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Redox Biology Jun 2024The effects of low energy availability (LEA) on the immune system are poorly understood. This study examined the effects of 14 days of LEA on immune cell redox balance...
INTRODUCTION
The effects of low energy availability (LEA) on the immune system are poorly understood. This study examined the effects of 14 days of LEA on immune cell redox balance and inflammation at rest and in response to acute exercise, and exercise performance in female athletes.
METHODS
Twelve female endurance athletes (age: 26.8 ± 3.4 yrs, maximum oxygen uptake (V˙O): 55.2 ± 5.1 mL × min × kg) were included in a randomized, single-blinded crossover study. They were allocated to begin with either 14 days of optimal energy availability diet (OEA, 52 ± 2 kcal × kg fat free mass (FFM) × day) or LEA diet (22 ± 2 kcal × kg FFM × day), followed by 3 days of refueling (OEA) with maintained training volume. Peripheral blood mononuclear cells (PBMCs) were isolated, and plasma obtained at rest before and after each dietary period. The PBMCs were used for analysis of mitochondrial respiration and HO emission and specific proteins. Exercise performance was assessed on cycle by a 20-min time trial and time to exhaustion at an intensity corresponding to ∼110 % V˙O).
RESULTS
LEA was associated with a 94 % (P = 0.003) increase in PBMC NADPH oxidase 2 protein content, and a 22 % (P = 0.013) increase in systemic cortisol. LEA also caused an alteration of several inflammatory related proteins (P < 0.05). Acute exercise augmented HO emission in PBMCs (P < 0.001) following both OEA and LEA, but to a greater extent following LEA. LEA also reduced the mobilization of white blood cells with acute exercise. After LEA, performance was reduced in both exercise tests (P < 0.001), and the reduced time trial performance remained after the 3 days of refueling (P < 0.001).
CONCLUSION
14 days of LEA in female athletes increased cortisol levels and had a pronounced effect on the immune system, including increased capacity for ROS production, altered plasma inflammatory proteome and lowered exercise induced mobilization of leukocytes. Furthermore, LEA resulted in a sustained impairment in exercise performance.
PubMed: 38936255
DOI: 10.1016/j.redox.2024.103250 -
Emerging Microbes & Infections Dec 2024Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral...
Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (= 0.048) and 96 (= 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770). ClinicalTrials.gov identifier: NCT04098770. ClinicalTrials.gov identifier: NCT02651376.
Topics: Humans; Male; Female; Adult; Middle Aged; Immunotherapy, Adoptive; Immunocompromised Host; HLA Antigens; Acquired Immunodeficiency Syndrome; Treatment Outcome; AIDS-Related Opportunistic Infections; Transplantation, Homologous; CD4-Positive T-Lymphocytes; CD4 Lymphocyte Count
PubMed: 38935839
DOI: 10.1080/22221751.2024.2364744 -
Frontiers in Immunology 2024Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER),... (Review)
Review
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. As a result, conventional hormonal and targeted therapies are largely ineffective, underscoring the urgent need for novel treatment strategies. γδT cells, known for their robust anti-tumor properties, show considerable potential in TNBC treatment as they can identify and eliminate tumor cells without reliance on MHC restrictions. These cells demonstrate extensive proliferation both and , and can directly target tumors through cytotoxic effects or indirectly by promoting other immune responses. Studies suggest that expansion and adoptive transfer strategies targeting Vδ2 and Vδ1 γδT cell subtypes have shown promise in preclinical TNBC models. This review compiles and discusses the existing literature on the primary subgroups of γδT cells, their roles in cancer therapy, their contributions to tumor cell cytotoxicity and immune modulation, and proposes potential strategies for future γδT cell-based immunotherapies in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Animals; Female; Receptors, Antigen, T-Cell, gamma-delta; Intraepithelial Lymphocytes; Immunotherapy, Adoptive; Immunotherapy
PubMed: 38933280
DOI: 10.3389/fimmu.2024.1420107 -
Frontiers in Immunology 2024Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are...
INTRODUCTION
Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.
METHODS
This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry and xenogenic tumor model .
RESULTS
We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity and .
DISCUSSION
Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA tumor effect and , bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.
Topics: Antibodies, Bispecific; Animals; Humans; T-Lymphocytes; Mice; Immunoglobulin G; Immunotherapy; Cell Line, Tumor; Multiple Myeloma; Xenograft Model Antitumor Assays; Lymphocyte Activation; CD3 Complex; Antigens, Neoplasm
PubMed: 38933272
DOI: 10.3389/fimmu.2024.1415834 -
Frontiers in Immunology 2024Anti-Thymocyte Globulin (ATG) is a cornerstone in immune suppression for solid organ transplantation. The treatment is a delicate balance between complications arising...
INTRODUCTION
Anti-Thymocyte Globulin (ATG) is a cornerstone in immune suppression for solid organ transplantation. The treatment is a delicate balance between complications arising from over-immunosuppression such as infections and cancer versus rejection stemming from under-immunosuppression. CD3 T-lymphocyte measurements are frequently employed for treatment monitoring. However, this analysis is costly and not always accessible. The aim of this study was to investigate whether the total count of lymphocytes could replace CD3 T-lymphocyte measurements based on data from our transplantation center combined with a review of the literature. The hypothesis was that the total lymphocyte count could serve as a diagnostic surrogate marker for CD3 T-lymphocytes.
METHODS
A retrospective cohort study was conducted, including patients who underwent kidney and/or a pancreas transplantation and received ATG as induction therapy or for rejection treatment. The inclusion criterium was that the total lymphocyte count and CD3 T-lymphocyte measurements were measured simultaneously on the same day. Additionally, PubMed and Embase were searched up to 18/10/2023 for published studies on solid organ transplantation, ATG, T-lymphocytes, lymphocyte count, and monitoring. In the retrospective cohort study, a total of 91 patients transplanted between 2016 and 2023, with 487 samples, were included.
RESULTS
Total lymphocyte counts below 0.3 x 10/L had a high sensitivity (86%) as a surrogate marker of CD3 T-lymphocytes below 0.05 x 10/L, but the specificity was low (52%) for total lymphocyte counts above 0.3 x 10/L as a surrogate marker for CD3 T-lymphocytes above 0.05 x 10/L. A review of the literature identified seven studies comparing total lymphocyte counts and CD3 T-lymphocytes in ATG monitoring. These studies supported the use of a low total lymphocyte count as a surrogate marker for CD3 T-lymphocytes and an indicator to omit ATG treatment. However, there was no consensus regarding high total lymphocyte counts as an indicator for continued treatment.
DISCUSSION
Results supports that the total lymphocyte count can be used to omit ATG treatment when below 0.3 x 10/L whereas the CD3 T-lymphocyte analysis should be reserved for higher total lymphocyte counts to avoid ATG overtreatment.
Topics: Humans; Antilymphocyte Serum; Lymphocyte Count; Retrospective Studies; Male; Female; Middle Aged; Adult; Graft Rejection; Immunosuppressive Agents; T-Lymphocytes; Kidney Transplantation; Aged; Pancreas Transplantation; CD3 Complex; Organ Transplantation
PubMed: 38933271
DOI: 10.3389/fimmu.2024.1419726 -
Frontiers in Immunology 2024Immune cells play a crucial role in the development and progression of pancreatic cancer, yet the causal relationship remains uncertain due to complex immune...
BACKGROUND
Immune cells play a crucial role in the development and progression of pancreatic cancer, yet the causal relationship remains uncertain due to complex immune microenvironments and conflicting research findings. Mendelian randomization (MR), this study aims to delineate the causal relationships between immune cells and pancreatic cancer while identifying intermediary factors.
METHODS
The genome-wide association study (GWAS) data on immune cells, pancreatic cancer, and plasma metabolites are derived from public databases. In this investigation, inverse variance weighting (IVW) as the primary analytical approach to investigate the causal relationship between exposure and outcome. Furthermore, this study incorporates MR-Egger, simple mode, weighted median, and weighted mode as supplementary analytical approaches. To ensure the reliability of our findings, we further assessed horizontal pleiotropy and heterogeneity and evaluated the stability of MR results using the Leave-one-out method. In conclusion, this study employed mediation analysis to elucidate the potential mediating effects of plasma metabolites.
RESULTS
Our investigation revealed a causal relationship between immune cells and pancreatic cancer, highlighting the pivotal roles of CD11c+ monocytes (odds ratio, OR=1.105; 95% confidence interval, 95%CI: 1.002-1.218; P=0.045), HLA DR+ CD4+ antigen-presenting cells (OR=0.920; 95%CI: 0.873-0.968; P=0.001), and HLA DR+ CD8br T cells (OR=1.058; 95%CI: 1.002-1.117; P=0.041) in pancreatic cancer progression. Further mediation analysis indicated that oxalate (proportion of mediation effect in total effect: -11.6%, 95% CI: -89.7%, 66.6%) and the mannose to trans-4-hydroxyproline ratio (-19.4, 95% CI: -136%, 96.8%) partially mediate the relationship between HLA DR+ CD8br T cells and pancreatic cancer in nature. In addition, our analysis indicates that adrenate (-8.39%, 95% CI: -18.3%, 1.54%) plays a partial mediating role in the association between CD11c+ monocyte and pancreatic cancer, while cortisone (-26.6%, 95% CI: 138%, -84.8%) acts as a partial mediator between HLA DR+ CD4+ AC and pancreatic cancer.
CONCLUSION
This MR investigation provides evidence supporting the causal relationship between immune cell and pancreatic cancer, with plasma metabolites serving as mediators. Identifying immune cell phenotypes with potential causal effects on pancreatic cancer sheds light on its underlying mechanisms and suggests novel therapeutic targets.
Topics: Humans; Pancreatic Neoplasms; Mendelian Randomization Analysis; Genome-Wide Association Study; Monocytes; Risk Factors; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 38933268
DOI: 10.3389/fimmu.2024.1402113 -
Frontiers in Immunology 2024B cell depleting anti-CD20 monoclonal antibodies (aCD20 mAbs) are highly effective in treatment of multiple sclerosis (MS) but fail to halt the formation of meningeal...
Single-cell profiling indicates a high similarity between immune cells in the cerebrospinal fluid and in meningeal ectopic lymphoid tissue in experimental autoimmune encephalomyelitis.
BACKGROUND AND OBJECTIVES
B cell depleting anti-CD20 monoclonal antibodies (aCD20 mAbs) are highly effective in treatment of multiple sclerosis (MS) but fail to halt the formation of meningeal ectopic lymphoid tissue (mELT) in the murine model experimental autoimmune encephalomyelitis (EAE). While mELT can be examined in EAE, it is not accessible in MS patients. Our key objectives were to compare the immune cells in cerebrospinal fluid (CSF), which is accessible in patients, with those in mELT, and to study the effects of aCD20 mAbs on CSF and mELT in EAE.
METHODS
Applying single cell RNA sequencing, we compared gene expression profiles in immune cells from (1) CSF with mELT and (2) aCD20 mAbs treated with control treated mice in a spontaneous 2D2xTh EAE model.
RESULTS
The immune cell composition in CSF and mELT was very similar. Gene expression profiles and pathway enrichment analysis revealed no striking differences between the two compartments. aCD20 mAbs led not only to a virtually complete depletion of B cells in the CSF but also to a reduction of naïve CD4+ T cells and marked increase of macrophages. No remarkable differences in regulated genes or pathways were observed.
DISCUSSION
Our results suggest that immune cells in the CSF may serve as a surrogate for mELT in EAE. Future studies are required to confirm this in MS patients. The observed increase of macrophages in B cell depleted CSF is a novel finding and requires verification in CSF of aCD20 mAbs treated MS patients. Due to unresolved technical challenges, we were unable to study the effects of aCD20 mAbs on mELT. This should be addressed in future studies.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Mice; Single-Cell Analysis; Meninges; B-Lymphocytes; Female; Tertiary Lymphoid Structures; Mice, Inbred C57BL; Antibodies, Monoclonal; Transcriptome; Gene Expression Profiling; Antigens, CD20; Cerebrospinal Fluid; Disease Models, Animal; Multiple Sclerosis
PubMed: 38933267
DOI: 10.3389/fimmu.2024.1400641 -
Frontiers in Immunology 2024Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We...
Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA used (hydrolysable (hSAgA) and non-hydrolysable 'click' SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Over time, the peptides induced an IgE-independent anaphylactic reaction, the incidence of which was significantly delayed when peptides were in SAgA form rather than in free form. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Immunologic anaphylaxis occurred in NOD mice in a dose-dependent manner but not in C57BL/6 or BALB/c mice; however, its incidence did not correlate with the level of anti-peptide antibodies. We provide evidence that SAgAs significantly improve the efficacy of peptides to induce tolerance and prevent autoimmune diabetes while at the same time reducing their anaphylactogenic potential.
Topics: Animals; Mice; Mice, Inbred NOD; Diabetes Mellitus, Type 1; Immune Tolerance; Peptides; Female; Autoantigens; T-Lymphocytes, Regulatory; Immunotherapy; Anaphylaxis; Desensitization, Immunologic
PubMed: 38933266
DOI: 10.3389/fimmu.2024.1258369 -
Frontiers in Immunology 2024Chronic inflammatory enteropathy (CIE) is a common condition in dogs causing recurrent or persistent gastrointestinal clinical signs. Pathogenesis is thought to involve...
Chronic inflammatory enteropathy (CIE) is a common condition in dogs causing recurrent or persistent gastrointestinal clinical signs. Pathogenesis is thought to involve intestinal mucosal inflammatory infiltrates, but histopathological evaluation of intestinal biopsies from dogs with CIE fails to guide treatment, inform prognosis, or correlate with clinical remission. We employed single-cell RNA sequencing to catalog and compare the diversity of cells present in duodenal mucosal endoscopic biopsies from 3 healthy dogs and 4 dogs with CIE. Through characterization of 35,668 cells, we identified 31 transcriptomically distinct cell populations, including T cells, epithelial cells, and myeloid cells. Both healthy and CIE samples contributed to each cell population. T cells were broadly subdivided into GZMA (putatively annotated as tissue resident) and IL7R (putatively annotated as non-resident) T cell categories, with evidence of a skewed proportion favoring an increase in the relative proportion of IL7R T cells in CIE dogs. Among the myeloid cells, neutrophils from CIE samples exhibited inflammatory (SOD2 and IL1A) gene expression signatures. Numerous differentially expressed genes were identified in epithelial cells, with gene set enrichment analysis suggesting enterocytes from CIE dogs may be undergoing stress responses and have altered metabolic properties. Overall, this work reveals the previously unappreciated cellular heterogeneity in canine duodenal mucosa and provides new insights into molecular mechanisms which may contribute to intestinal dysfunction in CIE. The cell type gene signatures developed through this study may also be used to better understand the subtleties of canine intestinal physiology in health and disease.
Topics: Animals; Dogs; Duodenum; Single-Cell Analysis; Dog Diseases; Transcriptome; Gene Expression Profiling; Intestinal Mucosa; Chronic Disease; Male; Female; T-Lymphocytes
PubMed: 38933260
DOI: 10.3389/fimmu.2024.1397590 -
Viruses Jun 2024The HIV envelope glycoprotein (Env) is a trimeric protein that facilitates viral binding and fusion with target cells. As the sole viral protein on the HIV surface, Env...
The HIV envelope glycoprotein (Env) is a trimeric protein that facilitates viral binding and fusion with target cells. As the sole viral protein on the HIV surface, Env is important both for immune responses to HIV and in vaccine designs. Targeting Env in clinical applications is challenging due to its heavy glycosylation, high genetic variability, conformational camouflage, and its low abundance on virions. Thus, there is a critical need to better understand this protein. Flow virometry (FV) is a useful methodology for phenotyping the virion surface in a high-throughput, single virion manner. To demonstrate the utility of FV to characterize Env, we stained HIV virions with a panel of 85 monoclonal antibodies targeting different regions of Env. A broad range of antibodies yielded robust staining of Env, with V3 antibodies showing the highest quantitative staining. A subset of antibodies tested in parallel on viruses produced in CD4 T cell lines, HEK293T cells, and primary cells showed that the cellular model of virus production can impact Env detection. Finally, in addition to being able to highlight Env heterogeneity on virions, we show FV can sensitively detect differences in Env conformation when soluble CD4 is added to virions before staining.
Topics: Humans; env Gene Products, Human Immunodeficiency Virus; HIV-1; Virion; HEK293 Cells; HIV Antibodies; Antibodies, Monoclonal; CD4-Positive T-Lymphocytes; HIV Infections
PubMed: 38932227
DOI: 10.3390/v16060935