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Translational Pediatrics Apr 2016Hemolytic disease of the newborn (HDN), an alloimmune disorder due to maternal and fetal blood type incompatibility, is associated with fetal and neonatal complications...
Hemolytic disease of the newborn (HDN), an alloimmune disorder due to maternal and fetal blood type incompatibility, is associated with fetal and neonatal complications related to red blood cell (RBC) hemolysis. After delivery, without placental clearance, neonatal hyperbilirubinemia may develop from ongoing maternal antibody-mediated RBC hemolysis. In cases refractory to intensive phototherapy treatment, exchange transfusions (ET) may be performed to prevent central nervous system damage by reducing circulating bilirubin levels and to replace antibody-coated red blood cells with antigen-negative RBCs. The risks and costs of treating HDN are significant, but appear to be decreased by delayed umbilical cord clamping at birth, a strategy that promotes placental transfusion to the newborn. Compared to immediate cord clamping (ICC), safe and beneficial short-term outcomes have been demonstrated in preterm and term neonates receiving delayed cord clamping (DCC), a practice that may potentially be effective in cases RBC alloimmunization.
PubMed: 27186530
DOI: 10.21037/tp.2016.04.02 -
Blood Jan 2021Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely...
Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B-cell plasmablast and plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B-cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin. Whereas nonalloimmunized SCD B cells were inhibited by exogenous heme, B cells from the alloimmunized group were nonresponsive to heme inhibition and readily differentiated into plasma cells. Consistent with a differential B-cell response to hemolysis, we found elevated B-cell basal levels of DOCK8 and higher HO-1-mediated inhibition of activated B cells in nonalloimmunized compared with alloimmunized SCD patients. To overcome the alloimmunized B-cell heme insensitivity, we screened several heme-binding molecules and identified quinine as a potent inhibitor of B-cell activity, reversing the resistance to heme suppression in alloimmunized patients. B-cell inhibition by quinine occurred only in the presence of heme and through HO-1 induction. Altogether, these data suggest that hemolysis can dampen the humoral B-cell response and that B-cell heme responsiveness maybe a determinant of alloimmunization risk in SCD. By restoring B-cell heme sensitivity, quinine may have therapeutic potential to prevent and inhibit alloimmunization in SCD patients.
Topics: Anemia, Hemolytic, Autoimmune; Anemia, Sickle Cell; B-Lymphocytes; Blood Transfusion; Cells, Cultured; Guanine Nucleotide Exchange Factors; Heme; Hemolysis; Humans; Isoantibodies; Lymphocyte Activation; Transfusion Reaction
PubMed: 33152749
DOI: 10.1182/blood.2020008511 -
Frontiers in Immunology 2020Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens,... (Review)
Review
Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil- and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial- and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial- and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-β and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.
Topics: Cytokines; Endothelial Cells; Extracellular Vesicles; Immune System; Kidney; Kidney Diseases; Kidney Transplantation; Kidney Tubules; Macrophages; Mesenchymal Stem Cells; Reperfusion Injury; T-Lymphocytes; Transplants
PubMed: 32180768
DOI: 10.3389/fimmu.2020.00074 -
Stem Cells Translational Medicine Mar 2014Blood transfusion is a common procedure in modern medicine, and it is practiced throughout the world; however, many countries report a less than sufficient blood supply.... (Review)
Review
Blood transfusion is a common procedure in modern medicine, and it is practiced throughout the world; however, many countries report a less than sufficient blood supply. Even in developed countries where the supply is currently adequate, projected demographics predict an insufficient supply as early as 2050. The blood supply is also strained during occasional widespread disasters and crises. Transfusion of blood components such as red blood cells (RBCs), platelets, or neutrophils is increasingly used from the same blood unit for multiple purposes and to reduce alloimmune responses. Even for RBCs and platelets lacking nuclei and many antigenic cell-surface molecules, alloimmunity could occur, especially in patients with chronic transfusion requirements. Once alloimmunization occurs, such patients require RBCs from donors with a different blood group antigen combination, making it a challenge to find donors after every successive episode of alloimmunization. Alternative blood substitutes such as synthetic oxygen carriers have so far proven unsuccessful. In this review, we focus on current research and technologies that permit RBC production ex vivo from hematopoietic stem cells, pluripotent stem cells, and immortalized erythroid precursors.
Topics: Antigens, CD; Biomarkers; Blood Transfusion; Cell Culture Techniques; Cell Differentiation; Cell Proliferation; Cell Separation; Erythrocytes; Erythropoiesis; Feeder Cells; Hematopoietic Stem Cells; Humans; Isoantigens; Pluripotent Stem Cells; Reticulocytes
PubMed: 24361925
DOI: 10.5966/sctm.2013-0054 -
Turkish Journal of Obstetrics and... Sep 2021This study aims to investigate the distribution of antibodies that cause hemolytic disease of the fetus and newborn (HDFN) and compare the clinical outcomes of...
OBJECTIVE
This study aims to investigate the distribution of antibodies that cause hemolytic disease of the fetus and newborn (HDFN) and compare the clinical outcomes of pregnancies affected by anti-D and anti-D combined with non-D Rh alloimmunization.
MATERIALS AND METHODS
We retrospectively searched and obtained the perinatal and neonatal data of patients with anti-D antibodies and anti-D combined with non-D Rh antibodies (anti-c, -C, -e, -E, and -Kell) from October 2015 to December 2018 at the University of Health Sciences Turkey, Kanuni Sultan Süleyman Training and Research Hospital. Univariate and multiple logistic regression analyses and adjusted odds ratios with their confidence intervals were used to define independent risk factors for non-D antibody positive.
RESULTS
The severe fetal hydrops rate was significantly higher in the anti-D combined non-D group (3/25, 12%) than in the anti-D group (1/128, 0.08%, p<0.001). The intrauterine transfusion (IUT) requirement in the anti-D combined non-D group (16/25, 64%) tended to be significantly higher than that in the anti-D group (5/128, 7.46%, p<0.001). The incidence of neonatal exchange transfusion, top-up transfusion, and postnatal phototherapy frequency in the anti-D combined non-D group was significantly higher than in the anti-D group.
CONCLUSION
Anti-D combined with another non-D Rh alloantibody resulted in significantly higher HDFN rates than the anti-D alloimmunized pregnancies. Also, anti-D in association with non-D Rh antibodies resulted in more severe HDFN requiring more invasive treatment procedures, including IUT, neonatal exchange transfusion, or top-up transfusion.
PubMed: 34580411
DOI: 10.4274/tjod.galenos.2021.68822 -
Asian Journal of Transfusion Science 2016Thalassemia is one of the most common monogenic disorders characterized by reduced production of globin chains. Although regular red blood cell (RBC) transfusion support...
BACKGROUND
Thalassemia is one of the most common monogenic disorders characterized by reduced production of globin chains. Although regular red blood cell (RBC) transfusion support is the main treatment for these patients, it may be associated with complications such as RBC alloimmunization.
AIM
The study aimed to determine the incidence of alloimmunization and autoimmunization to RBC antigens in β-thalassemia major patients from Zanjan, Zanjan Province, Iran.
MATERIALS AND METHODS
A total of 49 β-thalassemia major patients comprising 24 females and 25 males (mean age: 18.59 ± 8.16 years; range: 2-40 years) from Northwest Iran were included in a cross-sectional study. Alloantibody screening and identification were done using 3-cell and 10-cell reagent red blood cells, respectively. Autoantibody detection was performed using direct Coomb's test.
RESULTS
The incidence of alloimmunization was 16.32% with 10 alloantibodies identified in 8 patients. The most common clinically significant alloantibody identified in alloimmunized patients was anti-Kell (K-antigen) (60%) followed by anti-Rhesus (Rh) (E, c-antigens). The rate of alloimmunization was significantly lower in patients transfused with leukoreduced RBCs compared with those transfused with nonleukoreduced RBCs (9.53% vs 57.14%, P = 0.001). There was no significant correlation between alloantibody formation and the age, gender, hemoglobin levels, number of transfused units, and splenectomy.
CONCLUSION
Transfusion of leukoreduced and phenotypically matched red blood cells for Kell (K) and Rh (E, c) antigens may help reduce the alloimmunization rate in Iranian β-thalassemia major patients. Moreover, autoimmunization to RBC antigens was rare in our patients.
PubMed: 27011679
DOI: 10.4103/0973-6247.172179 -
Asian Journal of Transfusion Science Jul 2014The development of anti-red blood cell antibodies (both allo-and autoantibodies) remains a major problem in thalassemia major patients. We studied the frequency of red...
BACKGROUND
The development of anti-red blood cell antibodies (both allo-and autoantibodies) remains a major problem in thalassemia major patients. We studied the frequency of red blood cell (RBC) alloimmunization and autoimmunization among thalassemia patients who received regular transfusions at our center and analyzed the factors, which may be responsible for development of these antibodies.
MATERIALS AND METHODS
The study was carried out on 319 multiply transfused patients with β-thalassemia major registered with thalassemia clinic at our institute. Clinical and transfusion records of all the patients were examined for age of patients, age at initiation of transfusion therapy, total number of blood units transfused, transfusion interval, status of splenectomy or other interventions. Alloantibody screening and identification was done using three cell and 11 cell panel (Diapanel, Bio-rad, Switzerland) respectively. To detect autoantibodies, autocontrol was carried out using polyspecific coombs (IgG + C3d) gel cards.
RESULTS
Eighteen patients out of total 319 patients (5.64%) developed alloantibodies and 90 (28.2%) developed autoantibodies. Nine out of 18 patients with alloantibodies also had autoantibodies. Age at first transfusion was significantly higher in alloimmunized than non-immunized patients (P = 0.042). Out of 23 alloantibodies, 52.17% belonged to Rh blood group system (Anti-E = 17%, Anti D = 13%, Anti-C = 13%, Anti-C(w) = 9%), 35% belonged to Kell blood group system, 9% of Kidd and 4% of Xg blood group system.
CONCLUSION
Alloimmunization was detected in 5.64% of multitransfused thalassemia patients. Rh and Kell blood group system antibodies accounted for more than 80% of alloantibodies. This study re-emphasizes the need for RBC antigen typing before first transfusion and issue of antigen matched blood (at least for Rh and Kell antigen). Early institution of transfusion therapy after diagnosis is another means of decreasing alloimmunization.
PubMed: 25161344
DOI: 10.4103/0973-6247.137438 -
Acta Obstetricia Et Gynecologica... Jul 2019The advent of RhD immunoglobulin prophylaxis to prevent maternal RhD alloimmunization has reduced the incidence of this condition and its associated poor outcomes....
INTRODUCTION
The advent of RhD immunoglobulin prophylaxis to prevent maternal RhD alloimmunization has reduced the incidence of this condition and its associated poor outcomes. Consequently, non-D Rh antibodies now account for a greater proportion of alloimmunized pregnancies. These antibodies have been the subject of comparatively little research. This study investigated the incidence and clinical outcome of pregnancies affected by non-D Rh alloimmunization at an Australian tertiary maternity service.
MATERIAL AND METHODS
This was a retrospective study of all pregnancies with non-D Rh antibodies (namely anti-C, -E, -c, -e, -C as well as the compound antibodies anti-CD, -cE and -ce) managed at the Royal Women's Hospital, Victoria, Australia, from 2009 to 2013 inclusive. Information collected included maternal demographics, details of the antibodies, course of the pregnancy and neonatal outcomes.
RESULTS
During the study period, 115 non-D Rh alloimmunized pregnancies were identified in 102 mothers. Forty-nine pregnancies reached the critical titer (> 16) from non-D Rh alone and 11 fetuses received intrauterine red blood cell transfusion. Labor was induced or cesarean section performed in 38 cases. Forty-three neonates were admitted to the special care nursery and 59 received phototherapy. Nine received treatment for anemia and 10 neonates received intravenous immunoglobulin.
CONCLUSIONS
Non-D Rh alloimmunization is a relatively uncommon complication of pregnancy, occurring in only .33% of pregnancies in the study period. It can lead to significant fetal/neonatal morbidity (and may lead to mortality). The most severe outcomes (including perinatal deaths) were mostly associated with the compound antibodies anti-CD and anti-cE, or a non-D Rh antibody in conjunction with anti-D.
Topics: Anemia; Erythrocyte Transfusion; Female; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Isoantibodies; Phototherapy; Pregnancy; Pregnancy Outcome; Retrospective Studies; Rh Isoimmunization; Victoria
PubMed: 30723901
DOI: 10.1111/aogs.13555 -
Current Opinion in Organ Transplantation Feb 2016The purpose of this review is to provide a general update on recent developments in the immunobiology of IL-33 and IL-33-targeted immune cells. We also discuss emerging... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide a general update on recent developments in the immunobiology of IL-33 and IL-33-targeted immune cells. We also discuss emerging concepts regarding the potential role IL-33 appears to play in altering alloimmune responses mediating host-versus-graft and graft-versus-host alloresponses.
RECENT FINDINGS
Stromal cells and leukocytes display regulated expression of IL-33 and may actively or passively secrete this pleotropic cytokine. Type 2 innate lymphoid cells and a large proportion of tissue resident regulatory T cells (Treg) express membrane-bound suppressor of tumorigenicity 2 (ST2), the IL-33 receptor. Although Treg are appreciated suppressors of the inflammatory function of immune cells, both type 2 innate lymphoid cells and tissue resident Treg could play key roles in tissue repair and homeostasis. The functions of IL-33 in transplantation are poorly understood. However, like other disease models, the functions of IL-33 in alloimmunity appear to be quite pleiotropic. IL-33 is associated with immune regulation and graft protection in cardiac transplant settings. Yet, it is highly proinflammatory and stimulates lethal graft-versus-host disease through its capacity to stimulate type 1 immunity.
SUMMARY
Intensive studies on IL-33/ST2 signaling pathways and ST2 cell populations in solid organ and cell transplantation are warranted. A better understanding of this important pathway will provide promising therapeutic targets controlling pathogenic alloimmune responses, as well as potentially facilitating the function of regulatory and reparative immune cells posttransplantation.
Topics: Alarmins; Animals; Graft vs Host Disease; Humans; Interleukin-33; Lymphocytes; Signal Transduction
PubMed: 26709577
DOI: 10.1097/MOT.0000000000000265 -
Frontiers in Immunology 2022Myeloid-derived suppressor cells (MDSC) are defined as a group of myeloid cells with potent immunoregulatory functions that have been shown to be involved in a variety... (Review)
Review
Myeloid-derived suppressor cells (MDSC) are defined as a group of myeloid cells with potent immunoregulatory functions that have been shown to be involved in a variety of immune-related diseases including infections, autoimmune disorders, and cancer. In organ transplantation, MDSC promote tolerance by modifying adaptive immune responses. With aging, however, substantial changes occur that affect immune functions and impact alloimmunity. Since the vast majority of transplant patients are elderly, age-specific modifications of MDSC are of relevance. Furthermore, understanding age-associated changes in MDSC may lead to improved therapeutic strategies. Here, we provide a comprehensive update on the effects of aging on MDSC and discuss potential consequences on alloimmunity.
Topics: Aged; Aging; Humans; Immune Tolerance; Myeloid Cells; Myeloid-Derived Suppressor Cells; Organ Transplantation
PubMed: 35874716
DOI: 10.3389/fimmu.2022.917972