162 results on '"Zimring, James C."'
Search Results
2. The role of PIMT in Alzheimer's disease pathogenesis: A novel hypothesis.
- Author
-
D'Alessandro, Angelo, Lukens, John R., and Zimring, James C.
- Abstract
There are multiple theories of Alzheimer's disease pathogenesis. One major theory is that oxidation of amyloid beta (Aβ) promotes plaque deposition that directly contributes to pathology. A competing theory is that hypomethylation of DNA (due to altered one carbon metabolism) results in pathology through altered gene regulation. Herein, we propose a novel hypothesis involving L‐isoaspartyl methyltransferase (PIMT) that unifies the Aβ and DNA hypomethylation hypotheses into a single model. Importantly, the proposed model allows bidirectional regulation of Aβ oxidation and DNA hypomethylation. The proposed hypothesis does not exclude simultaneous contributions by other mechanisms (e.g., neurofibrillary tangles). The new hypothesis is formulated to encompass oxidative stress, fibrillation, DNA hypomethylation, and metabolic perturbations in one carbon metabolism (i.e., methionine and folate cycles). In addition, deductive predictions of the hypothesis are presented both to guide empirical testing of the hypothesis and to provide candidate strategies for therapeutic intervention and/or nutritional modification. HIGHLIGHTS: PIMT repairs L‐isoaspartyl groups on amyloid beta and decreases fibrillation.SAM is a common methyl donor for PIMT and DNA methyltransferases.Increased PIMT activity competes with DNA methylation and vice versa.The PIMT hypothesis bridges a gap between plaque and DNA methylation hypotheses. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Alloantigen Copy Number as a Critical Factor in RBC Alloimmunization.
- Author
-
Patel, Seema R., Maier, Cheryl L., and Zimring, James C.
- Abstract
• For human non-RhD RBC alloantigens immunogenicity increases as copy number decreases. • Copy number affects mechanisms of alloimmunization in mouse models. • In humans and mice, very low copy number alloantigens are weakly or nonimmunogenic. • In mice very low copy numbers become tolerogenic, which is untested in humans. • Interpretation of mouse studies must include transgene properties and mouse genetics. RBC alloimmunization remains a significant barrier to ongoing transfusion therapy leading to morbidity, and in extreme cases mortality, due to delayed or insufficient units of compatible RBCs. In addition, the monitoring and characterization of alloantibodies, often with multiple specificities in a single patient, consumes substantial health care resources. Extended phenotypic matching has mitigated, but not eliminated, RBC alloimmunization and is only logistically available for specialized populations. Thus, RBC alloimmunization remains a substantial problem. In recent decades it has become clear that mechanisms of RBC alloimmunization are distinct from other antigens and lack of mechanistic understanding likely contributes to the fact that there are no approved interventions to prevent RBC alloimmunization from transfusion. The combination of human studies and murine modeling have identified several key factors in RBC alloimmunization. In both humans and mice, immunogenicity is a function of alloantigen copy number on RBCs. Murine studies have further shown that copy number not only changes rates of immunization but the mechanisms of antibody formation. This review summarizes the current understanding of quantitative and qualitative effects of alloantigen copy number on RBC alloimmunization. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. THINKING SCIENTIFICALLY ABOUT SCIENTIFICALLY THINKING.
- Author
-
Zimring, James C.
- Subjects
PHILOSOPHY of science ,SOCIAL comparison ,REJECTION (Psychology) ,SCIENTIFIC method ,RELATIVITY (Physics) - Published
- 2020
- Full Text
- View/download PDF
5. Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients.
- Author
-
Thomas, Tiffany, Stefanoni, Davide, Dzieciatkowska, Monika, Issaian, Aaron, Nemkov, Travis, Hill, Ryan C., Francis, Richard O., Hudson, Krystalyn E., Buehler, Paul W., Zimring, James C., Hod, Eldad A., Hansen, Kirk C., Spitalnik, Steven L., and D'Alessandro, Angelo
- Published
- 2020
- Full Text
- View/download PDF
6. Serum Proteomics in COVID-19 Patients: Altered Coagulation and Complement Status as a Function of IL‑6 Level.
- Author
-
D'Alessandro, Angelo, Thomas, Tiffany, Dzieciatkowska, Monika, Hill, Ryan C., Francis, Richard O., Hudson, Krystalyn E., Zimring, James C., Hod, Eldad A., Spitalnik, Steven L., and Hansen, Kirk C.
- Published
- 2020
- Full Text
- View/download PDF
7. Serum Proteomics in COVID-19 Patients: Altered Coagulation and Complement Status as a Function of IL-6 Level
- Author
-
D’Alessandro, Angelo, Thomas, Tiffany, Dzieciatkowska, Monika, Hill, Ryan C., Francis, Richard O., Hudson, Krystalyn E., Zimring, James C., Hod, Eldad A., Spitalnik, Steven L., and Hansen, Kirk C.
- Abstract
Over 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which are in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of antifibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents. Raw data for this study are available through ProteomeXchange with identifier PXD020601.
- Published
- 2020
- Full Text
- View/download PDF
8. Evidence of Structural Protein Damage and Membrane Lipid Remodeling in Red Blood Cells from COVID-19 Patients
- Author
-
Thomas, Tiffany, Stefanoni, Davide, Dzieciatkowska, Monika, Issaian, Aaron, Nemkov, Travis, Hill, Ryan C., Francis, Richard O., Hudson, Krystalyn E., Buehler, Paul W., Zimring, James C., Hod, Eldad A., Hansen, Kirk C., Spitalnik, Steven L., and D’Alessandro, Angelo
- Abstract
The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, in particular, short- and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, or mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading and metabolic rewiring toward the hexose monophosphate shunt, RBCs from COVID-19 patients may be less capable of responding to environmental variations in hemoglobin oxygen saturation/oxidant stress when traveling from the lungs to peripheral capillaries and vice versa.
- Published
- 2020
- Full Text
- View/download PDF
9. Poly(I:C) causes failure of immunoprophylaxis to red blood cells expressing the KEL glycoprotein in mice
- Author
-
Escamilla-Rivera, Vicente, Liu, Jingchun, Gibb, David R., Santhanakrishnan, Manjula, Liu, Dong, Forsmo, James E., Eisenbarth, Stephanie C., Foxman, Ellen F., Stowell, Sean R., Luckey, Chance John, Zimring, James C., Hudson, Krystalyn E., and Hendrickson, Jeanne E.
- Abstract
Polyclonal anti-D (Rh immune globulin [RhIg]) therapy has mitigated hemolytic disease of the newborn over the past half century, although breakthrough anti-D alloimmunization still occurs in some treated females. We hypothesized that antiviral responses may impact the efficacy of immunoprophylaxis therapy in a type 1 interferon (IFN)-dependent manner and tested this hypothesis in a murine model of KEL alloimmunization. Polyclonal anti-KEL immunoprophylaxis (KELIg) was administered to wild-type or knockout mice in the presence or absence of polyinosinic-polycytidilic acid (poly[I:C]), followed by the transfusion of murine red blood cells (RBCs) expressing the human KEL glycoprotein. Anti-KEL alloimmunization, serum cytokines, and consumption of the transfused RBCs were evaluated longitudinally. In some experiments, recipients were treated with type 1 IFN (IFN-α/β). Recipient treatment with poly(I:C) led to breakthrough anti-KEL alloimmunization despite KELIg administration. Recipient CD4+ T cells were not required for immunoprophylaxis efficacy at baseline, and modulation of the KEL glycoprotein antigen occurred to the same extent in the presence or absence of recipient inflammation. Under conditions where breakthrough anti-KEL alloimmunization occurred, KEL RBC consumption by inflammatory monocytes and serum monocyte chemoattractant protein-1 and interleukin-6 were significantly increased. Poly(I:C) or type I IFN administration was sufficient to cause breakthrough alloimmunization, with poly(I:C) inducing alloimmunization even in the absence of recipient type I IFN receptors. A better understanding of how recipient antiviral responses lead to breakthrough alloimmunization despite immunoprophylaxis may have translational relevance to instances of RhIg failure that occur in humans.
- Published
- 2020
- Full Text
- View/download PDF
10. Poly(I:C) causes failure of immunoprophylaxis to red blood cells expressing the KEL glycoprotein in mice
- Author
-
Escamilla-Rivera, Vicente, Liu, Jingchun, Gibb, David R., Santhanakrishnan, Manjula, Liu, Dong, Forsmo, James E., Eisenbarth, Stephanie C., Foxman, Ellen F., Stowell, Sean R., Luckey, Chance John, Zimring, James C., Hudson, Krystalyn E., and Hendrickson, Jeanne E.
- Abstract
Polyclonal anti-D (Rh immune globulin [RhIg]) therapy has mitigated hemolytic disease of the newborn over the past half century, although breakthrough anti-D alloimmunization still occurs in some treated females. We hypothesized that antiviral responses may impact the efficacy of immunoprophylaxis therapy in a type 1 interferon (IFN)-dependent manner and tested this hypothesis in a murine model of KEL alloimmunization. Polyclonal anti-KEL immunoprophylaxis (KELIg) was administered to wild-type or knockout mice in the presence or absence of polyinosinic-polycytidilic acid (poly[I:C]), followed by the transfusion of murine red blood cells (RBCs) expressing the human KEL glycoprotein. Anti-KEL alloimmunization, serum cytokines, and consumption of the transfused RBCs were evaluated longitudinally. In some experiments, recipients were treated with type 1 IFN (IFN-α/β). Recipient treatment with poly(I:C) led to breakthrough anti-KEL alloimmunization despite KELIg administration. Recipient CD4+T cells were not required for immunoprophylaxis efficacy at baseline, and modulation of the KEL glycoprotein antigen occurred to the same extent in the presence or absence of recipient inflammation. Under conditions where breakthrough anti-KEL alloimmunization occurred, KEL RBC consumption by inflammatory monocytes and serum monocyte chemoattractant protein-1 and interleukin-6 were significantly increased. Poly(I:C) or type I IFN administration was sufficient to cause breakthrough alloimmunization, with poly(I:C) inducing alloimmunization even in the absence of recipient type I IFN receptors. A better understanding of how recipient antiviral responses lead to breakthrough alloimmunization despite immunoprophylaxis may have translational relevance to instances of RhIg failure that occur in humans.
- Published
- 2020
- Full Text
- View/download PDF
11. Passively transferred IgG enhances humoral immunity to a red blood cell alloantigen in mice
- Author
-
Gruber, David R., Richards, Amanda L., Howie, Heather L., Hay, Ariel M., Lebedev, Jenna N., Wang, Xiaohong, Zimring, James C., and Hudson, Krystalyn E.
- Abstract
Antibodies are typically thought of as the endpoint of humoral immunity that occur as the result of an adaptive immune response. However, affinity-matured antibodies can be present at the initiation of a new immune response, most commonly because of passive administration as a medical therapy. The current paradigm is that immunoglobulin M (IgM), IgA, and IgE enhance subsequent humoral immunity. In contrast, IgG has a “dual effect” in which it enhances responses to soluble antigens but suppresses responses to antigens on red blood cells (RBCs) (eg, immunoprophylaxis with anti-RhD). Here, we report a system in which passive antibody to an RBC antigen promotes a robust cellular immune response leading to endogenous CD4+T-cell activation, germinal center formation, antibody secretion, and immunological memory. The mechanism requires ligation of Fcγ receptors on a specific subset of dendritic cells that results in CD4+T-cell activation and expansion. Moreover, antibodies cross-enhance responses to a third-party antigen, but only if it is expressed on the same RBC as the antigen recognized by the antibody. Importantly, these observations were IgG subtype specific. Thus, these findings demonstrate that antibodies to RBC alloantigens can enhance humoral immunity in an IgG subtype-specific fashion and provide mechanistic elucidation of the enhancing effects.
- Published
- 2020
- Full Text
- View/download PDF
12. Biliverdin Reductase B Protects Against Primaquine Induced Hemolysis - Identification of a Novel Anti-Oxidant Pathway in Murine Erythrocytes
- Author
-
Dziewulska-Cronk, Karolina, Hay, Ariel M, D'Alessandro, Angelo, Reisz, Julie A, Garrett, Jordan, Buehler, Paul, Kao, Joseph, and Zimring, James C
- Abstract
Background: Biliverdin Reductase B (BlvrB) is the fourth most abundant enzyme in red blood cells (RBCs) and is widely expressed in other tissues. In normal heme catabolism, porphyrin is converted to biliverdin-alpha (by hemoxygenase (HO)) and then reduced to bilirubin-alpha (by biliverdin reductase A (BlvrA)). Bilirubin-alpha is then glucuronidated and excreted. The large body of literature investigating heme metabolism, bilirubin-based pathologies, and the oxidative biology of bilirubin/biliverdin in adults focuses almost exclusively on BlvrA and the alpha isomers of biliverdin and bilirubin. However, porphyrin is a tetrapyrrole with 4 distinct meso-carbon bridges, each of which can be broken to generate a distinct biliverdin isomer (alpha, beta, gamma, or delta). Although HO is exquisitely specific for the alpha-bond (generating only biliverdin-alpha), chemical coupled oxidation of heme yields all four biliverdin isomers. BlvrB (and not BlvrA) can reduce each of non-alpha biliverdin isomers into their corresponding bilirubin isomers (bilirubin-beta is prevalent in neonatal jaundice and kernicterus). BlvrB also reduces flavins and additional quinone metabolites. Despite BlvrB's abundance and evolutionary conservation, its only known function is a subtle effect on hematopoietic lineage fate (megakaryocyte vs. erythroid). BlvrB has no known function in mature RBCs. We hypothesized that BlvrB plays an important antioxidant role that would only become obvious when other redundant anti-oxidant pathways were limited.
- Published
- 2023
- Full Text
- View/download PDF
13. NXPE2 Is the Target of Ter-119 When Complexed with Gypa in Mice
- Author
-
Keele, Gregory R, Holness, Nadia, Jash, Arijita, Hay, Ariel M, Ewald, Sarah, Churchill, Gary A, D'Alessandro, Angelo, Dzieciatkowska, Monika, and Zimring, James C
- Abstract
Background: Red blood cells (RBCs) have a complex biology that allows regulation of metabolism, cellular rigidity, ion exchange, pH, and molecular communication with the vasculature. A central regulator of these biologies are macrocomplexes of integral membrane proteins that are both linked to cytoskeletal proteins and also differentially bind to metabolic enzymes based upon oxygenation status of the RBC. RBC surface staining, co-immunoprecipitation, and cross-linking proteomic approaches have generated a model of the macrocomplex encompassing Band 3, Rh, RhAG, CD47, glycophorin A, glycophorin B, and LW. TER-119 is a monoclonal antibody with exquisite specificity for the erythroid lineage in mice. However, the molecular target of TER-119 has remained unknown. TER-119 immunoprecipitates 4 specific protein bands, two of which are glycophorin A (GYPA) monomers or homodimers respectively; however, TER-119 is non-reactive to GYPA when assayed through Western blots and flow cytometry with erythroid cell lines expressing GYPA. These data led the originators of TER-119 to conclude it binds to a GYPA associated protein, but not GYPA itself. In contrast, others have concluded that TER-119 binds GYPA directly, and have inferred GYPA biology based upon TER-119 reactivity.
- Published
- 2023
- Full Text
- View/download PDF
14. Mechanisms of Primaquine Induced Hemolysis in a Novel Humanized Murine Model of Mediterranean G6PD Deficiency
- Author
-
Dziewulska-Cronk, Karolina, Reisz, Julie A, Nemkov, Travis, Hay, Ariel M, Issaian, Aaron, Cendali, Francesca, Dzieciatkowska, Monika, Gamboni, Fabia, Lamb, Derek, Palha, Mitasha, Kao, Joseph, Buehler, Paul, D'Alessandro, Angelo, Commons, Robert, and Zimring, James C
- Abstract
Background: Approximately half a billion individuals are genetically deficient in glucose 6-phosphate dehydrogenase (G6PD) due to amino acid variants generally thought to decrease enzyme half-life. Decreased G6PD activity limits the antioxidant capacity of red blood cells (RBCs). As such, certain drugs that induce oxidative stress can cause life-threatening hemolysis in G6PD deficient (G6DPd) individuals. Standard regiments of the only approved drugs that can cure liver phase Plasmodium vivax ( p. vivax) (i.e. primaquine and tafenoquine) are contraindicated in G6PDd patients due to risks of hemolysis. Effective treatment of G6PDd individuals infected with p. vivaxrequires a prolonged course of primaquine (8 weeks), leading to non-adherence, and subsequent reduced efficacy and increased risk of transmission. Despite decades of research and large drug screening programs, no non-hemolytic compound has been identified that can eradicate p. vivax. Lack of progress in this area has likely been hampered by an incomplete mechanistic understanding of primaquine induced hemolysis, in part due to the lack of an animal model that recapitulates G6PD instability.
- Published
- 2023
- Full Text
- View/download PDF
15. Genetic Polymorphisms in the Ferrireductase STEAP3 Regulate a Ferroptosis-like Process of Lipid Peroxidation-Induced Hemolysis in Murine and Human Red Blood Cells
- Author
-
D'Alessandro, Angelo, Keele, Gregory R, Hay, Ariel M, Nemkov, Travis, Stephenson, Daniel, Deng, Xutao, Stone, Mars, Kleinman, Steven, Spitalnik, Steven, Norris, Philip J, Busch, Michael Paul, Churchill, Gary A, and Zimring, James C
- Abstract
Red blood cell (RBC) storage in the blood bank induces a series of biochemical and morphological alterations, collectively denoted as the storage lesion(s). Membrane damage by lipid peroxidation is a hallmark of the storage lesion, a process thought to be triggered by oxidant stress. To identify the genetics underlying this phenomenon, we leveraged a novel murine system, the Jackson lab Diversity Outbred (JDO) mouse colony, which was obtained by extensively cross-breeding 8 founder mouse strains with extreme genetically heterogeneity ( Figure 1.A). A total of 350 fresh and stored (up to 7 days) murine RBC samples were tested by mass spectrometry-based metabolomics and lipidomics. At the end of storage, post-transfusion recovery (PTR), which measures intra- and extravascular hemolysis and is a gold standard for determining RBC storage quality, was determined by quantifying the percentage of stored RBCs that were still circulating 24h after their transfusion into Ubi-GFP+ recipient mice ( Figure 1.A). Genome wide-association studies identified a strong association between PTR and a polymorphic region on chromosome 1 ( Figure 1.A), which encodes STEAP3, a ferrireductase. This region was associated with altered metabolism of stored RBCs ( Figure 1.A), especially an elevation of lipid peroxidation products (hive plot in Figure 1.A). Mechanistically, these data support a role for STEAP3 in promoting Fenton and Haber-Weiss chemistry in iron-loaded RBCs. Specifically, ferrous iron participates in this chemistry, becoming oxidized to its ferric state with concomitant generation of hydroxyl or hydroperoxyl radicals; these in turn attack fatty acids (preferentially, poly- and highly-unsaturated fatty acids, such as octadecadienoic and eicosatetraenoic acid), thereby promoting lipid peroxidation (to hydroxyoctadecadienoic (HODE) and hydroxyeicosatetraenoic (HETE) acids, respectively). By reducing Fe 3+to Fe 2+, STEAP3 can shift the balance of this reaction by increasing the availability of the reactant, thereby favoring the generation of product radicals; this process is analogous to ferroptosis, as described in other biological systems.
- Published
- 2023
- Full Text
- View/download PDF
16. Novel Humanized G6PD Deficient Mice Reveal Mechanisms of Increased Tolerance to Exercise As Gleaned By Multi-Omics in Models of Critical Speed
- Author
-
Cendali, Francesca, Dzieciatkowska, Monika, Lisk, Christina, Irwin, David, Zimring, James C, Dziewulska-Cronk, Karolina, Nemkov, Travis, and D'Alessandro, Angelo
- Abstract
INTRODUCTION:Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is the most common enzymatic deficiency in humans, affecting ~500 million people or ~6% of mankind. G6PD is the rate limiting enzyme of the pentose phosphate pathway (PPP), the main antioxidant pathway in mature red blood cells (RBCs). Activation of the PPP generates NADPH, an essential reducing equivalent for antioxidant metabolism that protects against intra- and extra-vascular hemolysis in response to oxidant stress. Impaired G6PD activity makes RBCs susceptible to hemolysis induced by oxidant challenges. Exercise-induced oxidant stress is a well-established concept in the field of physiology. Individuals with G6PD deficiency are recommended to refrain from strenuous exercise, as they are deemed to be at increased risk for hemolytic events in response to exercise-induced oxidant stress. While biochemically sound, this rationale has never been tested mechanistically, owing to ethical and technical limitations. As such, knowledge is limited regarding molecular impacts of exercise activity in G6PD deficient individuals.
- Published
- 2023
- Full Text
- View/download PDF
17. Transfusion Medicine in the 21st Century: Beyond Rebalancing the Humors.
- Author
-
Hudson, Krystalyn E. and Zimring, James C.
- Published
- 2022
- Full Text
- View/download PDF
18. Differences in Steap3 expression are a mechanism of genetic variation of RBC storage and oxidative damage in mice
- Author
-
Howie, Heather L., Hay, Ariel M., de Wolski, Karen, Waterman, Hayley, Lebedev, Jenna, Fu, Xiaoyun, Culp-Hill, Rachel, D'Alessandro, Angelo, Gorham, James D., Ranson, Matthew S., Roback, John D., Thomson, Peter C., and Zimring, James C.
- Abstract
Red blood cells (RBCs) are the most numerous cell type in the body and serve a vital purpose of delivering oxygen to essentially all tissues. In addition to the central role of RBCs in health and disease, RBC storage is a requirement for the >90 million units of RBC transfusions given to millions of recipients each year, worldwide. It is well known that there is genetic donor-to-donor variability in how human RBCs store, rendering blood a nonstandardized therapeutic with a wide range of biological properties from unit to unit, by the time it is transfused. As with humans, genetic variation exists in how murine RBCs, from different strains of mice, store and perform after transfusion. The genetic mechanisms for variation, in humans and mice, both remain obscure. Combining advanced metabolomics, genetics, and molecular and cellular biology approaches, we identify genetic variation in six-transmembrane epithelial antigen of prostate 3 (Steap3) expression as a critical and previously unrecognized mechanism of oxidative damage of RBCs during storage. Increased levels of Steap3 result in degradation of cellular membrane through lipid peroxidation, leading to failure of RBC homeostasis and hemolysis/clearance of RBCs. This article is the first report of a role of Steap3 in mature RBCs; it defines a new mechanism of redox biology in RBCs with a substantial effect upon RBC function and provides a novel mechanistic determinant of genetic variation of RBC storage.
- Published
- 2019
- Full Text
- View/download PDF
19. Differences in Steap3 expression are a mechanism of genetic variation of RBC storage and oxidative damage in mice
- Author
-
Howie, Heather L., Hay, Ariel M., de Wolski, Karen, Waterman, Hayley, Lebedev, Jenna, Fu, Xiaoyun, Culp-Hill, Rachel, D’Alessandro, Angelo, Gorham, James D., Ranson, Matthew S., Roback, John D., Thomson, Peter C., and Zimring, James C.
- Abstract
Red blood cells (RBCs) are the most numerous cell type in the body and serve a vital purpose of delivering oxygen to essentially all tissues. In addition to the central role of RBCs in health and disease, RBC storage is a requirement for the >90 million units of RBC transfusions given to millions of recipients each year, worldwide. It is well known that there is genetic donor-to-donor variability in how human RBCs store, rendering blood a nonstandardized therapeutic with a wide range of biological properties from unit to unit, by the time it is transfused. As with humans, genetic variation exists in how murine RBCs, from different strains of mice, store and perform after transfusion. The genetic mechanisms for variation, in humans and mice, both remain obscure. Combining advanced metabolomics, genetics, and molecular and cellular biology approaches, we identify genetic variation in six-transmembrane epithelial antigen of prostate 3 (Steap3) expression as a critical and previously unrecognized mechanism of oxidative damage of RBCs during storage. Increased levels of Steap3 result in degradation of cellular membrane through lipid peroxidation, leading to failure of RBC homeostasis and hemolysis/clearance of RBCs. This article is the first report of a role of Steap3 in mature RBCs; it defines a new mechanism of redox biology in RBCs with a substantial effect upon RBC function and provides a novel mechanistic determinant of genetic variation of RBC storage.
- Published
- 2019
- Full Text
- View/download PDF
20. Reticulocytes Are an Unappreciated Risk Factor for RBC Alloimmunization at the Donor and Recipient Levels
- Author
-
Thomas, Tiffany, Qiu, Annie, Kim, Christopher Y, Gordy, Dominique E, Miller, Anabel, Tredicine, Maria, Stone, Elizabeth, Dzieciatkowska, Monika, Hod, Eldad A., D'Alessandro, Angelo, Spitalnik, Steven L, Zimring, James C, Akpan, Imo J, Luckey, Chance John, and Hudson, Krystalyn E
- Published
- 2022
- Full Text
- View/download PDF
21. Reticulocytes Are an Unappreciated Risk Factor for RBC Alloimmunization at the Donor and Recipient Levels
- Author
-
Thomas, Tiffany, Qiu, Annie, Kim, Christopher Y, Gordy, Dominique E, Miller, Anabel, Tredicine, Maria, Stone, Elizabeth, Dzieciatkowska, Monika, Hod, Eldad A., D'Alessandro, Angelo, Spitalnik, Steven L, Zimring, James C, Akpan, Imo J, Luckey, Chance John, and Hudson, Krystalyn E
- Published
- 2022
- Full Text
- View/download PDF
22. Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo
- Author
-
Nemkov, Travis, Stephenson, Daniel, Erickson, Christopher, Dzieciatkowska, Monika, Key, Alicia, Moore, Amy, Earley, Eric J., Page, Grier P., Lacroix, Ian S, Stone, Mars, Deng, Xutao, Raife, Thomas, Kleinman, Steven, Zimring, James C, Roubinian, Nareg, Hansen, Kirk C., Busch, Michael P., Norris, Philip J., and D’Alessandro, Angelo
- Abstract
•Kynurenine is a marker of osmotic fragility, and its levels are reproducible within a donor across donations.•Genetic polymorphisms in SLC7A5 and ATXN2 are associated with kynurenine levels in stored RBCs, Hgb increments, and in vivo hemolysis upon transfusion.
- Published
- 2023
- Full Text
- View/download PDF
23. Cellular immune responses in red blood cell alloimmunization
- Author
-
Zimring, James C. and Hudson, Krystalyn E.
- Abstract
In excess of 340 blood group antigens have now been described that vary between individuals. Thus, any unit of blood that is nonautologous represents a significant dose of alloantigen. Most blood group antigens are proteins, which differ by a single amino acid between donors and recipients. Approximately 1 out of every 70 individuals are transfused each year (in the United States alone), which leads to antibody responses to red blood cell (RBC) alloantigens in some transfusion recipients. When alloantibodies are formed, in many cases, RBCs expressing the antigen in question can no longer be safely transfused. However, despite chronic transfusion, only 3% to 10% of recipients (in general) mount an alloantibody response. In some disease states, rates of alloimmunization are much higher (eg, sickle cell disease). For patients who become alloimmunized to multiple antigens, ongoing transfusion therapy becomes increasingly difficult or, in some cases, impossible. While alloantibodies are the ultimate immune effector of humoral alloimmunization, the cellular underpinnings of the immune system that lead to ultimate alloantibody production are complex, including antigen consumption, antigen processing, antigen presentation, T-cell biology, and B-cell biology. Moreover, these cellular processes differ to some extent with regard to transfused RBCs as compared with other better-studied immune barriers (eg, infectious disease, vaccines, and solid organ transplantation). The current work focuses on illustrating the current paradigm of humoral immunity, with a specific focus on particulars of RBC alloimmunization and recent advances in the understanding thereof.
- Published
- 2016
- Full Text
- View/download PDF
24. Bridging channel dendritic cells induce immunity to transfused red blood cells
- Author
-
Calabro, Samuele, Gallman, Antonia, Gowthaman, Uthaman, Liu, Dong, Chen, Pei, Liu, Jingchun, Krishnaswamy, Jayendra Kumar, Nascimento, Manuela Sales L., Xu, Lan, Patel, Seema R., Williams, Adam, Tormey, Christopher A., Hod, Eldad A., Spitalnik, Steven L., Zimring, James C., Hendrickson, Jeanne E., Stowell, Sean R., and Eisenbarth, Stephanie C.
- Abstract
Red blood cell (RBC) transfusion is a life-saving therapeutic tool. However, a major complication in transfusion recipients is the generation of antibodies against non-ABO alloantigens on donor RBCs, potentially resulting in hemolysis and renal failure. Long-lived antibody responses typically require CD4+ T cell help and, in murine transfusion models, alloimmunization requires a spleen. Yet, it is not known how RBC-derived antigens are presented to naive T cells in the spleen. We sought to answer whether splenic dendritic cells (DCs) were essential for T cell priming to RBC alloantigens. Transient deletion of conventional DCs at the time of transfusion or splenic DC preactivation before RBC transfusion abrogated T and B cell responses to allogeneic RBCs, even though transfused RBCs persisted in the circulation for weeks. Although all splenic DCs phagocytosed RBCs and activated RBC-specific CD4+ T cells in vitro, only bridging channel 33D1+ DCs were required for alloimmunization in vivo. In contrast, deletion of XCR1+CD8+ DCs did not alter the immune response to RBCs. Our work suggests that blocking the function of one DC subset during a narrow window of time during RBC transfusion could potentially prevent the detrimental immune response that occurs in patients who require lifelong RBC transfusion support.
- Published
- 2016
- Full Text
- View/download PDF
25. Metabolomics of ADSOL (AS-1) Red Blood Cell Storage.
- Author
-
Roback, John D., Josephson, Cassandra D., Waller, Edmund K., Newman, James L., Karatela, Sulaiman, Uppal, Karan, Jones, Dean P., Zimring, James C., and Dumont, Larry J.
- Abstract
Abstract: Population-based investigations suggest that red blood cells (RBCs) are therapeutically effective when collected, processed, and stored for up to 42 days under validated conditions before transfusion. However, some retrospective clinical studies have shown worse patient outcomes when transfused RBCs have been stored for the longest times. Furthermore, studies of RBC persistence in the circulation after transfusion have suggested that considerable donor-to-donor variability exists and may affect transfusion efficacy. To understand the limitations of current blood storage technologies and to develop approaches to improve RBC storage and transfusion efficacy, we investigated the global metabolic alterations that occur when RBCs are stored in AS-1 (AS1-RBC). Leukoreduced AS1-RBC units prepared from 9 volunteer research donors (12 total donated units) were serially sampled for metabolomics analysis over 42 days of refrigerated storage. Samples were tested by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, and specific biochemical compounds were identified by comparison to a library of purified standards. Over 3 experiments, 185 to 264 defined metabolites were quantified in stored RBC samples. Kinetic changes in these biochemicals confirmed known alterations in glycolysis and other pathways previously identified in RBCs stored in saline, adenine, glucose and mannitol solution (SAGM-RBC). Furthermore, we identified additional alterations not previously seen in SAGM-RBCs (eg, stable pentose phosphate pathway flux, progressive decreases in oxidized glutathione), and we delineated changes occurring in other metabolic pathways not previously studied (eg, S-adenosyl methionine cycle). These data are presented in the context of a detailed comparison with previous studies of SAGM-RBCs from human donors and murine AS1-RBCs. Global metabolic profiling of AS1-RBCs revealed a number of biochemical alterations in stored blood that may affect RBC viability during storage as well as therapeutic effectiveness of stored RBCs in transfusion recipients. These results provide future opportunities to more clearly pinpoint the metabolic defects during RBC storage, to identify biomarkers for donor screening and prerelease RBC testing, and to develop improved RBC storage solutions and methodologies. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
26. Transfusion-Induced Bone Marrow Transplant Rejection Due to Minor Histocompatibility Antigens.
- Author
-
Patel, Seema R. and Zimring, James C.
- Abstract
Abstract: Traditionally, alloimmunization to transfused blood products has focused exclusively on recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunologic sequelae of alloimmunization have been antibody mediated effects (ie, hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection—under reduced intensity conditioning with HLA-matched or HLA-identical marrow. Bone marrow transplant of this nature is the only existing cure for a series of nonmalignant hematologic diseases (eg, sickle cell disease, thalassemias, etc); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion-induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or natural killer cells. In this case, rejection occurs in the absence of alloantibodies and would not be detected by existing immune-hematologic methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion, which current blood bank methodologies are unable to detect. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
27. Identification of IgG3-specific epitope that remedies problem in diagnostic IgG subclass determination due to human genetic variation
- Author
-
Howie, Heather L, Wang, Xiaohong, Kapp, Linda, Lebedev, Jenna N, and Zimring, James C
- Abstract
There are four subtypes of human IgG with different effector functions. Quantifying the relative amount of each IgG subtype is important for laboratory diagnosis in multiple settings. However, in an evolving landscape of the appreciation of human variability and the need for precision/personalised laboratory diagnosis, it has also been shown that there are numerous natural variants of IgG subtypes, with at least 29 having been described. It has recently been reported that commercially available polyclonal antisera to IgG3 cross react with variants of other IgG subtypes, while available monoclonal anti-IgG3 have a blind-spot for the IgG3-04 variant. Herein, we report that IgG3-04 contains an epitope in common with all known IgG3 variants and absent in other subtypes. A novel monoclonal anti-IgG3 is described that is specific to IgG3 but without any blind-spots for known IgG3 variants, providing a remedy to the problem of genetic variability of IgG3.
- Published
- 2018
- Full Text
- View/download PDF
28. Established and theoretical factors to consider in assessing the red cell storage lesion
- Author
-
Zimring, James C.
- Abstract
The collection and storage of red blood cells (RBCs) is a logistical necessity to provide sufficient blood products. However, RBC storage is an unnatural state, resulting in complicated biological changes, referred to collectively as the “storage lesion.” Specifics of the storage lesion have been studied for decades, including alterations to cellular properties, morphology, molecular biology of carbohydrates, proteins and lipids, and basic metabolism. Recently, mass spectrometry–based “omics” technology has been applied to the RBC storage lesion, resulting in many new observations, the initial effects of which are more information than understanding. Meanwhile, clinical research on RBC transfusion is considering both the efficacy and also the potential untoward effects of transfusing stored RBCs of different ages and storage conditions. The myriad biological changes that have now been observed during the storage lesion have been extensively reviewed elsewhere. This article focuses rather on an analysis of our current understanding of the biological effects of different elements of the storage lesion, in the context of evolving new clinical understanding. A synopsis is presented of both established and theoretical considerations of the RBC storage lesion and ongoing efforts to create a safer and more efficacious product.
- Published
- 2015
- Full Text
- View/download PDF
29. Established and theoretical factors to consider in assessing the red cell storage lesion
- Author
-
Zimring, James C.
- Abstract
The collection and storage of red blood cells (RBCs) is a logistical necessity to provide sufficient blood products. However, RBC storage is an unnatural state, resulting in complicated biological changes, referred to collectively as the “storage lesion.” Specifics of the storage lesion have been studied for decades, including alterations to cellular properties, morphology, molecular biology of carbohydrates, proteins and lipids, and basic metabolism. Recently, mass spectrometry–based “omics” technology has been applied to the RBC storage lesion, resulting in many new observations, the initial effects of which are more information than understanding. Meanwhile, clinical research on RBC transfusion is considering both the efficacy and also the potential untoward effects of transfusing stored RBCs of different ages and storage conditions. The myriad biological changes that have now been observed during the storage lesion have been extensively reviewed elsewhere. This article focuses rather on an analysis of our current understanding of the biological effects of different elements of the storage lesion, in the context of evolving new clinical understanding. A synopsis is presented of both established and theoretical considerations of the RBC storage lesion and ongoing efforts to create a safer and more efficacious product.
- Published
- 2015
- Full Text
- View/download PDF
30. Antigen Loss From Antibody-Coated Red Blood Cells.
- Author
-
Zimring, James C., Cadwell, Chantel M., and Spitalnik, Steven L.
- Abstract
Clinically significant signs and symptoms of hemolysis can result from the transfusion of crossmatch incompatible blood, the development of anti–red blood cell (RBC) alloantibodies posttransfusion, or the development of autoantibodies to RBCs (ie, autoimmune hemolytic anemia). However, a less understood and poorly appreciated phenomenon is when an antibody induces the loss of its target antigen without significant damage to the cells themselves. This has been referred to as “depressed antigen,” “antigen suppression,” “weakened antigenicity,” and “antigen loss.” This phenomenon has been observed for multiple blood group antigens on human RBCs, in addition to antigens on leukocytes, platelets, neurons, and neoplastic cells. This review discusses the published human case reports of antigen loss in each of the contexts described above and describes several experimental models, including whole animal models and in vitro culture systems. Our current understanding of the cellular and molecular mechanisms is discussed, and the role of antigen loss phenomena in both normal immune function and in disease states is reviewed. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
31. Animal Models of Transfusion-Related Acute Lung Injury.
- Author
-
Lögdberg, Lennart E., Vikulina, Tatyana, Zimring, James C., and Hillyer, Christopher D.
- Abstract
Currently, more than 50 years after its apparent early recognition in case reports, and more than 20 years after its name was coined to denote a distinct entity of pulmonary transfusion reactions, transfusion-related acute lung injury (TRALI) has emerged as a serious cause of transfusion-associated morbidity and the subject of an exponentially growing scientific literature. However, review articles, clinical case reports, and case series continue to dominate the published literature on the topic and experimental studies aimed at modeling and elucidating TRALI mechanisms are less frequent. This article reviews the current status of the known experimental models of TRALI, with particular emphasis on efforts to establish in vivo animal models of this important pulmonary transfusion reaction. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
32. Blood Donation and Blood Transfusion: Special Considerations for African Americans.
- Author
-
Shaz, Beth H., Zimring, James C., Demmons, Derrick G., and Hillyer, Christopher D.
- Abstract
Unique issues in blood donation and blood transfusion regarding African Americans (AA) in the United States span the donation process, manufacturing of products, and hospital transfusion service. As AAs become a growing population, a constant supply of blood donated by AAs is necessary to support this growth. Nationally, AAs are underrepresented in blood collection, which may be secondary to AAs having higher rates of anemia and other deferrable conditions or unique motivators as well as other barriers to blood donation. When investigating blood transfusion practices, blood utilization for different races and ethnicities is unknown. AAs may receive more red blood cell (RBC) transfusions because they have a higher proportion of diseases that require transfusion. Patients with sickle cell disease are at increased risk of RBC alloimmunization likely due to the predominance of RBC units from white donors in the existing blood supply, but it is not known if all AA recipients experience increased alloimmunization rates compared with whites. In conclusion, there is a need to increase donation by AAs, which can only be achieved by conducting studies to understand racial differences in donor recruitment and to better understand blood utilization and adverse events as a factor of race and ethnicity. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
33. Transfusion-Transmitted Cytomegalovirus: Lessons From a Murine Model.
- Author
-
Roback, John D., Su, Leon, Zimring, James C., and Hillyer, Christopher D.
- Abstract
Transfusion-transmitted cytomegalovirus (CMV) infection (TT-CMV) continues to complicate blood transfusion therapy, which can lead to severe morbidity or mortality in immunocompromised or immuno-immature recipients. The biological mechanisms that underlie TT-CMV (eg, viral latency in donor monocytes or stimulatory signals in the transfusion recipient leading to cytomegalovirus reactivation) are difficult to study in humans, but can be addressed in animal models. In this review, we discuss a mouse blood transfusion model, which can be used to investigate these issues as well as to validate methods to prevent TT-CMV in at-risk patients. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
34. Fresh versus old blood: are there differences and do they matter?
- Author
-
Zimring, James C.
- Abstract
The medical effects of transfusing stored RBCs is an area of significant concern that has received substantial attention in recent years. Retrospective trials show all possible outcomes, including sequelae from transfusing older RBCs, no difference between older and fresher RBCs, and a benefit to older RBCs. Several prospective clinical trials are under way to further investigate potential untoward effects of stored RBCs. Thus far, the issue of potential sequelae from transfusing stored RBCs remains a highly controversial issue. However, what is not controversial is that RBC storage is an unnatural state during which a series of substantial changes take place to the stored RBCs. These changes result in the formation of cellular and chemical entities known to have biological activities in other settings, giving rise to several distinct hypotheses by which stored RBCs may alter recipient biology. Herein, the clinical background and basic science of RBC storage are reviewed, with a particular focus on factors that may complicate hypothesis testing and obfuscate underlying biologies. The complexity of the RBC storage lesion, donor-to-donor variation, and the diversity of recipient pathophysiologies remain a challenge to prospective trials assessing the safety of stored RBCs.
- Published
- 2013
- Full Text
- View/download PDF
35. S1P has a negative effect on RBC storage quality
- Author
-
Hay, Ariel, Nemkov, Travis, Gamboni, Fabia, Dzieciatkowska, Monika, Key, Alicia, Galbraith, Matthew, Bartsch, Kyle, Sun, Kaiqi, Xia, Yang, Stone, Mars, Busch, Michael P., Norris, Philip J., Zimring, James C., and D’Alessandro, Angelo
- Abstract
•S1P declines during RBC storage. S1P supplementation to human or murine RBCs boosts energy metabolism at the expense of antioxidant pathways.•S1P worsens and Sphk1 KO, or hypoxia, promote stored RBC posttransfusion recoveries.
- Published
- 2022
- Full Text
- View/download PDF
36. Turning over a new leaf on turning over RBCs
- Author
-
Zimring, James C.
- Published
- 2020
- Full Text
- View/download PDF
37. Turning over a new leaf on turning over RBCs
- Author
-
Zimring, James C.
- Published
- 2020
- Full Text
- View/download PDF
38. A novel role for C3 in antibody-induced red blood cell clearance and antigen modulation
- Author
-
Girard-Pierce, Kathryn R., Stowell, Sean R., Smith, Nicole H., Arthur, C. Maridith, Sullivan, Harold C., Hendrickson, Jeanne E., and Zimring, James C.
- Abstract
Hemolytic transfusion reactions (HTRs) due to incompatible red blood cell (RBC) transfusions are a leading cause of transfusion associated death. Although many transfused incompatible RBCs are cleared, some remain in circulation despite the presence of RBC-specific antibodies, potentially due to “antigen modulation.” With a goal of better understanding incompatible RBC clearance, we generated a murine model with RBC-specific expression of a clinically significant human antigen (KEL2) known to be involved in antigen modulation as well as in HTRs. Wild-type (WT) recipients transfused with transgenic KEL2 RBCs generated anti-KEL glycoprotein alloantibodies, which fixed complement, led to intravascular hemolysis, and resulted in decreased levels of KEL2 antigen detectable on cells remaining in circulation. Antigen modulation did not appear to solely reflect removal of RBCs with higher antigen expression, because cells continued to display antigen modulation in the absence of significant clearance. Recipients genetically lacking complement exhibited lesser degrees of incompatible RBC clearance and antigen modulation in comparison with WT or FcγR knock-out (KO) animals, suggesting a role for complement in RBC clearance. In summary, this HTR model may serve as a platform to test strategies to downmodulate antigen and inhibit incompatible RBC clearance, thus potentially mitigating transfusion dangers.
- Published
- 2013
- Full Text
- View/download PDF
39. A novel role for C3 in antibody-induced red blood cell clearance and antigen modulation
- Author
-
Girard-Pierce, Kathryn R., Stowell, Sean R., Smith, Nicole H., Arthur, C. Maridith, Sullivan, Harold C., Hendrickson, Jeanne E., and Zimring, James C.
- Abstract
Hemolytic transfusion reactions (HTRs) due to incompatible red blood cell (RBC) transfusions are a leading cause of transfusion associated death. Although many transfused incompatible RBCs are cleared, some remain in circulation despite the presence of RBC-specific antibodies, potentially due to “antigen modulation.” With a goal of better understanding incompatible RBC clearance, we generated a murine model with RBC-specific expression of a clinically significant human antigen (KEL2) known to be involved in antigen modulation as well as in HTRs. Wild-type (WT) recipients transfused with transgenic KEL2 RBCs generated anti-KEL glycoprotein alloantibodies, which fixed complement, led to intravascular hemolysis, and resulted in decreased levels of KEL2 antigen detectable on cells remaining in circulation. Antigen modulation did not appear to solely reflect removal of RBCs with higher antigen expression, because cells continued to display antigen modulation in the absence of significant clearance. Recipients genetically lacking complement exhibited lesser degrees of incompatible RBC clearance and antigen modulation in comparison with WT or FcγR knock-out (KO) animals, suggesting a role for complement in RBC clearance. In summary, this HTR model may serve as a platform to test strategies to downmodulate antigen and inhibit incompatible RBC clearance, thus potentially mitigating transfusion dangers.
- Published
- 2013
- Full Text
- View/download PDF
40. Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model
- Author
-
Stowell, Sean R., Henry, Kate L., Smith, Nicole H., Hudson, Krystalyn E., Halverson, Greg R., Park, Jaekeun C., Bennett, Ashley M., Girard-Pierce, Kathryn R., Arthur, C. Maridith, Bunting, Silvia T., Zimring, James C., and Hendrickson, Jeanne E.
- Abstract
Exposure to nonself red blood cell (RBC) antigens, either from transfusion or pregnancy, may result in alloimmunization and incompatible RBC clearance. First described as a pregnancy complication 80 years ago, hemolytic disease of the fetus and newborn (HDFN) is caused by alloimmunization to paternally derived RBC antigens. Despite the morbidity/mortality of HDFN, women at risk for RBC alloimmunization have few therapeutic options. Given that alloantibodies to antigens in the KEL family are among the most clinically significant, we developed a murine model with RBC-specific expression of the human KEL antigen to evaluate the impact of maternal/fetal KEL incompatibility. After exposure to fetal KEL RBCs during successive pregnancies with KEL-positive males, 21 of 21 wild-type female mice developed anti-KEL alloantibodies; intrauterine fetal anemia and/or demise occurred in a subset of KEL-positive pups born to wild type, but not agammaglobulinemic mothers. Similar to previous observations in humans, pregnancy-associated alloantibodies were detrimental in a transfusion setting, and transfusion-associated alloantibodies were detrimental in a pregnancy setting. This is the first pregnancy-associated HDFN model described to date, which will serve as a platform to develop targeted therapies to prevent and/or mitigate the dangers of RBC alloantibodies to fetuses and newborns.
- Published
- 2013
- Full Text
- View/download PDF
41. Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model
- Author
-
Stowell, Sean R., Henry, Kate L., Smith, Nicole H., Hudson, Krystalyn E., Halverson, Greg R., Park, Jaekeun C., Bennett, Ashley M., Girard-Pierce, Kathryn R., Arthur, C. Maridith, Bunting, Silvia T., Zimring, James C., and Hendrickson, Jeanne E.
- Abstract
Exposure to nonself red blood cell (RBC) antigens, either from transfusion or pregnancy, may result in alloimmunization and incompatible RBC clearance. First described as a pregnancy complication 80 years ago, hemolytic disease of the fetus and newborn (HDFN) is caused by alloimmunization to paternally derived RBC antigens. Despite the morbidity/mortality of HDFN, women at risk for RBC alloimmunization have few therapeutic options. Given that alloantibodies to antigens in the KEL family are among the most clinically significant, we developed a murine model with RBC-specific expression of the human KEL antigen to evaluate the impact of maternal/fetal KEL incompatibility. After exposure to fetal KEL RBCs during successive pregnancies with KEL-positive males, 21 of 21 wild-type female mice developed anti-KEL alloantibodies; intrauterine fetal anemia and/or demise occurred in a subset of KEL-positive pups born to wild type, but not agammaglobulinemic mothers. Similar to previous observations in humans, pregnancy-associated alloantibodies were detrimental in a transfusion setting, and transfusion-associated alloantibodies were detrimental in a pregnancy setting. This is the first pregnancy-associated HDFN model described to date, which will serve as a platform to develop targeted therapies to prevent and/or mitigate the dangers of RBC alloantibodies to fetuses and newborns.
- Published
- 2013
- Full Text
- View/download PDF
42. Transfusion in the absence of inflammation induces antigen-specific tolerance to murine RBCs
- Author
-
Smith, Nicole H., Hod, Eldad A., Spitalnik, Steven L., Zimring, James C., and Hendrickson, Jeanne E.
- Abstract
Most human transfusion recipients fail to make detectable alloantibodies to foreign RBC antigens (“nonresponders”). Herein, we use a murine model to test the hypothesis that nonresponders may be immunologically tolerant. FVB mice transfused with RBCs expressing transgenic human glycophorin A (hGPA) antigen in the absence of inflammation produced undetectable levels of anti-hGPA immunoglobulins, unlike those transfused in the presence of polyinosinic:polycytidylic acid–induced inflammation. Mice in the nonresponder group failed to produce anti-hGPA after subsequent transfusions in the presence of polyinosinic:polycytidylic acid, whereas anti-hGPA levels increased in the responder group. This tolerance was antigen specific, because nonresponders to hGPA produced alloantibodies to RBCs that expressed a different transgenic antigen. This tolerance was not an idiosyncrasy of the hGPA antigen nor of the recipient strain, because B10.BR mice transfused with membrane-bound hen egg lysozyme antigen–transgenic RBCs also demonstrated induced nonresponsiveness. These data demonstrate that RBCs transfused in the absence of inflammation can induce tolerance.
- Published
- 2012
- Full Text
- View/download PDF
43. Transfusion in the absence of inflammation induces antigen-specific tolerance to murine RBCs
- Author
-
Smith, Nicole H., Hod, Eldad A., Spitalnik, Steven L., Zimring, James C., and Hendrickson, Jeanne E.
- Abstract
Most human transfusion recipients fail to make detectable alloantibodies to foreign RBC antigens (“nonresponders”). Herein, we use a murine model to test the hypothesis that nonresponders may be immunologically tolerant. FVB mice transfused with RBCs expressing transgenic human glycophorin A (hGPA) antigen in the absence of inflammation produced undetectable levels of anti-hGPA immunoglobulins, unlike those transfused in the presence of polyinosinic:polycytidylic acid–induced inflammation. Mice in the nonresponder group failed to produce anti-hGPA after subsequent transfusions in the presence of polyinosinic:polycytidylic acid, whereas anti-hGPA levels increased in the responder group. This tolerance was antigen specific, because nonresponders to hGPA produced alloantibodies to RBCs that expressed a different transgenic antigen. This tolerance was not an idiosyncrasy of the hGPA antigen nor of the recipient strain, because B10.BR mice transfused with membrane-bound hen egg lysozyme antigen–transgenic RBCs also demonstrated induced nonresponsiveness. These data demonstrate that RBCs transfused in the absence of inflammation can induce tolerance.
- Published
- 2012
- Full Text
- View/download PDF
44. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non–transferrin-bound iron
- Author
-
Hod, Eldad A., Brittenham, Gary M., Billote, Genia B., Francis, Richard O., Ginzburg, Yelena Z., Hendrickson, Jeanne E., Jhang, Jeffrey, Schwartz, Joseph, Sharma, Shruti, Sheth, Sujit, Sireci, Anthony N., Stephens, Hannah L., Stotler, Brie A., Wojczyk, Boguslaw S., Zimring, James C., and Spitalnik, Steven L.
- Abstract
Transfusions of RBCs stored for longer durations are associated with adverse effects in hospitalized patients. We prospectively studied 14 healthy human volunteers who donated standard leuko-reduced, double RBC units. One unit was autologously transfused “fresh” (3-7 days of storage), and the other “older” unit was transfused after 40 to 42 days of storage. Of the routine laboratory parameters measured at defined times surrounding transfusion, significant differences between fresh and older transfusions were only observed in iron parameters and markers of extravascular hemolysis. Compared with fresh RBCs, mean serum total bilirubin increased by 0.55 mg/dL at 4 hours after transfusion of older RBCs (P= .0003), without significant changes in haptoglobin or lactate dehydrogenase. In addition, only after the older transfusion, transferrin saturation increased progressively over 4 hours to a mean of 64%, and non–transferrin-bound iron appeared, reaching a mean of 3.2μM. The increased concentrations of non–transferrin-bound iron correlated with enhanced proliferation in vitro of a pathogenic strain of Escherichia coli(r= 0.94, P= .002). Therefore, circulating non–transferrin-bound iron derived from rapid clearance of transfused, older stored RBCs may enhance transfusion-related complications, such as infection. The trial was registered with www.clinicaltrials.govas #NCT01319552.
- Published
- 2011
- Full Text
- View/download PDF
45. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non–transferrin-bound iron
- Author
-
Hod, Eldad A., Brittenham, Gary M., Billote, Genia B., Francis, Richard O., Ginzburg, Yelena Z., Hendrickson, Jeanne E., Jhang, Jeffrey, Schwartz, Joseph, Sharma, Shruti, Sheth, Sujit, Sireci, Anthony N., Stephens, Hannah L., Stotler, Brie A., Wojczyk, Boguslaw S., Zimring, James C., and Spitalnik, Steven L.
- Abstract
Transfusions of RBCs stored for longer durations are associated with adverse effects in hospitalized patients. We prospectively studied 14 healthy human volunteers who donated standard leuko-reduced, double RBC units. One unit was autologously transfused “fresh” (3-7 days of storage), and the other “older” unit was transfused after 40 to 42 days of storage. Of the routine laboratory parameters measured at defined times surrounding transfusion, significant differences between fresh and older transfusions were only observed in iron parameters and markers of extravascular hemolysis. Compared with fresh RBCs, mean serum total bilirubin increased by 0.55 mg/dL at 4 hours after transfusion of older RBCs (P = .0003), without significant changes in haptoglobin or lactate dehydrogenase. In addition, only after the older transfusion, transferrin saturation increased progressively over 4 hours to a mean of 64%, and non–transferrin-bound iron appeared, reaching a mean of 3.2μM. The increased concentrations of non–transferrin-bound iron correlated with enhanced proliferation in vitro of a pathogenic strain of Escherichia coli (r = 0.94, P = .002). Therefore, circulating non–transferrin-bound iron derived from rapid clearance of transfused, older stored RBCs may enhance transfusion-related complications, such as infection. The trial was registered with www.clinicaltrials.gov as #NCT01319552.
- Published
- 2011
- Full Text
- View/download PDF
46. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation
- Author
-
Hod, Eldad A., Zhang, Ning, Sokol, Set A., Wojczyk, Boguslaw S., Francis, Richard O., Ansaldi, Daniel, Francis, Kevin P., Della-Latta, Phyllis, Whittier, Susan, Sheth, Sujit, Hendrickson, Jeanne E., Zimring, James C., Brittenham, Gary M., and Spitalnik, Steven L.
- Abstract
Although red blood cell (RBC) transfusions can be lifesaving, they are not without risk. In critically ill patients, RBC transfusions are associated with increased morbidity and mortality, which may increase with prolonged RBC storage before transfusion. The mechanisms responsible remain unknown. We hypothesized that acute clearance of a subset of damaged, stored RBCs delivers large amounts of iron to the monocyte/macrophage system, inducing inflammation. To test this in a well-controlled setting, we used a murine RBC storage and transfusion model to show that the transfusion of stored RBCs, or washed stored RBCs, increases plasma nontransferrin bound iron (NTBI), produces acute tissue iron deposition, and initiates inflammation. In contrast, the transfusion of fresh RBCs, or the infusion of stored RBC-derived supernatant, ghosts, or stroma-free lysate, does not produce these effects. Furthermore, the insult induced by transfusion of stored RBC synergizes with subclinical endotoxinemia producing clinically overt signs and symptoms. The increased plasma NTBI also enhances bacterial growth in vitro. Taken together, these results suggest that, in a mouse model, the cellular component of leukoreduced, stored RBC units contributes to the harmful effects of RBC transfusion that occur after prolonged storage. Nonetheless, these findings must be confirmed by prospective human studies.
- Published
- 2010
- Full Text
- View/download PDF
47. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation
- Author
-
Hod, Eldad A., Zhang, Ning, Sokol, Set A., Wojczyk, Boguslaw S., Francis, Richard O., Ansaldi, Daniel, Francis, Kevin P., Della-Latta, Phyllis, Whittier, Susan, Sheth, Sujit, Hendrickson, Jeanne E., Zimring, James C., Brittenham, Gary M., and Spitalnik, Steven L.
- Abstract
Although red blood cell (RBC) transfusions can be lifesaving, they are not without risk. In critically ill patients, RBC transfusions are associated with increased morbidity and mortality, which may increase with prolonged RBC storage before transfusion. The mechanisms responsible remain unknown. We hypothesized that acute clearance of a subset of damaged, stored RBCs delivers large amounts of iron to the monocyte/macrophage system, inducing inflammation. To test this in a well-controlled setting, we used a murine RBC storage and transfusion model to show that the transfusion of stored RBCs, or washed stored RBCs, increases plasma nontransferrin bound iron (NTBI), produces acute tissue iron deposition, and initiates inflammation. In contrast, the transfusion of fresh RBCs, or the infusion of stored RBC-derived supernatant, ghosts, or stroma-free lysate, does not produce these effects. Furthermore, the insult induced by transfusion of stored RBC synergizes with subclinical endotoxinemia producing clinically overt signs and symptoms. The increased plasma NTBI also enhances bacterial growth in vitro. Taken together, these results suggest that, in a mouse model, the cellular component of leukoreduced, stored RBC units contributes to the harmful effects of RBC transfusion that occur after prolonged storage. Nonetheless, these findings must be confirmed by prospective human studies.
- Published
- 2010
- Full Text
- View/download PDF
48. Regulation of primary alloantibody response through antecedent exposure to a microbial T-cell epitope
- Author
-
Hudson, Krystalyn E., Lin, Eugene, Hendrickson, Jeanne E., Lukacher, Aron E., and Zimring, James C.
- Abstract
Humoral alloimmunization to red blood cell (RBC) antigens is a clinically significant problem that can lead to transfusion reactions and difficulty in locating future compatible blood for transfusion. However, factors regulating responder/nonresponder status are only partially understood. Herein, we identify a series of microbes with 100% identity in 8– to 9–amino acid peptides containing the variant amino acids in Kell, Kidd, and Duffy antigens. To test the hypothesis that infection with such a microbe could predispose to RBC alloimmunization, a mouse model was developed using murine polyoma virus expressing a defined CD4+ T-cell epitope ovalbumin323-339 ((OVA)323-339) and subsequent transfusion with RBCs expressing a B-cell epitope (hen egg lysozyme [HEL]) fused to (OVA)323-339. Whereas infection alone induced no detectable anti-HEL, subsequent RBC transfusion induced 100- to 1000-fold more anti-HEL in mice that had been previously infected compared with control mice. This effect did not occur with wild-type polyoma virus or RBCs expressing HEL alone. Together, these data indicate that prior exposure to a pathogen with small peptide homology to RBC antigens can lead to an enhanced primary alloantibody response. As such priming is not detectable by current clinical tests, it is unknown to what extent this occurs in human alloimmunization.
- Published
- 2010
- Full Text
- View/download PDF
49. Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model
- Author
-
Desmarets, Maxime, Cadwell, Chantel M., Peterson, Kenneth R., Neades, Renee, and Zimring, James C.
- Abstract
When successful, human leukocyte antigen (HLA)–matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex–matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8+T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.
- Published
- 2009
- Full Text
- View/download PDF
50. Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model
- Author
-
Desmarets, Maxime, Cadwell, Chantel M., Peterson, Kenneth R., Neades, Renee, and Zimring, James C.
- Abstract
When successful, human leukocyte antigen (HLA)–matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex–matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8+ T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.