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James C Zimring - One of the best experts on this subject based on the ideXlab platform.
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type i ifn is necessary and sufficient for inflammation induced red blood cell Alloimmunization in mice
Journal of Immunology, 2017Co-Authors: David R Gibb, James C Zimring, Prabitha Natarajan, Manjula Santhanakrishnan, David J Madrid, Stephanie C Eisenbarth, Akiko Iwasaki, Jeanne E HendricksonAbstract: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.
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the nlrp3 inflammasome does not regulate Alloimmunization to transfused red blood cells in mice
EBioMedicine, 2016Co-Authors: David R Gibb, James C Zimring, Jeanne E Hendrickson, Christopher A Tormey, Steven L Spitalnik, Samuele Calabro, Stephanie C EisenbarthAbstract: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.
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transfusion induced Alloimmunization and platelet refractoriness in a mouse model mechanisms and interventions
Transfusion, 2016Co-Authors: Hayley R Waterman, Linda M Kapp, Adam D Munday, Katherine Odemdavis, James C ZimringAbstract: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.
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factors influencing rbc Alloimmunization lessons learned from murine models
Transfusion Medicine and Hemotherapy, 2014Co-Authors: Alex B Ryder, James C Zimring, Jeanne E HendricksonAbstract:Red blood cell (RBC) Alloimmunization may occur following transfusion or pregnancy/delivery. Although observational human studies have described the immunogenicity of RBC antigens and the clinical significance of RBC alloantibodies, studies of factors influencing RBC Alloimmunization in humans are inherently limited by the large number of independent variables involved. This manuscript reviews data generated in murine models that utilize transgenic donor mice, which express RBC-specific model or authentic human blood group antigens. Transfusion of RBCs from such donors into nontransgenic but otherwise genetically identical recipient mice allows for the investigation of individual donor or recipient-specific variables that may impact RBC Alloimmunization. Potential donor-related variables include methods of blood product collection, processing and storage, donor-specific characteristics, RBC antigen-specific factors, and others. Potential recipient-related variables include genetic factors (MHC/HLA type and polymorphisms of immunoregulatory genes), immune activation status, phenotype of regulatory immune cell subsets, immune cell functional characteristics, prior antigen exposures, and others. Although murine models are not perfect surrogates for human biology, these models generate phenomenological and mechanistic hypotheses of RBC Alloimmunization and lay the groundwork for follow-up human studies. Long-term goals include improving transfusion safety and minimizing the morbidity/mortality associated with RBC Alloimmunization.
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Alloimmunization against rbc or plt antigens is independent of trim21 expression in a murine model
Molecular Immunology, 2011Co-Authors: Seema R Patel, Jeanne E Hendrickson, Nicole H Smith, Chantel M Cadwell, Keiko Ozato, Herbert C Morse, Ryusuke Yoshimi, James C ZimringAbstract:Generation of alloantibodies to transfused RBCs can be a serious medical problem for patients who require chronic RBC transfusion therapy. Patients with sickle cell disease have a substantially increased rate of Alloimmunization compared to other chronically transfused populations. A recent study has forwarded the hypothesis that a polymorphism in an immunoregulatory gene in close proximity to beta-globin (TRIM21 rs660) plays a role in the increased rates of RBC Alloimmunization in sickle cell patients. In particular, it was hypothesized that rs660C/T decreases expression of TRIM21, resulting in loss of a negative feedback pathway in immune responses and increased RBC Alloimmunization. To test the effects of TRIM21 expression on Alloimmunization, we analyzed antibody responses to alloantigens on RBCs and platelets transfused into wild-type and TRIM21 KO mice. No significant increases were seen in the frequency or magnitude of humoral immunization to alloantigens on transfused RBCs or platelets in adult or juvenile TRIM21 KO recipients compared to wild-type controls. Moreover, recipient inflammation with poly (I:C) enhanced RBC Alloimmunization to similar degrees in both TRIM21 KO and wild-type control recipients. Together, these data rule out the hypothesis that decreased TRIM21 expression enhances transfusion induced humoral Alloimmunization, in the context of a reductionist murine model.
Jeanne E Hendrickson - One of the best experts on this subject based on the ideXlab platform.
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type i ifn is necessary and sufficient for inflammation induced red blood cell Alloimmunization in mice
Journal of Immunology, 2017Co-Authors: David R Gibb, James C Zimring, Prabitha Natarajan, Manjula Santhanakrishnan, David J Madrid, Stephanie C Eisenbarth, Akiko Iwasaki, Jeanne E HendricksonAbstract: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.
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understanding red blood cell Alloimmunization triggers
Hematology, 2016Co-Authors: Jeanne E Hendrickson, Christopher A TormeyAbstract: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.
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the nlrp3 inflammasome does not regulate Alloimmunization to transfused red blood cells in mice
EBioMedicine, 2016Co-Authors: David R Gibb, James C Zimring, Jeanne E Hendrickson, Christopher A Tormey, Steven L Spitalnik, Samuele Calabro, Stephanie C EisenbarthAbstract: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.
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impact of red blood cell Alloimmunization on sickle cell disease mortality a case series
Transfusion, 2016Co-Authors: Robert Sheppard Nickel, Jeanne E Hendrickson, Cassandra D Josephson, Ross M Fasano, Erin K Meyer, Anne M Winkler, Peter A Lane, Yuritzi A Jones, Farzana Pashankar, Sean R StowellAbstract:BACKGROUND Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in Alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC Alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC Alloimmunization itself contributes to premature death. RESULTS The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC Alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION Future work examining the clinical impact of RBC Alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.
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immunophenotypic parameters and rbc Alloimmunization in children with sickle cell disease on chronic transfusion
American Journal of Hematology, 2015Co-Authors: Robert Sheppard Nickel, Jeanne E Hendrickson, Cassandra D Josephson, Ross M Fasano, Erin K Meyer, Anne M Winkler, John T Horan, Leslie S KeanAbstract:Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non-responders), a cross-sectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC Alloimmunization was present in 26/90 (29%) patients, with anti-E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non-alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P = 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P = 0.020) than non-alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC Alloimmunization. Alloimmunized patients had a significantly increased percentage of CD4+ T memory cells compared to non-alloimmunized patients (57% vs. 49%, P = 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC Alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent Alloimmunization. Am. J. Hematol., 2015. © 2015 Wiley Periodicals, Inc.
Sherrill J. Slichter - One of the best experts on this subject based on the ideXlab platform.
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clinical and laboratory correlates of platelet Alloimmunization and refractoriness in the plado trial
Vox Sanguinis, 2016Co-Authors: John R Hess, Sherrill J. Slichter, Felicia L Trachtenberg, Susan F Assmann, Darrell J Triulzi, Richard M Kaufman, R G Strauss, Suzanne GrangerAbstract: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.
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Clinical and laboratory correlates of platelet Alloimmunization and refractoriness in the PLADO trial
Vox Sanguinis, 2016Co-Authors: John R Hess, Felicia L Trachtenberg, Susan F Assmann, Darrell J Triulzi, Richard M Kaufman, R G Strauss, Suzanne Granger, Sherrill J. SlichterAbstract: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
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current problems and future directions of transfusion induced Alloimmunization summary of an nhlbi working group
Transfusion, 2011Co-Authors: James C Zimring, Paul Michael Ness, Sherrill J. Slichter, Lis Welniak, John W Semple, Steven L SpitalnikAbstract: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.
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Current problems and future directions of transfusion-induced Alloimmunization
Transfusion, 2011Co-Authors: James C Zimring, Paul Michael Ness, Sherrill J. Slichter, Lis Welniak, John W Semple, Steven L SpitalnikAbstract: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.
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Understanding the Mechanisms Of Platelet Alloimmunization And Its Prevention
2008Co-Authors: Sherrill J. Slichter, Karen Nelson, Yvette Latchman, Lakshmi K. GaurAbstract:Abstract : The purpose of our experiments is to identify methods of preventing Alloimmunization to donor platelets in a dog platelet transfusion model. We have established DLA Class II typing to select antigen incompatible donor-recipient pairs for our transfusion experiments. In addition, we are evaluating potential allostimulatory WBC that must be removed to prevent platelet Alloimmunization or WBCs that must remain to induce tolerance to donor platelet transfusions. Flow cytometry techniques using antisera that detect various classes of WBCs are being used to identify cells that are removed versus those that remain using different leukoreduction filters. The results of these white cell characterization studies will be correlated with the results of donor platelet transfusion experiments where different filters have been used to leukoreduce donor platelets prior to transfusion. Our current platelet transfusion experiments have evaluated gamma-irradiation alone or combined with leukoreduction to prevent Alloimmunization to donor platelets. These experiments have demonstrated that none of these methods prevent platelet Alloimmunization. Our next experiments will combine UV-irradiation along with filtration leukoreduction to determine if this combination can prevent alloimmune platelet refractoriness.
Ross M Fasano - One of the best experts on this subject based on the ideXlab platform.
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impact of red blood cell antigen matching on Alloimmunization and transfusion complications in patients with sickle cell disease a systematic review
Transfusion Medicine Reviews, 2019Co-Authors: Ross M Fasano, Erin K Meyer, Jane Branscomb, Mia S White, Robert W Gibson, James R EckmanAbstract:Abstract Red blood cells (RBC) transfusion is critical in managing acute and chronic complications in sickle cell disease (SCD); however, it is complicated by RBC Alloimmunization, iron overload, transfusion reactions and infection. Several reports documented an increased incidence of alloantibodies in transfused individuals with SCD, especially for Rh and Kell antigens. As a result, the National Institutes of Health Expert Panel and British Society for Haematology guidelines recommend primary matching for C/c, E/e and K antigens in addition to ABO/RhD for RBC transfusions. However, the evidence supporting these recommendations was cited as limited and understanding of Alloimmunization in SCD is evolving. To examine the limitations of the evidence, we undertook a systematic review of evidence behind recommendations for limited and extended serologic and genotypic RBC antigen matching to reduce Alloimmunization, autoimmunization and transfusion reactions. Searches of PubMed, Embase, Cochrane, and Web of Science databases using MeSH index and free text terms between 1976 through October 2015 and papers and captured through July 2016 through review references in papers, word of mouth, and ongoing Google Scholar and Medline Alerts identified 303 unique articles. Nineteen articles met inclusion criteria and were classified by the Oxford Centre Evidence Based levels of evidence. Strengthening the Reporting of Observational Studies in Epidemiology checklists were completed for 18 of the 19 studies. There were no prospective randomized controlled trials. Sixteen of the articles were cohort studies, two were cross-sectional studies, and one decision tree model examining costs. Low-quality evidence from observational cohort studies supports that Alloimmunization prevalence can be decreased by extending serological RBC antigen matching. Transfusion reactions are generally poorly and inconsistently reported. There was no evidence reporting the effect prophylactic genotypic matching has on Alloimmunization, autoimmunization or transfusion reactions. There were no studies comparing prophylactic genotypic matching to serologic matching. High-quality evidence was lacking to support clinical decision making regarding best transfusion practices. Multicenter prospective randomized clinical trials are needed to determine best strategies for reducing the rate of Alloimmunization using serologic and genotypic matching.
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impact of red blood cell Alloimmunization on sickle cell disease mortality a case series
Transfusion, 2016Co-Authors: Robert Sheppard Nickel, Jeanne E Hendrickson, Cassandra D Josephson, Ross M Fasano, Erin K Meyer, Anne M Winkler, Peter A Lane, Yuritzi A Jones, Farzana Pashankar, Sean R StowellAbstract:BACKGROUND Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in Alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC Alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC Alloimmunization itself contributes to premature death. RESULTS The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC Alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION Future work examining the clinical impact of RBC Alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.
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protective effect of hla dqb1 alleles against Alloimmunization in patients with sickle cell disease
Human Immunology, 2016Co-Authors: Zohreh Tataricalderone, Ross M Fasano, Heather Gordishdressman, Michael Riggs, Catherine Fortier, Andrew D Campbell, Dominique Charron, Victor R Gordeuk, Naomi L C LubanAbstract:Abstract Background Alloimmunization or the development of alloantibodies to Red Blood Cell (RBC) antigens is considered one of the major complications after RBC transfusions in patients with sickle cell disease (SCD) and can lead to both acute and delayed hemolytic reactions. It has been suggested that polymorphisms in HLA genes, may play a role in Alloimmunization. We conducted a retrospective study analyzing the influence of HLA-DRB1 and DQB1 genetic diversity on RBC-Alloimmunization. Study design Two-hundred four multi-transfused SCD patients with and without RBC-Alloimmunization were typed at low/medium resolution by PCR-SSO, using IMGT–HLA Database. HLA-DRB1 and DQB1 allele frequencies were analyzed using logistic regression models, and global p -value was calculated using multiple logistic regression. Results While only trends towards associations between HLA-DR diversity and Alloimmunization were observed, analysis of HLA-DQ showed that HLA-DQ2 ( p = 0.02), -DQ3 ( p = 0.02) and -DQ5 ( p = 0.01) alleles were significantly higher in non-alloimmunized patients, likely behaving as protective alleles. In addition, multiple logistic regression analysis showed both HLA-DQ2/6 ( p = 0.01) and HLA-DQ5/5 ( p = 0.03) combinations constitute additional predictor of protective status. Conclusion Our data suggest that particular HLA-DQ alleles influence the clinical course of RBC transfusion in patients with SCD, which could pave the way towards predictive strategies.
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immunophenotypic parameters and rbc Alloimmunization in children with sickle cell disease on chronic transfusion
American Journal of Hematology, 2015Co-Authors: Robert Sheppard Nickel, Jeanne E Hendrickson, Cassandra D Josephson, Ross M Fasano, Erin K Meyer, Anne M Winkler, John T Horan, Leslie S KeanAbstract:Alloimmunization against red blood cell (RBC) antigens is a cause of morbidity and mortality in transfused patients with sickle cell disease (SCD). To investigate distinguishing characteristics of patients who develop RBC alloantibodies after transfusion (responders) versus those who do not (non-responders), a cross-sectional study of 90 children with SCD on chronic RBC transfusion therapy at a single institution was conducted in which 18 immune parameters (including T and B cell subsets) were tested via flow cytometry, and medical records were reviewed. RBC Alloimmunization was present in 26/90 (29%) patients, with anti-E, K, and C among the most commonly detected alloantibodies despite prophylactic matching for these antigens at the study institution. In addition, RBC autoantibodies had been detected in 18/26 (69%) of alloimmunized versus 7/64 (11%) of non-alloimmunized patients (P < 0.0001). Alloimmunized patients were significantly older (median 13.0 years vs. 10.7 years, P = 0.010) and had more RBC unit exposures (median 148 U vs. 82 U, P = 0.020) than non-alloimmunized patients. Sex, age at initiation of chronic transfusion, splenectomy, stroke, and transfusion outside of the study institution were not significantly associated with RBC Alloimmunization. Alloimmunized patients had a significantly increased percentage of CD4+ T memory cells compared to non-alloimmunized patients (57% vs. 49%, P = 0.0047), with no other significant differences in immune cell subsets or laboratory values detected between these groups. Additional research of RBC Alloimmunization is needed to optimize transfusion therapy and to develop strategies to prevent Alloimmunization. Am. J. Hematol., 2015. © 2015 Wiley Periodicals, Inc.
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red blood cell Alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease
British Journal of Haematology, 2015Co-Authors: Ross M Fasano, Garrett S Booth, Megan R Miles, Liping Du, Tatsuki Koyama, Emily R Meier, Naomi L C LubanAbstract:Summary Sickle cell disease (SCD) patients are at increased risk of red blood cell (RBC) Alloimmunization. Recipient inflammatory state at time of transfusion has been shown to regulate Alloimmunization in murine models, but evidence is lacking in SCD patients. We retrospectively studied a cohort of alloimmunized SCD patients to determine the influence of pro-inflammatory SCD-related complications at time of transfusion on Alloimmunization. For each transfusion, the presence of pro-inflammatory state, degree of RBC antigen matching, unit age, storage solution and alloantibody detection date were ascertained. Transfusion-associated pro-inflammatory events were compared between transfusions resulting and not resulting in new alloantibodies. Univariate analysis and multivariate logistic regression were performed. Fifty-two patients received 3166 pre-storage leuco-reduced transfusions of which 128 resulted in alloantibodies. Transfusions during inflammatory events were associated with increased alloantibody risk on univariate and multivariate analysis; acute chest syndrome and vaso-occlusive crisis showed strongest associations with Alloimmunization. Increased antigen matching demonstrated a protective effect on Alloimmunization (univariate and multivariate analysis). Although an association was seen between citrate-phosphate-dextrose (adenine) stored units and Alloimmunization on univariate analysis, no effect was found on multivariate analysis. Identifying recipient pro-inflammatory states at time of transfusion that promote Alloimmunization can impact RBC unit selection decisions for SCD patients at risk for Alloimmunization.
Naomi L C Luban - One of the best experts on this subject based on the ideXlab platform.
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protective effect of hla dqb1 alleles against Alloimmunization in patients with sickle cell disease
Human Immunology, 2016Co-Authors: Zohreh Tataricalderone, Ross M Fasano, Heather Gordishdressman, Michael Riggs, Catherine Fortier, Andrew D Campbell, Dominique Charron, Victor R Gordeuk, Naomi L C LubanAbstract:Abstract Background Alloimmunization or the development of alloantibodies to Red Blood Cell (RBC) antigens is considered one of the major complications after RBC transfusions in patients with sickle cell disease (SCD) and can lead to both acute and delayed hemolytic reactions. It has been suggested that polymorphisms in HLA genes, may play a role in Alloimmunization. We conducted a retrospective study analyzing the influence of HLA-DRB1 and DQB1 genetic diversity on RBC-Alloimmunization. Study design Two-hundred four multi-transfused SCD patients with and without RBC-Alloimmunization were typed at low/medium resolution by PCR-SSO, using IMGT–HLA Database. HLA-DRB1 and DQB1 allele frequencies were analyzed using logistic regression models, and global p -value was calculated using multiple logistic regression. Results While only trends towards associations between HLA-DR diversity and Alloimmunization were observed, analysis of HLA-DQ showed that HLA-DQ2 ( p = 0.02), -DQ3 ( p = 0.02) and -DQ5 ( p = 0.01) alleles were significantly higher in non-alloimmunized patients, likely behaving as protective alleles. In addition, multiple logistic regression analysis showed both HLA-DQ2/6 ( p = 0.01) and HLA-DQ5/5 ( p = 0.03) combinations constitute additional predictor of protective status. Conclusion Our data suggest that particular HLA-DQ alleles influence the clinical course of RBC transfusion in patients with SCD, which could pave the way towards predictive strategies.
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red blood cell Alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease
British Journal of Haematology, 2015Co-Authors: Ross M Fasano, Garrett S Booth, Megan R Miles, Liping Du, Tatsuki Koyama, Emily R Meier, Naomi L C LubanAbstract:Summary Sickle cell disease (SCD) patients are at increased risk of red blood cell (RBC) Alloimmunization. Recipient inflammatory state at time of transfusion has been shown to regulate Alloimmunization in murine models, but evidence is lacking in SCD patients. We retrospectively studied a cohort of alloimmunized SCD patients to determine the influence of pro-inflammatory SCD-related complications at time of transfusion on Alloimmunization. For each transfusion, the presence of pro-inflammatory state, degree of RBC antigen matching, unit age, storage solution and alloantibody detection date were ascertained. Transfusion-associated pro-inflammatory events were compared between transfusions resulting and not resulting in new alloantibodies. Univariate analysis and multivariate logistic regression were performed. Fifty-two patients received 3166 pre-storage leuco-reduced transfusions of which 128 resulted in alloantibodies. Transfusions during inflammatory events were associated with increased alloantibody risk on univariate and multivariate analysis; acute chest syndrome and vaso-occlusive crisis showed strongest associations with Alloimmunization. Increased antigen matching demonstrated a protective effect on Alloimmunization (univariate and multivariate analysis). Although an association was seen between citrate-phosphate-dextrose (adenine) stored units and Alloimmunization on univariate analysis, no effect was found on multivariate analysis. Identifying recipient pro-inflammatory states at time of transfusion that promote Alloimmunization can impact RBC unit selection decisions for SCD patients at risk for Alloimmunization.
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red blood cell Alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease
Blood, 2013Co-Authors: Ross M Fasano, Garrett S Booth, Megan R Miles, Liping Du, Tatsuki Koyama, Emily R Meier, Naomi L C LubanAbstract:Background Red blood cell (RBC) Alloimmunization occurs at a much higher rate in patients with sickle cell disease (SCD) compared to other multiply transfused populations. Reasons for this include: altered immunologic responses, frequent transfusions during times of elevated inflammatory states, and disparate donor/recipient RBC antigens. Providing Rh and Kell matched RBCs has been shown to decrease but not eliminate RBC Alloimmunization in patients with SCD. Although it has been shown in murine models that recipient inflammatory state at time of transfusion has the ability to regulate Alloimmunization, direct clinical evidence for this effect is lacking in SCD patients. Methods With IRB approval, medical records of alloimmunized pediatric SCD patients were retrospectively reviewed to determine the influence of SCD-related complications often considered to be pro-inflammatory, at time of transfusion on RBC Alloimmunization. The degree of antigen matching, age, and additive solution of each RBC unit were also assessed. Potential pro-inflammatory states were classified as: acute chest syndrome (ACS), acute stroke, acute febrile illness in the absence of another sickle-co morbidity, splenic sequestration, aplastic crisis, priapism, VOC with and without leukocytosis (WBC count ≥ 20k/μL) and elective surgery. Initial alloantibody detection dates were ascertained from blood bank records. Clinical events at time of transfusion were compared between transfusions resulting in a new alloantibody (AlloAb) and transfusions that did not. Univariable analysis was performed using Wilcoxon rank sum and Pearson’s Chi square test. Logistic regression modeling was used to estimate adjusted effects of stated variables on Alloimmunization. Results A total of 3166 prestorage leukoreduced RBC transfusions (mean age 19.3 days) were provided to 52 SCD patients; 128 transfusions resulted in RBC alloantibodies; 3038 transfusions did not. On univariable analysis, 14.1% of transfusions during any inflammatory event resulted in a new AlloAb compared to 1.4% of transfusions in the absence of inflammation (p<.0001); ACS and VOC with elevated WBC count showed the strongest association. Twenty percent and 27% of transfusions during ACS and VOC with elevated WBC resulted in AlloAbs respectively versus 2% and 4% of transfusions in the absence of these events (p<.0001). On multivariable analysis, the presence of an inflammatory event at time of transfusion was associated with increase risk for AlloAbs (OR: 8.9; 95%CI 5.9-13.5; p<.0001) with ACS showing the highest association (OR: 13.2; 95%CI 8.4-20.8; p<.0001). Any degree of antigen matching beyond ABO/Rh was associated with a significant protective effect on AlloAb formation (OR: 0.24; 95%CI: 0.13-0.46). Multivariable analysis for adjusted unit age effect demonstrated that both fresh and older units exhibited a trend toward reduced probability of Alloimmunization; however, there was a paucity of units transfused at the shelf life extremes to allow definitive continuous variable analysis. There was no significant association between the additive solution of the units and AlloAb formation. Conclusion We provide clinical evidence in SCD patients that recipient pro-inflammatory state (most notably ACS) at time of transfusion directly impacts RBC Alloimmunization. These results offer indirect evidence that different types of inflammatory states within the recipient induce qualitatively different immunologic processes, which may or may not promote Alloimmunization, thereby substantiating previously published mouse model findings. Further investigation of the immunologic processes involved in various pro-inflammatory states, especially ACS, is warranted. Additional data are needed to determine if the age of the RBCs influences the likelihood of Alloimmunization. Disclosures: Fasano: ApoPharma: Honoraria.
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The association of CD81 polymorphisms with Alloimmunization in sickle cell disease
Clinical & Developmental Immunology, 2013Co-Authors: Zohreh Tatari-calderone, Naomi L C Luban, Ryad Tamouza, Gama P. Le Bouder, Ramita Dewan, Jacqueline Lasserre, Jacqueline Maury, François Lionnet, Rajagopal Krishnamoorthy, Robert GirotAbstract:The goal of the present work was to identify the candidate genetic markers predictive of Alloimmunization in sickle cell disease (SCD). Red blood cell (RBC) transfusion is indicated for acute treatment, prevention, and abrogation of some complications of SCD. A well-known consequence of multiple RBC transfusions is Alloimmunization. Given that a subset of SCD patients develop multiple RBC allo-/autoantibodies, while others do not in a similar multiple transfusional setting, we investigated a possible genetic basis for Alloimmunization. Biomarker(s) which predicts (predict) susceptibility to Alloimmunization could identify patients at risk before the onset of a transfusion program and thus may have important implications for clinical management. In addition, such markers could shed light on the mechanism(s) underlying Alloimmunization. We genotyped 27 single nucleotide polymorphisms (SNPs) in the CD81, CHRNA10, and ARHG genes in two groups of SCD patients. One group (35) of patients developed alloantibodies, and another (40) had no alloantibodies despite having received multiple transfusions. Two SNPs in the CD81 gene, that encodes molecule involved in the signal modulation of B lymphocytes, show a strong association with Alloimmunization. If confirmed in prospective studies with larger cohorts, the two SNPs identified in this retrospective study could serve as predictive biomarkers for Alloimmunization.