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Alloimmunization

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James C Zimring – 1st expert on this subject based on the ideXlab platform

  • type i ifn is necessary and sufficient for inflammation induced red blood cell Alloimmunization in mice
    Journal of Immunology, 2017
    Co-Authors: David R Gibb, James C Zimring, Prabitha Natarajan, Manjula Santhanakrishnan, David J Madrid, Stephanie C Eisenbarth, Akiko Iwasaki, Jeanne E Hendrickson

    Abstract:

    During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN-α/β) are induced in inflammatory conditions associated with increased Alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-α/β receptor is required for inflammation-induced Alloimmunization. Additionally, mitochondrial antiviral signaling protein–mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic-polycytidylic acid–induced IFN-α/β production and Alloimmunization. We further report that IFN-α, in the absence of an adjuvant, is sufficient to induce RBC Alloimmunization. These findings raise the possibility that patients with IFN-α/β–mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC Alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies.

  • the nlrp3 inflammasome does not regulate Alloimmunization to transfused red blood cells in mice
    EBioMedicine, 2016
    Co-Authors: David R Gibb, James C Zimring, Jeanne E Hendrickson, Christopher A Tormey, Steven L Spitalnik, Samuele Calabro, Stephanie C Eisenbarth

    Abstract:

    Abstract Red blood cell (RBC) transfusions are essential for patients with hematological disorders and bone marrow failure syndromes. Despite ABO matching, RBC transfusions can lead to production of alloantibodies against “minor” blood group antigens. Non-ABO Alloimmunization is a leading cause of transfusion-associated mortality in the U.S. Despite its clinical importance, little is known about the immunological factors that promote Alloimmunization. Prior studies indicate that inflammatory conditions place patients at higher risk for Alloimmunization. Additionally, co-exposure to pro-inflammatory pathogen associated molecular patterns (PAMPs) promotes Alloimmunization in animal models, suggesting that RBC Alloimmunization depends on innate immune cell activation. However, the specific innate immune stimuli and sensors that induce a T cell-dependent alloantibody response to transfused RBCs have not been identified. The NLRP3 inflammasome senses chemically diverse PAMPs and damage associated molecular patterns (DAMPs), including extracellular ATP and iron-containing heme. We hypothesized that activation of the NLRP3 inflammasome by endogenous DAMPs from RBCs promotes the alloimmune response to a sterile RBC transfusion. Using genetically modified mice lacking either NLRP3 or multiple downstream inflammasome response elements, we ruled out a role for the NLRP3 inflammasome or any Caspase-1 or -11 dependent inflammasome in regulating RBC alloantibody production to a model antigen.

  • transfusion induced Alloimmunization and platelet refractoriness in a mouse model mechanisms and interventions
    Transfusion, 2016
    Co-Authors: Hayley R Waterman, Linda M Kapp, Adam D Munday, Katherine Odemdavis, James C Zimring

    Abstract:

    BACKGROUND

    Platelet (PLT) transfusions can be an essential therapy for patients with thrombocytopenia to maintain hemostasis. However, some patients become alloimmunized to antigens on PLTs (typically HLA), which can prevent efficacy of PLT transfusion due to antibody-mediated clearance. In extreme cases, patients with Alloimmunization to multiple HLAs can become “refractory” to PLT transfusion, such that insufficient compatible PLT units can be found to meet transfusion needs.

    MATERIALS AND METHODS

    An in vivo murine model of PLT-induced Alloimmunization was refined so as to include both transfusion with allogeneic leukoreduced PLTs and studies of posttransfusion PLT recoveries, allowing assessment of Alloimmunization and refractoriness. Basic mechanisms of antibody-mediated PLT clearance were investigated using recipients missing either the C3 complement gene or the common gamma chain for Fc receptors. In addition, the efficacy of using costimulatory blockade as a therapeutic intervention was assessed by testing CTLA4-Ig administration before PLT transfusion.

    RESULTS

    Fcγ receptors (but not complement C3) are required for alloantibody-mediated PLT refractoriness. In addition, levels of anti-MHC predict the extent of refractoriness in a given animal. Finally, costimulatory blockade as a therapeutic modality prevents transfusion-induced PLT refractoriness.

    CONCLUSIONS

    Together these findings introduce new experimental methods, basic mechanistic understanding, and a potential therapeutic intervention for Alloimmunization to MHC-based antigens on transfused PLTs.

Jeanne E Hendrickson – 2nd expert on this subject based on the ideXlab platform

  • type i ifn is necessary and sufficient for inflammation induced red blood cell Alloimmunization in mice
    Journal of Immunology, 2017
    Co-Authors: David R Gibb, James C Zimring, Prabitha Natarajan, Manjula Santhanakrishnan, David J Madrid, Stephanie C Eisenbarth, Akiko Iwasaki, Jeanne E Hendrickson

    Abstract:

    During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN-α/β) are induced in inflammatory conditions associated with increased Alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-α/β receptor is required for inflammation-induced Alloimmunization. Additionally, mitochondrial antiviral signaling protein–mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic-polycytidylic acid–induced IFN-α/β production and Alloimmunization. We further report that IFN-α, in the absence of an adjuvant, is sufficient to induce RBC Alloimmunization. These findings raise the possibility that patients with IFN-α/β–mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC Alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies.

  • understanding red blood cell Alloimmunization triggers
    Hematology, 2016
    Co-Authors: Jeanne E Hendrickson, Christopher A Tormey

    Abstract:

    Abstract Blood group Alloimmunization is “triggered” when a person lacking a particular antigen is exposed to this antigen during transfusion or pregnancy. Although exposure to an antigen is necessary for Alloimmunization to occur, it is not alone sufficient. Blood group antigens are diverse in structure, function, and immunogenicity. In addition to red blood cells (RBCs), a recipient of an RBC transfusion is exposed to donor plasma, white blood cells, and platelets; the potential contribution of these elements to RBC Alloimmunization remains unclear. Much attention in recent years has been placed on recipient factors that influence RBC alloantibody responses. Danger signals, identified in murine and human studies alike as being risk factors for Alloimmunization, may be quite diverse in nature. In addition to exogenous or condition-associated inflammation, autoimmunity is also a risk factor for alloantibody formation. Triggers for Alloimmunization in pregnancy are not well-understood beyond the presence of a fetal/maternal bleed. Studies using animal models of pregnancy-induced RBC Alloimmunization may provide insight in this regard. A better understanding of Alloimmunization triggers and signatures of “responders” and “nonresponders” is needed for prevention strategies to be optimized. A common goal of such strategies is increased transfusion safety and improved pregnancy outcomes.

  • the nlrp3 inflammasome does not regulate Alloimmunization to transfused red blood cells in mice
    EBioMedicine, 2016
    Co-Authors: David R Gibb, James C Zimring, Jeanne E Hendrickson, Christopher A Tormey, Steven L Spitalnik, Samuele Calabro, Stephanie C Eisenbarth

    Abstract:

    Abstract Red blood cell (RBC) transfusions are essential for patients with hematological disorders and bone marrow failure syndromes. Despite ABO matching, RBC transfusions can lead to production of alloantibodies against “minor” blood group antigens. Non-ABO Alloimmunization is a leading cause of transfusion-associated mortality in the U.S. Despite its clinical importance, little is known about the immunological factors that promote Alloimmunization. Prior studies indicate that inflammatory conditions place patients at higher risk for Alloimmunization. Additionally, co-exposure to pro-inflammatory pathogen associated molecular patterns (PAMPs) promotes Alloimmunization in animal models, suggesting that RBC Alloimmunization depends on innate immune cell activation. However, the specific innate immune stimuli and sensors that induce a T cell-dependent alloantibody response to transfused RBCs have not been identified. The NLRP3 inflammasome senses chemically diverse PAMPs and damage associated molecular patterns (DAMPs), including extracellular ATP and iron-containing heme. We hypothesized that activation of the NLRP3 inflammasome by endogenous DAMPs from RBCs promotes the alloimmune response to a sterile RBC transfusion. Using genetically modified mice lacking either NLRP3 or multiple downstream inflammasome response elements, we ruled out a role for the NLRP3 inflammasome or any Caspase-1 or -11 dependent inflammasome in regulating RBC alloantibody production to a model antigen.

Sherrill J. Slichter – 3rd expert on this subject based on the ideXlab platform

  • clinical and laboratory correlates of platelet Alloimmunization and refractoriness in the plado trial
    Vox Sanguinis, 2016
    Co-Authors: John R Hess, Sherrill J. Slichter, Felicia L Trachtenberg, Susan F Assmann, Darrell J Triulzi, Richard M Kaufman, R G Strauss, Suzanne Granger

    Abstract:

    Background and Objectives

    Platelet Alloimmunization and refractoriness to platelet transfusion are complications of platelet transfusion therapy. The platelet dose (PLADO) trial, as the largest prospective randomized trial of prophylactic platelet therapy to date, afforded an opportunity to analyse these two issues.

    Materials and Methods

    PLADO patient records were examined for evidence of platelet Alloimmunization, defined as an increase in HLA Class I panel-reactive antibodies (PRA) to ≥20%, and clinical refractoriness, defined as two consecutive ≤4 h posttransfusion corrected platelet count increments (CCI) of <5000. Multivariate logistic regression, restricted to platelet-transfused subjects who received exclusively either in-process leucoreduction apheresis or whole blood-derived (WBD) leucocyte-reduced platelets, compared the frequency of these outcomes by platelet unit and patient characteristics. Results Forty of 816 evaluable platelet-transfused patients (5%) became alloimmunized during the trial. Prior pregnancy, chemotherapy only compared to progenitor cell transplant, and low platelet dose – all were associated with significantly higher rates of Alloimmunization. Among 35 alloimmunized patients evaluated for refractoriness, 8 (23%) had two consecutive CCI < 5000/μl. Regardless of Alloimmunization status, CCIs < 5000/μl were observed following 17% of platelet transfusions. Among 734 patients receiving at least two platelet transfusions, two consecutive CCIs of ≤5000 occurred in 102 (14%). Conclusions The incidence of new platelet Alloimmunization was low in the PLADO study, but follow-up was at most 30 days. Alloimmunization was present in only 8 of 102 (8%) of observed cases of refractoriness, suggesting that other causes of poor posttransfusion increments are frequent.

  • Clinical and laboratory correlates of platelet Alloimmunization and refractoriness in the PLADO trial
    Vox Sanguinis, 2016
    Co-Authors: John R Hess, Felicia L Trachtenberg, Susan F Assmann, Darrell J Triulzi, Richard M Kaufman, R G Strauss, Suzanne Granger, Sherrill J. Slichter

    Abstract:

    Background and Objectives

    Platelet Alloimmunization and refractoriness to platelet transfusion are complications of platelet transfusion therapy. The platelet dose (PLADO) trial, as the largest prospective randomized trial of prophylactic platelet therapy to date, afforded an opportunity to analyse these two issues.

    Materials and Methods

    PLADO patient records were examined for evidence of platelet Alloimmunization, defined as an increase in HLA Class I panel-reactive antibodies (PRA) to ≥20%, and clinical refractoriness, defined as two consecutive ≤4 h posttransfusion corrected platelet count increments (CCI) of

  • current problems and future directions of transfusion induced Alloimmunization summary of an nhlbi working group
    Transfusion, 2011
    Co-Authors: James C Zimring, Paul Michael Ness, Lis Welniak, John W Semple, Sherrill J. Slichter, Steven L Spitalnik

    Abstract:

    In April 2010, a working group sponsored by the National Heart, Lung, and Blood Institute was assembled to identify research strategies to improve our understanding of Alloimmunization caused by the transfusion of allogeneic blood components and to evaluate potential approaches to both reduce its occurrence and manage its effects. Significant sequelae of Alloimmunization were discussed and identified, including difficulties in maintaining chronic transfusion of red blood cells and platelets, hemolytic disease of the newborn, neonatal alloimmune thrombocytopenia, and rejection of transplanted cells and tissues. The discussions resulted in a consensus that identified key areas of future research and developmental areas, including genetic and epigenetic recipient factors that regulate Alloimmunization, biochemical specifics of transfused products that affect Alloimmunization, and novel technologies for high-throughput genotyping to facilitate extensive and efficient antigen matching between donor and recipient. Additional areas of importance included analysis of unappreciated medical sequelae of Alloimmunization, such as cellular immunity and its effect upon transplant and autoimmunity. In addition, support for research infrastructure was discussed, with an emphasis on encouraging collaboration and synergy of animal models biology and human clinical research. Finally, training future investigators was identified as an area of importance. In aggregate, this communication provides a synopsis of the opinions of the working group on the above issues and presents both a list of suggested priorities and the rationale for the topics of focus. The areas of research identified in this report represent potential fertile ground for the medical advancement of preventing and managing Alloimmunization in its different forms and mitigating the clinical problems it presents to multiple patient populations.