The impact of vaccination on RBC alloimmunization in a murine model.
Ontology highlight
ABSTRACT:
SUBMITTER: Natarajan P
PROVIDER: S-EPMC5575953 | biostudies-literature | 2017 Aug
REPOSITORIES: biostudies-literature
Publications
The impact of vaccination on RBC alloimmunization in a murine model.
Natarajan P P Santhanakrishnan M M Tormey C A CA Hendrickson J E JE
Vox sanguinis 20170608 6
Emerging data in animal models and humans suggest that pathogen-associated and damage-associated molecular patterns variably impact RBC alloantibody formation. In this study, we tested the hypothesis that vaccinations may enhance immune responses to transfused RBCs. The Pneumovax23 vaccine decreased the magnitude of anti-KEL alloimmunization in a murine model, whereas the hepB vaccine did not impact the response; RBC transfusion did not alter immune responses to either vaccine. These data highli ...[more]
Similar Datasets
Project description:Red blood cell (RBC) transfusion exposes recipients to hundreds of unmatched minor RBC antigens. This exposure can lead to production of alloantibodies that promote clinically significant hemolytic events. Multiple studies have reported an increased frequency of RBC alloimmunization in patients with autoimmunity. However, cellular and molecular mechanisms that underlie autoimmunity-induced alloimmunization have not been reported. Patients with systemic lupus erythematosus (SLE) have a high frequency of alloimmunization and express a type 1 interferon (IFNα/β) gene signature. Thus, we utilized the pristane-induced lupus mouse model to test the hypothesis that inflammation in lupus promotes RBC alloimmunization, and to examine the potential role of IFNα/β. Intraperitoneal injection of pristane, a hydrocarbon oil, led to autoantibody production, glomerulonephritis, and pulmonary hemorrhage in wild type (WT) mice. Pristane treatment significantly induced serum IFNα and expression of multiple interferon-stimulated genes (ISGs) in peripheral blood and peritoneal fluid cells, including inflammatory macrophages. Following transfusion with allogeneic RBCs expressing the KEL glycoprotein, pristane-treated WT mice produced significantly elevated levels of anti-KEL IgM and anti-KEL IgG, compared to untreated mice. Pristane induced comparable levels of inflammatory cells and cytokines in mice lacking the IFNα/β receptor (IFNAR1-/-) or the IFNα/β-inducing transcriptions factors (IRF3/7-/-), compared to WT mice. However, pristane-treated IFNAR1-/- and IRF3/7-/- mice failed to produce ISGs and produced significantly lower levels of transfusion-induced anti-KEL IgG, compared to WT mice. Thus, pristane induction of a lupus-like phenotype promoted alloimmunization to the KEL RBC antigen in an IFNα/β-dependent manner. To our knowledge, this is the first examination of molecular mechanisms contributing to RBC alloimmunization in a model of autoimmunity. These results warrant further investigation of the role of IFNα/β in alloimmunization to other RBC antigens and the contribution of the IFNα/β gene signature to the elevated frequency of alloimmunization in patients with SLE.
| S-EPMC7546415 | biostudies-literature
Project description: Not available
| S-EPMC5394864 | biostudies-literature
Project description:Individuals that become immunized to red blood cell (RBC) alloantigens can experience an increased rate of antibody formation to additional RBC alloantigens following subsequent transfusion. Despite this, how an immune response to one RBC immunogen may impact subsequent alloimmunization to a completely different RBC alloantigen remains unknown. Our studies demonstrate that Kell blood group antigen (KEL) RBC transfusion in the presence of inflammation induced by poly (I:C) (PIC) not only enhances anti-KEL antibody production through a CD4+ T-cell-dependent process but also directly facilitates anti-HOD antibody formation following subsequent exposure to the disparate HOD (hen egg lysozyme, ovalbumin, fused to human blood group antigen Duffy b) antigen. PIC/KEL priming of the anti-HOD antibody response required that RBCs express both the KEL and HOD antigens (HOD × KEL RBCs), as transfusion of HOD RBCs plus KEL RBCs or HOD RBCs alone failed to impact anti-HOD antibody formation in recipients previously primed with PIC/KEL. Transfer of CD4+ T cells from PIC/KEL-primed recipients directly facilitated anti-HOD antibody formation following (HOD × KEL) RBC transfusion. RBC alloantigen priming was not limited to PIC/KEL enhancement of anti-HOD alloantibody formation, as HOD-reactive CD4+ T cells enhanced anti-glycophorin A (anti-GPA) antibody formation in the absence of inflammation following transfusion of RBCs coexpressing GPA and HOD. These results demonstrate that immune priming to one RBC alloantigen can directly enhance a humoral response to a completely different RBC alloantigen, providing a potential explanation for why alloantibody responders may exhibit increased immune responsiveness to additional RBC alloantigens following subsequent transfusion.
| S-EPMC5787868 | biostudies-literature
Project description:Transfusion therapy remains a mainstay of treatment for patients with thalassemia major and to a lesser extent for the less anemic patients with thalassemia intermedia. We have previously reported a role for regulatory T cells (Tregs) in the control of antibody responses in wild-type C57BL/6 (WT) mice exposed to allogeneic red blood cell transfusions. As an initial step to study and characterize immune regulation in thalassemias, we performed an immunologic cell-type characterization of C57BL/6 Hbb(th-1)/Hbb(th-1) mouse model of thalassemia intermedia (Thal) in steady state as well as after transfusions with allogeneic blood.The myeloid and lymphocyte compartments including Tregs and T helper (Th) responses were analyzed in transfusion naive Thal and WT mouse spleens. The effect of allogeneic transfusions on Treg and global T helper responses was also measured.We found elevated levels and activity of splenic Tregs in Thal mice with lower Th type 1/Th type 2 ratios before as well as after transfusion. Furthermore, pretransfused Thal mice had altered ratios of the splenic myeloid compartment with increased proportion of macrophages but lower frequency of conventional dendritic cells. Surprisingly, transfusions resulted in lower alloimmunization levels in Thal compared to WT mice.These data suggest that this experimental model of thalassemia intermedia has an intrinsic alteration in splenic immunoregulation with an increased resistance to alloimmunization, raising the possibility that studying this animal model may help to identify potential immunoregulatory networks to inhibit alloimmunization.
| S-EPMC4221584 | biostudies-literature
Project description:The implications of administration of mRNA vaccines to individuals with chronic inflammatory diseases, including myocarditis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), are unclear. We investigated mRNA vaccine effects in a chronic inflammation mouse model implanted with an LPS pump, focusing on toxicity and immunogenicity. Under chronic inflammation, mRNA vaccines exacerbated cardiac damage and myocarditis, inducing mild heart inflammation with heightened pro-inflammatory cytokine production and inflammatory cell infiltration in the heart. Concurrently, significant muscle damage occurred, with disturbances in mitochondrial fusion and fission factors signaling impaired muscle repair. However, chronic inflammation did not adversely affect muscles at the vaccination site or humoral immune responses; nevertheless, it partially reduced the cell-mediated immune response, particularly T-cell activation. These findings underscore the importance of addressing mRNA vaccine toxicity and immunogenicity in the context of chronic inflammation, ensuring their safe and effective utilization, particularly among vulnerable populations with immune-mediated inflammatory diseases.
| S-EPMC10869740 | biostudies-literature
Project description:Passive immunization with anti-D can prevent maternal alloimmunization to RhD thereby preventing hemolytic disease of the fetus and newborn. Unexpectedly, anti-D fails in some cases and some monoclonal anti-D preparations paradoxically enhances alloimmunization. The underlying mechanisms modulating humoral alloimmunization by anti-D are unknown. We previously reported that IgG antibody subclasses differentially regulate alloimmunity in response to red blood cell (RBC) transfusions in a mouse model; in particular, IgG2c significantly enhanced RBC alloantibody responses. Initial mechanistic studies revealed that IgG2c:RBC immune complexes were preferentially consumed by the splenic dendritic cell (DC) subsets that play a role in RBC alloimmunization. The deletion of activating Fc-gamma receptors (FcγRs) (i.e., FcγRI, FcγRIII, and FcγRIV) on DCs abrogated IgG2c-mediated enhanced alloimmunization. Because DCs express high levels of FcγRIV, which has high affinity for the IgG2c subclass, we hypothesized that FcγRIV was required for enhanced alloimmunization. To test this hypothesis, knockout mice and blocking antibodies were used to manipulate FcγR expression. The data presented herein demonstrate that FcγRIV, but not FcγRI or FcγRIII, is required for IgG2c-mediated enhancement of RBC alloantibody production. Additionally, FcγRI is alone sufficient for IgG2c-mediated RBC clearance but not for increased alloimmunization, demonstrating that RBC clearance can occur without inducing alloimmunization. Together, these data, combined with prior observations, support the hypothesis that passive immunization with an RBC-specific IgG2c antibody increases RBC alloantibody production through FcγRIV ligation on splenic conventional DCs (cDCs). This raises the question of whether standardizing antibody subclasses in immunoprophylaxis preparations is desirable and suggests which subclasses may be optimal for generating monoclonal anti-D therapeutics.
| S-EPMC9519184 | biostudies-literature
Project description:BackgroundOnly a fraction of red blood cell (RBC) transfusion recipients form alloantibodies, and variables determining responsiveness or nonresponsiveness are poorly understood. We and others have previously shown in animal models that pretreatment with toll-like receptor agonists that mimic different types of infections impacts the magnitude or frequency of RBC alloantibody responses. We hypothesized that influenza infection, coexistent with transfusion, would impact responses to transfused RBCs in a manner dependent on Type 1(α/β) interferon (IFN) signaling and tested this in a murine model.Study design and methodsWild-type mice or mice lacking the ability to respond to Type 1 IFN were infected with influenza prior to the transfusion of transgenic murine RBCs (K1) expressing the human KEL glycoprotein or the triple fusion HOD protein. Alloantibody responses were measured longitudinally after transfusion by flow cytometric crossmatch, and posttransfusion RBC recovery and survival was evaluated.ResultsInfluenza-infected mice transfused with K1 RBCs developed robust anti-KEL alloantibodies, whereas animals transfused in the absence of infection remained nonresponders; influenza-associated RBC alloimmunization was also observed after transfusion of HOD RBCs. Recipient Type 1 IFN production was critical to the mechanism of action of influenza-induced RBC alloimmunization, with alloimmunization being significantly decreased in mice unable to sense Type 1 IFN (through antibody blockade or genetic approaches).ConclusionThese and other data suggest that Type 1 IFN responses to toll-like receptor agonists or infections regulate RBC alloantibody responses. Studies investigating whether such a correlation exists in humans may be informative.
| S-EPMC6785373 | biostudies-literature
Project description:Background: Long-chain polyunsaturated fatty acids (PUFAs) are important modulators of red blood cell (RBC) rheology. Dietary PUFAs are readily incorporated into the RBC membrane, improving RBC deformability, fluidity, and hydration. However, enriching the lipid membrane with PUFAs increases the potential for peroxidation in oxidative environments (e.g., refrigerated storage), resulting in membrane damage. Substitution of bis-allylic hydrogens with deuterium ions in PUFAs decreases hydrogen abstraction, thereby inhibiting peroxidation. If lipid peroxidation is a causal factor in the RBC storage lesion, incorporation of deuterated linoleic acid (DLA) into the RBC membrane should decrease lipid peroxidation, thereby improving RBC lifespan, deformability, filterability, and post-transfusion recovery (PTR) after cold storage. Study Design and Methods: Mice associated with good (C57BL/6J) and poor (FVB) RBC storage quality received diets containing 11,11-D2-LA Ethyl Ester (1.0 g/100 g diet; deuterated linoleic acid) or non-deuterated LA Ethyl Ester (control) for 8 weeks. Deformability, filterability, lipidomics, and lipid peroxidation markers were evaluated in fresh and stored RBCs. Results: DLA was incorporated into RBC membranes in both mouse strains. DLA diet decreased lipid peroxidation (malondialdehyde) by 25.4 and 31% percent in C57 mice and 12.9 and 79.9% in FVB mice before and after cold storage, respectively. In FVB, but not C57 mice, deformability filterability, and post-transfusion recovery were significantly improved. Discussion: In a mouse model of poor RBC storage, with elevated reactive oxygen species production, DLA attenuated lipid peroxidation and significantly improved RBC storage quality.
| S-EPMC9086239 | biostudies-literature
Project description:It is difficult to predict RBC consumption accurately. This paper aims to use big data to establish a XGBoost Model to understand the trend of RBC accurately, and forecast the demand in time. XGBoost, which implements machine learning algorithms under the Gradient Boosting framework can provide a parallel tree boosting. The daily RBC usage and inventory (May 2014-September 2017) were investigated, and rules for RBC usage were analysed. All data were divided into training sets and testing sets. A XGBoost Model was established to predict the future RBC demand for durations ranging from a day to a week. In addition, the alert range was added to the predicted value to ensure RBC demand of emergency patients and surgical accidents. The gap between RBC usage and inventory was fluctuant, and had no obvious rule. The maximum residual inventory of a certain blood group was up to 700 units one day, while the minimum was nearly 0 units. Upon comparing MAE (mean absolute error):A:10.69, B:11.19, O:10.93, and AB:5.91, respectively, the XGBoost Model was found to have a predictive advantage over other state-of-the-art approaches. It showed the model could fit the trend of daily RBC usage. An alert range could manage the demand of emergency patients or surgical accidents. The model had been built to predict RBC demand, and the alert range of RBC inventory is designed to increase the safety of inventory management.
| S-EPMC7900290 | biostudies-literature
Project description:Extracellular vesicles (EVs) mediate intercellular signaling by transferring their cargo to recipient cells, but the functional consequences of signaling are not fully appreciated. RBC-derived EVs are abundant in circulation and have been implicated in regulating immune responses. Here, we use a transgenic mouse model for fluorescence-based mapping of RBC-EV recipient cells to assess the role of this intercellular signaling mechanism in heart disease. Using fluorescent-based mapping, we detected an increase in RBC-EV-targeted cardiomyocytes in a murine model of ischemic heart failure. Single cell nuclear RNA sequencing of the heart revealed a complex landscape of cardiac cells targeted by RBC-EVs, with enrichment of genes implicated in cell proliferation and stress signaling pathways compared with non-targeted cells. Correspondingly, cardiomyocytes targeted by RBC-EVs more frequently express cellular markers of DNA synthesis, suggesting the functional significance of EV-mediated signaling. In conclusion, our mouse model for mapping of EV-recipient cells reveals a complex cellular network of RBC-EV-mediated intercellular communication in ischemic heart failure and suggests a functional role for this mode of intercellular signaling.
| S-EPMC8548207 | biostudies-literature