44 results on '"Zimring, James C."'
Search Results
2. Contributors
- Author
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Abrams, Charles S., primary, Abshire, Thomas C., additional, Arinsburg, Suzanne A., additional, Avecilla, Scott T., additional, Babic, Aleksandar M., additional, Bellone, Michael, additional, Bennett, Carolyn M., additional, Briones, Michael A., additional, Bussel, James B., additional, Chandler, Wayne L., additional, Csete, Marie, additional, Cuker, Adam C., additional, Cushing, Melissa M., additional, Desormeaux, Marie-Laure, additional, Dodd, Roger Y., additional, Dunn, Amy L., additional, Francis, Richard O., additional, Garbaini, Jennifer, additional, Ginzberg, Yelena Z., additional, Goodrich, Raymond P., additional, Goss, Cheryl A., additional, Greco, Benjamin J., additional, Hendrickson, Jeanne E., additional, Hillyer, Christopher D., additional, Hod, Eldad A., additional, Hume, Heather A., additional, Jalikis, Florencia G., additional, Jobe, Shawn M., additional, Josephson, Casssandra D., additional, Karafin, Matthew S., additional, Karim, Sadiqa, additional, Katz, Louis M., additional, Kempton, Christine L., additional, Kessler, Debra A., additional, Lal, Devika, additional, Lambert, Michele P., additional, Lim, Wendy, additional, Maramica, Irina Knezevic, additional, Marschner, Susanne, additional, Mcguinn, Catherine E., additional, Meeks, Shannon L., additional, Miller, Connie H., additional, Mitchell, W. Beau, additional, Monis, Grace F., additional, Nester, Theresa, additional, Pham, Huy Phu, additional, Quinley, Eva D., additional, Rennert, Hanna, additional, Reyes, Morayma, additional, Rich, Anna-Sophie, additional, Roshal, Mikhail, additional, Ruch, Joshua M., additional, Savage, William J., additional, Scaradavou, Andromachi, additional, Schwartz, Joseph, additional, Shaz, Beth H., additional, Shi, Patricia, additional, Sood, Suman, additional, Weinberg, Rona S., additional, Westhoff, Connie M., additional, Winkler, Anne M., additional, Yan, Jiong, additional, and Zimring, James C., additional
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- 2013
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3. Transfusion-Related Immunomodulation
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Zimring, James C., primary and Nester, Theresa, additional
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- 2013
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4. Laboratory Diagnosis of Hyperhomocysteinemia
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Zimring, James C., primary
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- 2009
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5. Leukoreduction of Blood Products
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Zimring, James C., primary
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- 2009
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6. Introduction to Coagulation Testing
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Zimring, James C., primary
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- 2009
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7. Proteins C, S and Z Testing
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Zimring, James C., primary
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- 2009
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8. Platelet Count
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Zimring, James C., primary
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- 2009
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9. Laboratory Diagnosis of Factor Level Abnormalities Associated with Thrombosis
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Zimring, James C., primary
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- 2009
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10. Lipoprotein (a) Testing
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Winkler, Anne M., primary and Zimring, James C., additional
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- 2009
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11. Prothrombin Gene Mutation Testing
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Winkler, Anne M., primary and Zimring, James C., additional
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- 2009
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12. Laboratory Support for Heparin Monitoring
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Winkler, Anne M., primary and Zimring, James C., additional
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- 2009
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13. Transfusion Related Immunomodulation
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Zimring, James C., primary
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- 2009
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14. Prothrombin Time and Activated Partial Thromboplastin Time
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Zimring, James C., primary
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- 2009
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15. Antithrombin Testing
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Zimring, James C., primary
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- 2009
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16. Preface
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Hillyer, Christopher D., primary, Shaz, Beth H., additional, Abshire, Thomas C., additional, and Zimring, James C., additional
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- 2009
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17. Laboratory Diagnosis of Heparin-induced Thrombocytopenia
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Winkler, Anne M., primary and Zimring, James C., additional
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- 2009
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18. Activated Protein C Resistance and Factor V Leiden Testing
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Winkler, Anne M., primary and Zimring, James C., additional
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- 2009
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19. Coagulation Factor Preparations
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Zimring, James C., primary and Duncan, Alexander, additional
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- 2007
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20. Principles of Red Blood Cell Allo- and Autoantibody Formation and Function
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Zimring, James C., primary
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- 2007
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21. Contributors
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Adams, Sharon, primary, Alving, Barbara, additional, Anderson, Kenneth C., additional, AuBuchon, James P., additional, Bandarenko, Nicholas, additional, Barrett, Jon, additional, Benjamin, Richard J., additional, Benn, Howard, additional, Beyer, Ginine M., additional, Blajchman, Morris A., additional, Blumberg, Neil, additional, Brecher, Mark E., additional, Broxmeyer, Hal E., additional, Busch, Michael P., additional, Callum, Jeannie L., additional, Campbell-Lee, Sally A., additional, Carson, Jeffrey L., additional, Clark, Kenneth A., additional, Corash, Laurence, additional, Crookes, Robert L., additional, Culler, Elizabeth E., additional, Cunningham, Melody J., additional, Davey, Richard J., additional, Devine, Dana V., additional, Dodd, Roger Y., additional, Duncan, Alexander, additional, Dzik, Walter H., additional, Eckman, James R., additional, Eisenbrey, A. Bradley, additional, Fiebig, Eberhard W., additional, Fisk, John M., additional, Geiger, Terrence L., additional, Goldman, Mindy, additional, Harris, Shealynn B., additional, Heal, Joanna M., additional, Hébert, Paul C., additional, Heddle, Nancy, additional, Hess, John R., additional, Hillyer, Christopher D., additional, Hillyer, Krista L., additional, Holland, Paul V., additional, Janatpour, Kim A., additional, Johnson, Viviana V., additional, Josephson, Cassandra D., additional, Kaufman, Richard M., additional, Kickler, Thomas S., additional, Killion, Diane, additional, King, Karen E., additional, Kleinman, Steven H., additional, Kunicki, Thomas J., additional, Lee, Tzong-Hae, additional, Lipton, Karen Shoos, additional, Lögdberg, Lennart E., additional, Luban, Naomi L.C., additional, Manno, Catherine S., additional, Mantha, Simon, additional, Marincola, Francesco M., additional, McLeod, Bruce C., additional, Menitove, Jay E., additional, Millward, Peter A., additional, Murphy, Edward L., additional, Ness, Paul M., additional, Nugent, Diane J., additional, Perrotta, Peter L., additional, Pisciotto, Patricia T., additional, Price, Thomas H., additional, Ramasethu, Jayashree, additional, Ramirez-Arcos, Sandra M., additional, Reed, William, additional, Reid, Marion E., additional, Roback, John D., additional, Rowley, Scott D., additional, Sandler, S. Gerald, additional, Schuetz, Audrey N., additional, Selogie, Eileen, additional, Shaz, Beth, additional, Shirey, R. Sue, additional, Shulman, Ira A., additional, Shusterman, Suzanne, additional, Silberstein, Leslie E., additional, Sloan, Steven R., additional, Snyder, Edward L., additional, Strauss, Ronald G., additional, Stroncek, David F., additional, Strong, D. Michael, additional, Su, Leon L., additional, Szczepiorkowski, Zbigniew M., additional, Tegtmeier, Gary E., additional, Tinmouth, Alan, additional, Wang, Ena, additional, Webert, Kathryn E., additional, Westhoff, Connie M., additional, Winslow, Robert M., additional, Wong, Edward C.C., additional, Zeger, Gary, additional, and Zimring, James C., additional
- Published
- 2007
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22. Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro.
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Nemkov T, Key A, Stephenson D, Earley EJ, Keele GR, Hay A, Amireault P, Casimir M, Dussiot M, Dzieciatkowska M, Reisz JA, Deng X, Stone M, Kleinman S, Spitalnik SL, Hansen KC, Norris PJ, Churchill GA, Busch MP, Roubinian N, Page GP, Zimring JC, Arduini A, and D'Alessandro A
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- Humans, Animals, Mice, Polymorphism, Single Nucleotide, Erythrocyte Aging, Genome-Wide Association Study, Male, Female, Solute Carrier Family 22 Member 5 genetics, Solute Carrier Family 22 Member 5 metabolism, Blood Preservation methods, Carnitine metabolism, Hemolysis, Erythrocytes metabolism
- Abstract
Abstract: Recent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor. We also measured l-carnitine and acyl-carnitines in 13 091 packed RBC units from donors in the Recipient Epidemiology and Donor Evaluation study. Genome-wide association studies against 879 000 polymorphisms identified critical genetic factors contributing to interdonor heterogeneity in end-of-storage carnitine levels, including common nonsynonymous polymorphisms in genes encoding carnitine transporters (SLC22A16, SLC22A5, and SLC16A9); carnitine synthesis (FLVCR1 and MTDH) and metabolism (CPT1A, CPT2, CRAT, and ACSS2), and carnitine-dependent repair of lipids oxidized by ALOX5. Significant associations between genetic polymorphisms on SLC22 transporters and carnitine pools in stored RBCs were validated in 525 Diversity Outbred mice. Donors carrying 2 alleles of the rs12210538 SLC22A16 single-nucleotide polymorphism exhibited the lowest l-carnitine levels, significant elevations of in vitro hemolysis, and the highest degree of vesiculation, accompanied by increases in lipid peroxidation markers. Separation of RBCs by age, via in vivo biotinylation in mice, and Percoll density gradients of human RBCs, showed age-dependent depletions of l-carnitine and acyl-carnitine pools, accompanied by progressive failure of the reacylation process after chemically induced membrane lipid damage. Supplementation of stored murine RBCs with l-carnitine boosted posttransfusion recovery, suggesting this could represent a viable strategy to improve RBC storage quality., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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23. Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo.
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Nemkov T, Stephenson D, Erickson C, Dzieciatkowska M, Key A, Moore A, Earley EJ, Page GP, Lacroix IS, Stone M, Deng X, Raife T, Kleinman S, Zimring JC, Roubinian N, Hansen KC, Busch MP, Norris PJ, and D'Alessandro A
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- Humans, Kynurenine metabolism, Large Neutral Amino Acid-Transporter 1 metabolism, Erythrocytes metabolism, Metabolomics, Blood Preservation methods, Blood Donors, Hemolysis
- Abstract
Abstract: In the field of transfusion medicine, the clinical relevance of the metabolic markers of the red blood cell (RBC) storage lesion is incompletely understood. Here, we performed metabolomics of RBC units from 643 donors enrolled in the Recipient Epidemiology and Donor Evaluation Study, REDS RBC Omics. These units were tested on storage days 10, 23, and 42 for a total of 1929 samples and also characterized for end-of-storage hemolytic propensity after oxidative and osmotic insults. Our results indicate that the metabolic markers of the storage lesion poorly correlated with hemolytic propensity. In contrast, kynurenine was not affected by storage duration and was identified as the top predictor of osmotic fragility. RBC kynurenine levels were affected by donor age and body mass index and were reproducible within the same donor across multiple donations from 2 to 12 months apart. To delve into the genetic underpinnings of kynurenine levels in stored RBCs, we thus tested kynurenine levels in stored RBCs on day 42 from 13 091 donors from the REDS RBC Omics study, a population that was also genotyped for 879 000 single nucleotide polymorphisms. Through a metabolite quantitative trait loci analysis, we identified polymorphisms in SLC7A5, ATXN2, and a series of rate-limiting enzymes (eg, kynurenine monooxygenase, indoleamine 2,3-dioxygenase, and tryptophan dioxygenase) in the kynurenine pathway as critical factors affecting RBC kynurenine levels. By interrogating a donor-recipient linkage vein-to-vein database, we then report that SLC7A5 polymorphisms are also associated with changes in hemoglobin and bilirubin levels, suggestive of in vivo hemolysis in 4470 individuals who were critically ill and receiving single-unit transfusions., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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24. Turning over a new leaf on turning over RBCs.
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Zimring JC
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- Erythrocytes, Humans, Plant Leaves, Hemolysis, Spleen
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- 2020
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25. Poly(I:C) causes failure of immunoprophylaxis to red blood cells expressing the KEL glycoprotein in mice.
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Escamilla-Rivera V, Liu J, Gibb DR, Santhanakrishnan M, Liu D, Forsmo JE, Eisenbarth SC, Foxman EF, Stowell SR, Luckey CJ, Zimring JC, Hudson KE, and Hendrickson JE
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- Animals, CD4-Positive T-Lymphocytes immunology, Cytokines blood, Disease Models, Animal, Erythroblastosis, Fetal blood, Erythroblastosis, Fetal immunology, Erythroblastosis, Fetal prevention & control, Erythrocyte Transfusion adverse effects, Female, Humans, Immunization, Passive, Interferon Type I blood, Isoantigens blood, Isoantigens genetics, Kell Blood-Group System blood, Kell Blood-Group System genetics, Membrane Glycoproteins immunology, Metalloendopeptidases immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phagocytosis immunology, Pregnancy, Erythrocytes drug effects, Erythrocytes immunology, Membrane Glycoproteins blood, Membrane Glycoproteins genetics, Metalloendopeptidases blood, Metalloendopeptidases genetics, Poly I-C pharmacology
- 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., (© 2020 by The American Society of Hematology.)
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- 2020
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26. Common murine immunoglobulin detection reagents have diminished reactivity with IgG3 - A vulnerability to misinterpretation.
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Howie HL, Wang X, Kapp L, Lebedev J, Hudson KE, and Zimring JC
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- Animals, Goats, Humans, Immune Sera immunology, Immunity, Humoral, Immunoglobulin Class Switching, Immunologic Tests, Mice, Epitopes metabolism, Immunoglobulin G metabolism
- Abstract
Methods designed to monitor humoral immune responses, in a variety of settings, typically use a broadly reactive detection reagent (e.g. polyclonal anti-Ig (immunoglobulin)) in order to characterize antibody responses. In the context of murine models of immunity, which are widely used, this would typically be antisera to mouse Ig or mouse IgG. However, there are 4 different subtypes of mouse IgG; thus, the validity of the above approach, as a general screen for humoral immune responses, depends upon the assumption that the antisera recognize all IgG subtypes. This seems like a reasonable assumption, since polyclonal antisera recognize multiple epitopes; however, herein we report that two commercial sources of goat anti-mouse Ig are hyporeactive with IgG3. Given that relative IgG3 levels are different in distinct types of immune response, these findings demonstrate a potential for misinterpretation, and suggest a need to modify immunological methods in this context., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2018
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27. Does AC stand for acylcarnitine, anticoagulant, or both?
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Zimring JC
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- Female, Humans, Male, Carnitine analogs & derivatives, Factor Xa metabolism, Factor Xa Inhibitors metabolism, Venous Thrombosis metabolism
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It has long been appreciated that hemostatic systems represent complicated dynamics, involving multiple factors, which work in concert to regulate the balance between coagulation and bleeding in both health and disease. In this issue of Blood, Deguchi et al present evidence to support a novel role for acylcarnitines as anticoagulants.
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- 2015
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28. Established and theoretical factors to consider in assessing the red cell storage lesion.
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Zimring JC
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- Erythrocytes physiology, Humans, Blood Preservation, Blood Transfusion, Erythrocytes cytology
- 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., (© 2015 by The American Society of Hematology.)
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- 2015
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29. The fat and the skinny on acute lung injury.
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Zimring JC
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- Animals, Male, Acute Lung Injury prevention & control, Aspirin pharmacology, Lipoxins metabolism, Neutrophils drug effects, Platelet Aggregation drug effects
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- 2014
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30. A novel role for C3 in antibody-induced red blood cell clearance and antigen modulation.
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Girard-Pierce KR, Stowell SR, Smith NH, Arthur CM, Sullivan HC, Hendrickson JE, and Zimring JC
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- Animals, Blood Group Incompatibility immunology, Blood Group Incompatibility pathology, Cell Survival, Erythrocyte Transfusion, Erythrocytes pathology, Glycoproteins immunology, Humans, Immunization, Passive, Isoantibodies immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding, Receptors, IgG metabolism, Time Factors, Antibodies immunology, Antigens immunology, Complement C3 metabolism, Erythrocytes immunology
- 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.
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- 2013
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31. Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model.
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Stowell SR, Henry KL, Smith NH, Hudson KE, Halverson GR, Park JC, Bennett AM, Girard-Pierce KR, Arthur CM, Bunting ST, Zimring JC, and Hendrickson JE
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- Anemia, Hemolytic genetics, Animals, Blood Transfusion, Cytokines metabolism, Female, Green Fluorescent Proteins metabolism, Immunoglobulin G immunology, Kell Blood-Group System genetics, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pregnancy, Pregnancy, Animal, Anemia, Hemolytic immunology, Erythrocytes cytology, Isoantibodies immunology, Kell Blood-Group System immunology, Models, Animal
- 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.
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- 2013
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32. Location, location, location: advancing veto cell therapies.
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Zimring JC
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- Animals, Female, Humans, CD8-Positive T-Lymphocytes immunology, Transplantation Chimera immunology, Transplantation Conditioning methods
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- 2013
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33. Keeping the Kell away from immunity.
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Zimring JC and Johnsen JM
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- Female, Humans, Male, Pregnancy, Epitopes, T-Lymphocyte immunology, Kell Blood-Group System immunology, T-Lymphocytes, Helper-Inducer immunology
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- 2012
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34. Transfusion in the absence of inflammation induces antigen-specific tolerance to murine RBCs.
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Smith NH, Hod EA, Spitalnik SL, Zimring JC, and Hendrickson JE
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- Analysis of Variance, Animals, Antibodies blood, Antibodies immunology, Antigens immunology, Enzyme-Linked Immunosorbent Assay, Erythrocytes metabolism, Female, Glycophorins genetics, Glycophorins immunology, Humans, Inflammation blood, Isoantibodies blood, Isoantibodies immunology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muramidase genetics, Muramidase immunology, Erythrocyte Transfusion methods, Erythrocytes immunology, Immune Tolerance immunology, Inflammation immunology
- 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.
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- 2012
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35. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron.
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Hod EA, Brittenham GM, Billote GB, Francis RO, Ginzburg YZ, Hendrickson JE, Jhang J, Schwartz J, Sharma S, Sheth S, Sireci AN, Stephens HL, Stotler BA, Wojczyk BS, Zimring JC, and Spitalnik SL
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- Adult, Alanine Transaminase blood, Aspartate Aminotransferases blood, Bacterial Infections etiology, Blood Cell Count, Blood Donors, Blood Preservation adverse effects, Chlorides blood, Creatinine blood, Erythrocytes metabolism, Female, Human Experimentation, Humans, Inflammation etiology, Iron metabolism, Male, Prospective Studies, Serum Albumin metabolism, Sodium blood, Time Factors, Transferrin metabolism, Transplantation, Autologous, Young Adult, Blood Preservation methods, Erythrocyte Transfusion methods, Erythrocytes cytology, Hemolysis, Iron blood
- 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.
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- 2011
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36. Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation.
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Hod EA, Zhang N, Sokol SA, Wojczyk BS, Francis RO, Ansaldi D, Francis KP, Della-Latta P, Whittier S, Sheth S, Hendrickson JE, Zimring JC, Brittenham GM, and Spitalnik SL
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- Acute-Phase Reaction blood, Acute-Phase Reaction etiology, Animals, Deferoxamine pharmacology, Disease Models, Animal, Endotoxemia blood, Endotoxemia etiology, Endotoxins blood, Erythrocyte Aging, Escherichia coli Infections blood, Escherichia coli Infections etiology, Hemoglobins metabolism, Humans, Inflammation blood, Inflammation prevention & control, Inflammation Mediators blood, Iron metabolism, Iron Chelating Agents pharmacology, Kidney metabolism, Liver metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Spleen metabolism, Time Factors, Blood Preservation adverse effects, Erythrocyte Transfusion adverse effects, Inflammation etiology, Iron blood
- 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.
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- 2010
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37. Regulation of primary alloantibody response through antecedent exposure to a microbial T-cell epitope.
- Author
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Hudson KE, Lin E, Hendrickson JE, Lukacher AE, and Zimring JC
- Subjects
- Adoptive Transfer, Animals, Bacteria immunology, Enzyme-Linked Immunosorbent Assay, Epitopes, B-Lymphocyte immunology, Erythrocytes microbiology, Erythrocytes virology, Flow Cytometry, Genome, Viral genetics, Humans, Mice, Mice, Inbred C57BL, Muramidase genetics, Ovalbumin genetics, Polymerase Chain Reaction, Polyomavirus genetics, Polyomavirus immunology, Bacterial Proteins immunology, Epitopes, T-Lymphocyte immunology, Erythrocytes immunology, Isoantibodies immunology, Muramidase immunology, Ovalbumin immunology, Peptide Fragments immunology
- 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 ovalbumin(323-339) ((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
38. Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model.
- Author
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Desmarets M, Cadwell CM, Peterson KR, Neades R, and Zimring JC
- Subjects
- Anemia, Aplastic immunology, Anemia, Aplastic therapy, Anemia, Sickle Cell immunology, Anemia, Sickle Cell therapy, Animals, Disease Models, Animal, Humans, Mice, Mice, Inbred BALB C, Mice, Transgenic, Transplantation, Homologous, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes immunology, Erythrocyte Transfusion, Graft Rejection immunology, Leukocyte Reduction Procedures, Minor Histocompatibility Antigens immunology
- 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
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39. Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion reactions.
- Author
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Hod EA, Cadwell CM, Liepkalns JS, Zimring JC, Sokol SA, Schirmer DA, Jhang J, and Spitalnik SL
- Subjects
- Animals, Blood Group Incompatibility, Glycophorins, Humans, Immunoglobulin G, Inflammation, Mice, Mice, Transgenic, Models, Animal, Cytokines biosynthesis, Hemolysis immunology, Transfusion Reaction
- Abstract
Cytokines are hypothesized to play a central role in the pathophysiology of IgG-mediated hemolytic transfusion reactions (HTRs), and deeper understanding is required for improving therapy for these events. After establishing well-defined mouse models of HTRs, we tested whether cytokines were involved. Red blood cells (RBCs) from human glycophorin A transgenic (hGPA-Tg) or wild-type (WT) mice were transfused into non-Tg recipients passively immunized with monoclonal antibodies (Mabs). Only transfusions of incompatible RBCs induced IgG-mediated HTRs, exemplified by rapid clearance and hemoglobinuria. Very high plasma levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), and lower levels of tumor necrosis factor-alpha (TNF-alpha), were induced after incompatible transfusion. No significant changes in IL-10, IL-12, or interferon-gamma (IFN-gamma) levels were observed. The proinflammatory cytokines elaborated in this in vivo mouse model are also implicated in the systemic inflammatory response syndrome (SIRS) and confirm the hypothesis that cytokine storm occurs as a result of HTRs.
- Published
- 2008
- Full Text
- View/download PDF
40. Inflammation enhances consumption and presentation of transfused RBC antigens by dendritic cells.
- Author
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Hendrickson JE, Chadwick TE, Roback JD, Hillyer CD, and Zimring JC
- Subjects
- Animals, Antigen-Presenting Cells immunology, Immunization, Inflammation chemically induced, Inflammation immunology, Inflammation pathology, Liver immunology, Lymph Nodes immunology, Macrophages immunology, Mice, Poly I-C pharmacology, Spleen drug effects, Spleen immunology, Antigens immunology, Dendritic Cells immunology, Erythrocyte Transfusion adverse effects, Erythrocytes immunology
- Abstract
Factors regulating which patients become alloimmunized to red blood cell (RBC) antigens are poorly understood. Using a murine model of transfusion, we recently reported that viral-like inflammation with polyinosinic polycytidylic acid [poly (I:C)] significantly enhances RBC alloimmunization. Herein, we tested the hypothesis that poly (I:C) exerts this effect, at least in part, at the level of antigen-presenting cells (APCs). Using a novel in vivo method, we report that in the noninflamed state, most transfused RBCs were consumed by splenic macrophages, with only trace consumption by splenic dendritic cells (DCs). To a lesser extent, RBCs were also consumed by APCs in the liver. However, unlike soluble antigens, no RBCs were consumed by APCs in the lymph nodes. Inflammation with poly (I:C) induced significant consumption of transfused RBCs by splenic DCs, with a concomitant increase in costimulatory molecule expression. Moreover, this resulted in increased proliferation of CD4(+) T cells specific for the mHEL RBC alloantigen. Finally, splenectomy abrogated the enhancing effects of poly (I:C) on RBC alloimmunization. Together, these data provide additional insight into the nature of transfused RBCs as an immunogen and provide a mechanism by which viral-like inflammation enhances alloimmunization to transfused RBCs.
- Published
- 2007
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- View/download PDF
41. Nonhemolytic antigen loss from red blood cells requires cooperative binding of multiple antibodies recognizing different epitopes.
- Author
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Zimring JC, Cadwell CM, Chadwick TE, Spitalnik SL, Schirmer DA, Wu T, Parkos CA, and Hillyer CD
- Subjects
- Animals, Antibodies, Monoclonal metabolism, Antigens, Surface metabolism, Epitopes metabolism, Erythrocytes metabolism, Flow Cytometry, Immunoglobulin Fab Fragments immunology, Immunoglobulin Fc Fragments immunology, Immunoglobulin G immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Muramidase immunology, Muramidase metabolism, Antibodies, Monoclonal immunology, Antigen-Antibody Reactions immunology, Antigens, Surface immunology, Epitopes immunology, Erythrocytes immunology
- Abstract
Transfusion of crossmatch-incompatible red blood cells (RBCs) can result in antibody-mediated hemolysis. However, in some patients, crossmatch-incompatible RBCs lose the incompatible antigen from their surface, and then circulate normally ("antigen loss"). Although antigen loss has been reported in the settings of autoimmune hemolytic anemia and transfusion of crossmatch-incompatible RBCs, mechanistic understanding of this phenomenon is limited. Using an in vivo murine model of antigen loss, we report that, unlike polyclonal antisera, monoclonal antibodies did not induce antigen loss. However, the combination of 2 monoclonal antibodies that recognized separate epitopes on the same antigen induced antigen loss. This was not due to an increased number of Fc domains bound to the cell surface, because antigen loss still occurred when combining intact monoclonal IgG and F(ab')2 fragments recognizing different epitopes. Together, these data lead to the hypothesis that antigen-antibody crosslinking is required for nonhemolytic antigen loss to occur.
- Published
- 2007
- Full Text
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42. Analysis of CD8+ T cell-mediated anti-viral responses in mice with targeted deletions of the M1 or M5 muscarinic cholinergic receptors.
- Author
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Vezys V, Masopust D, Desmarets M, Wess J, and Zimring JC
- Subjects
- Animals, CD8-Positive T-Lymphocytes virology, Female, Flow Cytometry, Gene Deletion, Lymphocytic choriomeningitis virus growth & development, Lymphocytic choriomeningitis virus immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Muscarinic M1 genetics, Receptor, Muscarinic M5 genetics, Time Factors, Vesicular stomatitis Indiana virus growth & development, Vesicular stomatitis Indiana virus immunology, CD8-Positive T-Lymphocytes immunology, Receptor, Muscarinic M1 physiology, Receptor, Muscarinic M5 physiology, Virus Diseases immunology
- Abstract
A number of studies have demonstrated that non-neuronal acetylcholine can play a role in the regulation of T cell function. Recently, we reported that CD8(+) T cells, from mice with a targeted deletion of the M(1) muscarinic receptor, had a defect in differentiating into cytolytic T lymphocytes when stimulated in vitro. In the current report, we analyze the in vivo function of CD8(+) T cells from mice with targeted deletions of either M(1) or M(5) muscarinic receptors. M(1) or M(5) knockout mice were infected with either lymphocytic choriomeningitis virus or vesicular stomatitis virus. Expansion of anti-viral CD8(+) T cells was monitored by staining with tetramer reagents specific for the immunodominant peptides of the viruses. No defect in expansion of CD8(+) T cells was observed in either M(1) or M(5) knockout mice. The extent to which one can draw a generalized conclusion that M(1) and M(5) are not involved in anti-viral immunity depends upon issues of antigen strength, genetic background, induction of redundant receptors, and the potential for qualitative defects in the expanded CD8(+) T cells.
- Published
- 2007
- Full Text
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43. Immunization to minor histocompatibility antigens on transfused RBCs through crosspriming into recipient MHC class I pathways.
- Author
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Zimring JC, Hair GA, Deshpande SS, and Horan JT
- Subjects
- Animals, Bone Marrow Transplantation adverse effects, Bone Marrow Transplantation immunology, CD8-Positive T-Lymphocytes immunology, Chickens, Graft Rejection etiology, Graft Rejection immunology, Leukocyte Reduction Procedures, Mice, Ovalbumin, Cross-Priming, Erythrocyte Transfusion, Erythrocytes immunology, Histocompatibility Antigens Class I immunology, Immunization, Minor Histocompatibility Antigens immunology
- Abstract
Increased rates of graft rejection after bone marrow transplantation (BMT) are observed in patients whose illnesses--such as sickle cell disease, thalassemia, and aplastic anemia--necessitate chronic transfusion before BMT. Because BM transplants in these patients are routinely HLA matched, any immunization responsible for increased rejection is likely against minor histocompatibility antigens (mHAs). It has been assumed that contaminating leukocytes in red blood cell (RBC) units are the main sources of immunization to mHAs. However, in this report, we demonstrate that antigens on donor RBCs are presented in the major histocompatibility complex (MHC) class I pathway of recipient antigen-presenting cells, resulting in activation and expansion of recipient CD8+ T cells specific for donor mHAs. Given that human hematopoietic progenitor cells express many of the known mHAs, this observation provides a mechanism by which chronic transfusion of even stringently leukoreduced RBCs may result in sufficient mHA immunization to increase the frequency of BMT rejection.
- Published
- 2006
- Full Text
- View/download PDF
44. Nonhemolytic antibody-induced loss of erythrocyte surface antigen.
- Author
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Zimring JC, Hair GA, Chadwick TE, Deshpande SS, Anderson KM, Hillyer CD, and Roback JD
- Subjects
- Animals, Immunization, Immunoglobulin G, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Models, Animal, Muramidase administration & dosage, Muramidase genetics, Muramidase immunology, Receptors, IgG immunology, Transfusion Reaction, Antigen-Antibody Reactions immunology, Antigens, Surface immunology, Erythrocytes immunology, Isoantibodies immunology
- Abstract
Transfusion of red blood cells (RBCs) into patients with anti-donor RBC antibodies (crossmatch-incompatible transfusion) can result in lethal antibody-mediated hemolysis. Less well appreciated is the ability of anti-RBC antibodies to specifically remove their target antigen from donor RBCs without compromising cell survival or adversely affecting the transfusion recipient. In an effort to elucidate the mechanistic details of this process, we describe the first animal model of nonhemolytic antibody-induced RBC antigen loss. RBCs from transgenic mHEL mice express surface hen egg lysozyme (HEL) as a transmembrane protein. Transfusion of mHEL RBCs into mice immunized with HEL results in selective loss of HEL antigen from donor RBCs without affecting other blood group antigens or reducing the circulatory life span of the transfused RBCs. While this process does not require the presence of a spleen, it requires both anti-RBC immunoglobulin G (IgG) antibodies and the FcgammaIII receptor. These studies provide mechanistic insight into the phenomenon of antigen loss during incompatible transfusion in humans.
- Published
- 2005
- Full Text
- View/download PDF
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