrid immunity on the durability of immunoglobulin G (IgG), neutralizing antibodies, and cellular immune responses over a two-year period. Methods: This longitudinal study was conducted from February 2021 to December 2023 at the Public Health Institute in Ostrava, Czech Republic. Anti-S IgG was measured using ELISA (Euroimmun), neutralizing antibodies via an in-house virus neustralization test (VNT), and cellular immune response using the IGRA test (ELISA, Euroimmun). Participants also completed a questionnaire on demographics, COVID-19 history, symptoms, and vaccination. Statistical analysis included descriptive and non-parametric tests (Mann–Whitney U, Kruskal–Wallis) at a 5% significance level. Results: The cohort included 149 individuals, 97.3% of whom were vaccinated with Comirnaty (Pfizer/BioNTech). A total of 17% had confirmed infection prior to vaccination and showed up to two-fold higher neutralizing antibody levels (p < 0.001) within 2–6 weeks postvaccination. Postvaccination infection was reported in 35% of participants. Although antibody levels declined over the 2–100 week period, participants remained seropositive across all three parameters. Cellular immune response (interferon-γ) remained consistently high throughout follow-up. Conclusions: The study demonstrates long-term durability of IgG and neutralizing antibodies and confirms durable cellular immunity up to two years postvaccination. Hybrid immunity significantly enhanced neutralizing antibody levels, supporting its added value in protective immunity against SARS-CoV-2. Full article

Background and Objectives: Primary Epstein–Barr virus (EBV) infection in pediatric kidney transplant recipients with donor/recipient mismatch (D+/R−) carries the highest risk of post-transplant lymphoproliferative disorder (PTLD). Current prophylactic strategies are not standardized. Intravenous immunoglobulins (IVIG), containing anti-EBV antibodies, have been proposed as a potential preventive option, but evidence is lacking. This single-center retrospective case–control study evaluated the efficacy of serial IVIG administration in preventing primary EBV infection and promoting long-term immunity in this high-risk population. Materials and Methods: We retrospectively analyzed 26 pediatric kidney transplant recipients (age 1–18 years) with EBV D+/R− mismatch and a median follow-up of 7.5 years. Fourteen patients received scheduled IVIG infusions (200 mg/kg monthly for six months post-transplantation), while twelve received no EBV-directed prophylaxis. The primary endpoint was the cumulative incidence of primary EBV infection, defined as EBV-DNA > 1000 copies/mL in peripheral blood. The secondary endpoint was Epstein–Barr Nuclear Antigen-Immunoglobulin G (EBNA-IgG) seroconversion. Results: Patients receiving IVIG were significantly younger than controls (median age 4.2 vs. 10.8 years, p = 0.01). No significant variations were observed between groups in renal function or immunosuppressive levels during follow-up. IVIG prophylaxis was unexpectedly linked to a higher cumulative incidence of EBV infection compared with controls (64% vs. 25%, p = 0.047). Time-to-event analysis confirmed an increased, although not statistically significant, risk of EBV acquisition in the IVIG group (Hazard Ratio [HR] 3.24, 95% Confidence Interval [CI] 0.87–12.01; p = 0.079). EBV-specific immunity, assessed by EBNA-IgG seroconversion, was comparable between groups (HR 1.78; p = 0.45), confirming no immunological advantage of IVIG. One IVIG-treated patient (7.1%) developed PTLD, while none did in the control group. Conclusions: Scheduled IVIG administration during the first six months after transplantation does not constitute an effective strategy to prevent primary EBV infection or to enhance long-term immunity in high-risk EBV D+/R− pediatric kidney recipients and may even increase susceptibility to viral acquisition. These findings argue against the use of IVIG as EBV prophylaxis in this population. Full article

Bovine colostrum stands out as a natural supplement with rich bioactive components that attract attention for its therapeutic potential in the maintenance and improvement of gastrointestinal (GI) health. The major bioactive components of bovine colostrum include immunoglobulin (Ig) (especially immunoglobulin G), lactoferrin (LF), growth Factors (IGF-I, TGF-β, EGF), oligosaccharides (OS), and bioactive peptides. These components play a role in epithelial repair, suppression of inflammation, balancing the microbiota, and enhancing the mucosal barrier. Various animal models and recent human studies show that bovine colostrum has various positive effects against gastrointestinal tract diseases such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), non-steroidal anti-Inflammatory drug (NSAID)-induced enteropathy, and necrotizing enterocolitis (NEC). These effects include preservation of epithelial integrity, reduction of inflammatory markers, and improvement of intestinal permeability. Studies on the tolerability and efficacy profiles of various bovine colostrum formulations for oral, oropharyngeal, and enteral administration are increasing. In this review, the multifaceted effects of bovine colostrum on the gastrointestinal tract are explained at a mechanistic level, and potential areas of study for clinical translation are presented. Bovine Colostrum stands out as a promising natural biotherapeutic agent for both preventive and therapeutic approaches. Full article

This study aimed to evaluate the individual and combined effects of dandelion extract and akebia extract on growth, inflammation, and gut microbiota in weaned rabbits. Using a two-factor randomized design, 120 rabbits (1.219 kg ± 0.077 kg, 35 days of age) were divided into four groups (10 replicates/group). Growth metrics (feed intake, fecal score, weight gain) and biological samples (blood, liver, jejunal/ileal mucosa, digesta) were analyzed over 28 days. Key results indicated that combined dandelion and akebia supplementation significantly increased daily weight gain during the first week (p < 0.05). Dandelion alone reduced liver Immunoglobulin G (IgG) and jejunal interleukin 6 (IL-6) (p < 0.05). Akebia supplementation decreased serum immunoglobulin A (IgA)/IL-6, liver interleukin 1β (IL-1β)/IL-6/IgG, and jejunal IL-1β/IL-6/IgG/IgA (p < 0.05). Gene expression revealed dandelion downregulated liver interferon-γ (IFN-γ)/interleukin 10 (IL-10) and jejunal IL-1β/interleukin 10 (TNF-α) (p < 0.05), while akebia suppressed hepatic C-C Motif Chemokine Ligand 3 (CCL3)/C-X-C Motif Chemokine Ligand 10 (CXCL10)/IFN-γ/IL-1β and mucosal IL-1β/IFN-γ (p < 0.05). A significant interaction effect (p < 0.05) between dandelion and akebia reduced ileal IL-6/IL-10/TNF-α and jejunal CXCL10/IL-10 mRNA expression. Akebia also increased cecal microbial diversity and the abundance of Oxalibacilli and Sutterella while reducing Firmicutes abundance (p < 0.05). In conclusion, both extracts modulated immunity and attenuated inflammatory responses through modulation of immunoglobulins, cytokines, and chemokines. Their combination demonstrated synergistic anti-inflammatory effects, alongside beneficial shifts in gut microbiota composition. Full article

The optimal timing for initiating starter feeding in lambs remains controversial, warranting a systematic evaluation of its effects across multiple indicators. This study investigated the effects of initiating starter feeding at 7, 14, or 21 days of age on growth performance, rumen fermentation, serum immunity, gastrointestinal development, and microbiota in Hu lambs. Forty-five newborn lambs were randomly assigned to three groups (n = 15 per group) and fed starter until slaughter at weaning (60 days). The 14-day group exhibited significantly higher body weight (BW) at 49 and 60 days compared with the 7-day group (p < 0.05), and greater average daily gain (ADG) during 28–35 days than the 21-day group. Rumen ammonia nitrogen (NH₃-N), acetate, propionate, valerate, and total volatile fatty acids (VFAs) were higher in the 7-day and 14-day groups than in the 21-day group (p < 0.05). The 14-day group showed lower pro-inflammatory cytokines (IL-1β, TNF-α) and higher immunoglobulins (IgA, IgG, IgM) and anti-inflammatory cytokines (IL-2, IL-4) (p < 0.05). This group also displayed improved rumen papilla width, jejunal villus dimensions, and reduced crypt depth. Beneficial microbes such as Christensenellaceae_R-7_group and Butyrivibrio were enriched in the 14-day and 21-day groups. In conclusion, initiating starter feeding at 14 days of age optimizes growth, rumen function, immune response, and colonization of beneficial microbiota in Hu lambs. Full article

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The pathophysiology of IBD is multifactorial including genetic predisposition, mucosal and epithelial dysfunction, environmental injury, and both innate and adaptive immune response abnormalities. Several predisposing genetic factors have been associated with IBD explaining the strong hereditary risk for both CD and UC. For example, Caspase Recruitment Domain 9 (CARD9) variant rs10781499 increases risk for IBD, while other variants are specific to either CD or UC. CD is related to loss-of-function mutations in the nucleotide oligomerization domain containing the protein 2 (NOD2) gene and Autophagy-Related 16-like 1 (ATG16L1) gene. UC risk is increased particularly in Chinese populations by the A-1661G polymorphism of the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene. This abnormal CTLA-4 interferes with B- and T-cell responses causing predisposition to autoimmune conditions. Previous studies suggested that IBD results from breakdown of the adaptive immune system, primarily of T-cells. However, new evidence suggests that a primary breakdown of the innate immune system in both CD and UC increases susceptibility to invasion by viruses and bacteria, with a compensatory overactivation of the adaptive immune system as a result. When this viral and microbial invasion continues, further damage is incurred, resulting in a downward cycle of further cytokine activation and epithelial damage. Released biomarkers also affect the permeability of the epithelial membrane, including lactoferrin, nitric oxide (NO), myeloperoxidase (MPO) and its activation of hypochlorous acid, matrix metalloproteinases (MMPs), especially MMP-9, omentin-1, and others. Increased macrophage and dendritic cell dysfunction, increased neutrophil activity, increased numbers of innate lymphoid cells, increased T-cells with decreased regulatory T-cells (Tregs), and changes in B-cell populations and immunoglobulin (Ig) functions are all associated with IBD. Finally, treatment of IBD has typically consisted of medical management (e.g., aminosalicylates and corticosteroids) and lifestyle modification, and surgical intervention in extreme cases. New classes of medications with more favorable side effect profiles include anti-integrin antibodies, vedolizumab, etrolizumab, and carotegrast methyl. Additionally, fecal microbiota transplant (FMT) is a newer area of research for treatment of IBD along with TNF-blockers, JAK inhibitors, and S1PR modulators. However, expense and long preparation time have limited the usefulness of FMT. Full article

Rheumatoid arthritis (RA) is the most common inflammatory polyarthritis. In addition, 60–80% of patients express anti-citrullinated protein antibodies (ACPAs), which serve as a diagnostic marker for RA. The effector functions of these autoantibodies can be heavily affected by the N-glycosylation of their Fc region. Here we present a comparison of the Fc N-glycosylation of ACPA IgG to that of non-ACPA IgG from the same patients, and of healthy controls, in an IgG isoform-specific manner. We isolated ACPA and normal serum IgG, digested by trypsin, and separated the resulting peptide mixture by a reversed-phase nanoLC coupled to a Bruker Maxis II Q-TOF, and determined the relative abundance of glycoforms. The paired analysis of galactosylation and sialylation of the IgG subclasses of ACPA and non-ACPA IgG has shown a significant, moderate negative correlation with the inflammatory markers, the level of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), as well as with rheuma-factor (RF), but not with the disease activity score (DAS) or cyclic citrullinated peptide specific antibodies (anti-CCP). However, we detected a significant negative correlation between glycosylation and DAS in the non-ACPA IgG fractions. Furthermore, the isoform-specific analysis revealed additional insight into the changes of the glycosylation features of IgG in RA: changes in the frequencies of the bisecting GlcNAc unit between sample groups could be explained by only the IgG1 isoform; while invariance in fucosylation is the result of the superposition of two isoforms with opposite changes. These results highlight the importance of analyzing immunoglobulin glycosylation in an isoform-specific manner. Full article

Background: The hepatitis A virus (HAV) is a major cause of acute viral hepatitis and a significant global health concern. This study provides a pre-vaccination baseline for Oman, enabling longitudinal comparison with post-hepatitis A vaccination cohorts. This study aimed to determine the pre-vaccination seroprevalence of HAV antibodies (anti-HAV) in Oman and explore the associated demographic factors. Methods: A cross-sectional study was conducted from April 2014 to August 2015 among patients attending the medical outpatient clinic of the Medical City Hospital for Military and Security Services. Demographic data were collected via a structured questionnaire, and serum samples were tested for anti-HAV immunoglobulin IgG and IgM using enzyme-linked immunosorbent assays. Multivariate analysis was performed to identify the predictors of anti-HAV seroprevalence. Results: Among 1975 participants, 88.1% were positive for anti-HAV IgG. The mean age was 37.4 ± 16.1 years; however, those negative for anti-HAV IgG were considerably younger (mean age: 24.8 ± 15.7 years). Anti-HAV IgG seroprevalence was 37% in individuals aged ≤18 years and 91% in those >18 years (p < 0.001). The factors associated with seropositivity included older age (p < 0.001), consuming food prepared outside the home (p < 0.001), occupation (p < 0.001), and education level (p = 0.003). In the multivariable analysis, only age showed a strong independent association with serostatus: per 10-year increase, the aOR for anti-HAV IgG seropositivity was 2.87 (95% CI 2.25–3.63; p < 0.001). Conclusions: Our study estimates show high anti-HAV IgG seroprevalence and serve as a pre-vaccination baseline for evaluating the hepatitis A vaccination program in Oman over time. Given the lower natural exposure among younger cohorts, continued routine vaccination, scheduled serosurveys, and strengthened surveillance are required to identify emerging immunity gaps and prevent future HAV outbreaks. Full article

Ochratoxin A (OTA), a common mycotoxin contaminant, poses significant health risks through its multi-organ toxicity. While OTA is known to cause immune organ dysfunction leading to immunotoxicity, its precise mechanistic pathways remain unclear. The spleen is an important immune organ of the body and plays a key role in immune defense and homeostasis maintenance. Astaxanthin (AST), a potent antioxidant with demonstrated immunomodulatory properties, exhibits a broad therapeutic potential including anti-inflammatory, wound-healing, anti-aging, and hepatoprotective effects. Therefore, this study aimed to explore the mechanism by which AST attenuates OTA-induced immunotoxicity using a chicken OTA/AST treatment model. Sixty 1-day-old, white-feathered, sex-undifferentiated chicks were randomly allocated into four groups (n = 15): (1) Control, (2) OTA (1 mg/kg), (3) AST (100 mg/kg), and (4) OTA + AST (1 mg/kg OTA + 100 mg/kg AST). The experiment lasted for 21 days to establish the model. Subsequently, serum ELISA, antioxidant capacity assays, qRT-PCR, and western blot (WB) analyses were employed to explore the protective role of AST against immunotoxicity. The results showed that AST increased splenic organ coefficients and serum immunoglobulin (IgM and IgG) concentrations (p < 0.01) and decreased the expression of inflammatory factors (IL-8, IL-6, and IL-1β) (p < 0.01). We found that OTA was involved in the expression of the PTEN/PI3K/AKT signaling pathway (PTEN, PI3K, AKT, p-AKT (Ser473)) and apoptotic genes (Bcl-2, Bax, Caspase3, Caspase9). Notably, AST significantly attenuated OTA-induced oxidative damage (ROS, MDA, T-AOC) in the spleen (p < 0.05), upregulated the expression of PI3K and p-AKT (Ser473) (p < 0.05) and inhibited the expression of PTEN and apoptosis-related genes (p < 0.05). In summary, AST attenuates OTA-induced immunotoxicity by alleviating oxidative stress and modulating the PTEN/PI3K/AKT signaling pathway. Full article

Hepatitis B virus (HBV) remains a major global health concern, as it is not only one of the most common hepatotropic viruses but also ranks as the seventh leading cause of mortality worldwide. The most significant routes of infection include vertical transmission (from mother to child before, during, or after birth, including transplacental infection) and horizontal transmission in early childhood through close household contact with infected parents. The aim of our study was to assess the prevalence of chronic and occult hepatitis B virus infection among pregnant women in St. Petersburg (Russia), including molecular characterization. We analyzed plasma samples from 1368 local pregnant women. ELISA screening for HBV markers included qualitative detection of HBsAg, anti-HBs IgG, and anti-HBcore IgG. HBV DNA was identified using highly sensitive nested PCR, followed by whole-genome sequencing for HBV DNA-positive cases. Our study evaluated the prevalence of serological and molecular HBV markers and their association with age, vaccination status, and number of pregnancies. Serological markers HBsAg, anti-HBs IgG, and anti-HBcore IgG were detected in 1.9%, 63.8%, and 12.9% of participants, respectively. HBV DNA was found in 4.7% of pregnant women, including 2.8% with occult HBV infection (OBI). We observed a positive correlation between anti-HBcore IgG and age, but an inverse correlation with anti-HBs IgG; an inverse correlation between anti-HBcore IgG and vaccination status, while anti-HBs IgG showed a positive correlation; and a positive correlation between HBsAg, anti-HBcore IgG, and HBV DNA with the number of pregnancies. We also analyzed the prevalence of clinically significant mutations, including drug resistance mutations, escape mutations (affecting diagnostic detection and vaccine efficacy), and mutations associated with disease progression. The detection of HBsAg-negative HBV infection was linked to circulating viral variants carrying escape mutations, which evade HBsAg detection in diagnostic assays and neutralization by vaccine-induced antibodies. The predominance of HBV isolates in pregnant women harboring dual-threat mutations (those causing diagnostic failure via HBsAg negativity, reduced vaccine/immunoglobulin efficacy, viral reactivation, disease progression) poses a significant public health risk and warrants further investigation. Full article

This systematic review critically evaluates the efficacy and safety of monoclonal (mAb) and polyclonal (pAb) antibody therapies in adult sepsis and septic shock by synthesizing data from 29 randomized controlled trials (RCTs) encompassing over 10,000 patients. Sepsis and septic shock continue to be major critical-care mortality causes worldwide because of simultaneous hyperinflammatory and immunosuppressive responses. The clinical results from using targeted antibody therapies to manage this dysregulated response have shown inconsistent results. We conducted a comprehensive search of MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Google Scholar (through February 2025) to identify RCTs that compared mAb and pAb treatments to placebo or standard care in adult patients with sepsis or septic shock. Monoclonal antibodies against single cytokines e.g., Tumor Necrosis Factor-alpha (TNF-α) and endotoxin, did not significantly reduce 28-day mortality in unselected cohorts, though subgroup analyses of patients with elevated Interleukin-6 (IL-6) or early septic shock showed trends toward benefit. Intravenous Immunoglobulin (IVIG) enriched for Immunoglobulin M (IgM) demonstrated the most consistent mortality reduction when administered early in hyperinflammatory phases. Emerging precision strategies—including checkpoint inhibitors targeting Programmed Cell Death Protein 1/Programmed Death-Ligand 1 inhibitors (anti–PD-1/PD-L1), complement component 5a inhibitors (anti–C5a), and anti–adrenomedullin—were safe and improved organ-support-free days and Sequential Organ Failure Assessment (SOFA) scores. According to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, evidence showed moderate confidence for mortality, high certainty for safety and low to moderate certainty for secondary outcomes. The use of broad single-target monoclonal treatments has failed to deliver significant improvements in sepsis patient outcomes. The most promising approaches for sepsis treatment involve biomarker-guided precision strategies and polyclonal IgM-enriched IVIG. Future sepsis trials need to implement rapid immune profiling and adaptive designs and combination regimens to achieve optimal efficacy and establish personalized guideline-based sepsis management. Full article