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Transfusion and Apheresis Science :... Oct 2020Alloimmunization to non-ABO, red blood cell (RBC) antigens remains one of the most clinically-relevant complexities faced by blood banking practitioners. In the setting... (Review)
Review
Alloimmunization to non-ABO, red blood cell (RBC) antigens remains one of the most clinically-relevant complexities faced by blood banking practitioners. In the setting of transfusion therapy, these antibodies raise risks for incompatibilities, while for pregnant patients they can mediate deadly forms of hemolytic disease of the fetus and newborn. As such, a thorough understanding of pathways that lead to alloimmunization, as well as the tools used by blood banks to detect alloantibodies, is critical to transfusion practice. In this review, in which alloimmunization in the setting of pregnancy will be emphasized, we will review: 1) the clinical impacts of RBC alloantibodies in the peri-partum period; 2) the current pathophysiologic mechanisms thought to influence non-ABO antigen alloimmunization; 3) the strengths and weaknesses of laboratory tools used in aiding alloimmunization detection; and 4) future directions of the transfusion community related to alloimmunization impacting pregnancy.
Topics: Erythroblastosis, Fetal; Female; Hematologic Diseases; Humans; Infant, Newborn; Isoantibodies; Pregnancy
PubMed: 32962917
DOI: 10.1016/j.transci.2020.102946 -
Biomedicines Jun 2022The polymorphic human leukocyte antigen (HLA) system has been considered the main target for alloimmunity, but the non-HLA antibodies and autoimmunity have gained... (Review)
Review
The polymorphic human leukocyte antigen (HLA) system has been considered the main target for alloimmunity, but the non-HLA antibodies and autoimmunity have gained importance in kidney transplantation (KT). Apart from the endothelial injury, secondary self-antigen exposure and the presence of polymorphic alloantigens, respectively, auto- and allo- non-HLA antibodies shared common steps in their development, such as: antigen recognition via indirect pathway by recipient antigen presenting cells, autoreactive T cell activation, autoreactive B cell activation, T helper 17 cell differentiation, loss of self-tolerance and epitope spreading phenomena. Both alloimmunity and autoimmunity play a synergic role in the formation of non-HLA antibodies, and the emergence of transcriptomics and genome-wide evaluation techniques has led to important progress in understanding the mechanistic features. Among them, non-HLA mismatches between donors and recipients provide valuable information regarding the role of genetics in non-HLA antibody immunity and development.
PubMed: 35884811
DOI: 10.3390/biomedicines10071506 -
Transfusion Clinique Et Biologique :... Nov 2022Post-transfusion alloimmunisation is the main complication of all those observed after one or more transfusion episodes. Alloimmunisation is observed after the... (Review)
Review
Post-transfusion alloimmunisation is the main complication of all those observed after one or more transfusion episodes. Alloimmunisation is observed after the transfusion of red blood cell concentrates but also of platelet concentrates. Besides alloimmunisation due to antigens carried almost exclusively by red blood cells such as those of the Rhesus-Kell system, alloimmunisation often raises against HLA antigens; the main responsibility for that, apart from platelet transfusions, lies with residual leukocytes in the products transfused, hence the central importance of effective leukoreduction right from the blood product preparation stage. Alloimmunization is not restricted to transfusion, but it is also observed during pregnancies, carrying out microtransfusions of blood from the fetus immunizing the mother through the placenta (in a retrograde way). Preexisting maternal-fetal immunization can complicate a transfusion program and intensify the creation of alloantibodies in several blood and tissue group systems. The occurrence of autoantibodies, created by several pathogenic reasons, can also interfere with the propensity of certain recipients of blood components to produce alloantibodies. The genetic condition of individuals is in fact strongly linked to the ability or not to recognize antigenic variants foreign to their own biological program and mount an alloimmune response. Some hemoglobin diseases, in carriers of which transfusions can be iterative and lifelong, are complicated by frequent alloimmunizations and amplification of the complications of these alloimmunizations, imposing even stricter transfusion rules. This review details the mechanisms favoring the occurrence of alloimmunization and the immunological principles for the production of molecular and cellular tools for alloimmunization. It concludes with the main preventive measures available to limit the occurrence of these frequent complications of varying severity but sometimes severe.
Topics: Humans; Isoantibodies; Erythrocytes; Blood Transfusion; Platelet Transfusion; Kell Blood-Group System
PubMed: 35970488
DOI: 10.1016/j.tracli.2022.08.140 -
Open Biology Nov 2019The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in... (Review)
Review
The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in host defence, autoimmunity and alloimmunity. The emerging effects of Notch signalling in T cell responses build upon a more established role for Notch in T cell development. Here, we provide a critical review of this burgeoning literature to make sense of what has been learned so far and highlight the experimental strategies that have been most useful in gleaning physiologically relevant information. We outline the functional consequences of Notch signalling in mature T cells in addition to key specific Notch ligand-receptor interactions and downstream molecular signalling pathways. Our goal is to help clarify future directions for this expanding body of work and the best approaches to answer important open questions.
Topics: Animals; Autoimmunity; Cell Differentiation; Homeostasis; Humans; Infections; Receptors, Notch; Signal Transduction; T-Lymphocytes
PubMed: 31690218
DOI: 10.1098/rsob.190187 -
Immunohematology Dec 2022Variant alleles are found mainly in Afro-descendant individuals, as well as in patients with sickle cell disease (SCD). The most common variants are related to the...
Variant alleles are found mainly in Afro-descendant individuals, as well as in patients with sickle cell disease (SCD). The most common variants are related to the allele, which can generate partial e and c antigens. Although variant alleles have been extensively studied, defining their clinical significance is a difficult task. We evaluated the risk of RhCE alloimmunization as a consequence of partial antigens in patients with a positive phenotype transfused with red blood cell (RBC) units with the corresponding antigen. A retrospective study was performed with Brazilian patients, evaluating the number of antigen-positive transfused RBC units (incompatible due to partial antigen) in 27 patients with SCD carrying variant alleles who did not develop antibodies as well as evaluating the variants present in 12 patients with partial phenotype and correlated antibody (one patient with SCD and 11 patients with other pathologies). Two patients showed variant alleles with molecular changes that had not yet been described. Variant alleles were identified in a previous study using molecular methods. was the most frequent allele found among the patients without antibodies. Six patients with partial c antigen had a mean of 3.8 c+ RBC units transfused, and 10 patients with partial e antigen were exposed for a mean of 7.2 e+ RBC units. Among the variant alleles found in alloimmunized patients, the most frequent was which was found in five patients; the antibodies developed were anti-hr and/or anti-c. Our results showed that is indeed the most frequent variant allele in our cohort of patients with SCD, but the partial antigens that were identified have low risk of alloimmunization. is the most impactful variant in the Brazilian population with high risk of alloimmunization and clinically significant anti-hr formation.
Topics: Humans; Rh-Hr Blood-Group System; Alleles; Brazil; Retrospective Studies; Anemia, Hemolytic, Autoimmune; Isoantibodies; Anemia, Sickle Cell
PubMed: 36789463
DOI: 10.21307/immunohematology-2022-054 -
The Journal of Clinical Investigation Oct 2022Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis...
Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.
Topics: Animals; Bronchiolitis Obliterans; Decorin; Granzymes; Lung Transplantation; Macrophages, Alveolar; Mice; Monocytes; Receptors, CCR2; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta
PubMed: 36189800
DOI: 10.1172/JCI159229 -
JCI Insight Feb 2024While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data...
While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils' role in alloimmunity. Due to their prevalence in the lung, and their defined role in other pulmonary pathologies such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody-secreting cell differentiation and resulted in de novo generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD-1+ T follicular helper (Tfh) cells, which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh cell generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naive CD4+ T cells. Our data thus describe what we believe is a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggest that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.
Topics: Eosinophils; Germinal Center; Antibodies; Transplantation, Homologous; Lung Transplantation
PubMed: 38329123
DOI: 10.1172/jci.insight.168911 -
Journal of Obstetrics and Gynaecology... Dec 2021Noninvasive fetal rhesus D (RhD) blood group genotyping may prevent unnecessary use of anti-D immunoglobulin (RhIG) in non-alloimmunized RhD-negative pregnancies and can... (Review)
Review
OBJECTIVE
Noninvasive fetal rhesus D (RhD) blood group genotyping may prevent unnecessary use of anti-D immunoglobulin (RhIG) in non-alloimmunized RhD-negative pregnancies and can guide management of alloimmunized pregnancies. We conducted a systematic review of the economic literature to determine the cost-effectiveness of this intervention over usual care.
DATA SOURCES
Systematic literature searches of bibliographic databases (Ovid MEDLINE, Embase, and Cochrane) until February 26, 2019, and auto-alerts until October 30, 2020, and of grey literature sources were performed to retrieve all English-language studies.
STUDY SELECTION
We included studies done in serologically confirmed non-alloimmunized or alloimmunized RhD-negative pregnancies, comparing costs and effectiveness of the intervention versus usual care.
DATA EXTRACTION AND SYNTHESIS
Two reviewers extracted data from the eligible studies and assessed their methodological quality (risk of bias) using the Quality of Health Economic Studies (QHES) and Drummond tools. We narratively synthesized findings. Our review included 8 economic studies that evaluated non-invasive fetal RhD genotyping followed by targeted RhIG prophylaxis in non-alloimmunized pregnancies. Five studies further considered a subsequent alloimmunized pregnancy. The cost-effectiveness of the intervention versus usual care (e.g., universal RhIG or prophylaxis conditional on results of paternal testing) for non-alloiummunized pregnancies was inconsistent. Two studies indicated greater benefits and lower costs for the intervention, and another 2 suggested a trade-off. In 4 studies, the intervention was less effective and costlier than alternatives. Three studies were determined to be of high quality by both tools. Two of these studies favoured the intervention, and one assessed benefits in quality-adjusted life-years. No study clearly examined the cost-effectiveness of repetitive use of fetal genotyping in multiple non-alloimmunized or alloimmunized pregnancies. The cost of genotyping was the most influential parameter.
CONCLUSION
The cost-effectiveness of noninvasive fetal RhD genotyping for non-alloimmunized pregnancies varies between studies. Potential savings from targeted management of alloimmunized pregnancies requires further research.
Topics: Cost-Benefit Analysis; Female; Fetal Blood; Genotype; Humans; Pregnancy; Prenatal Diagnosis; Rh Isoimmunization; Rh-Hr Blood-Group System
PubMed: 34390866
DOI: 10.1016/j.jogc.2021.07.014 -
Frontiers in Pediatrics 2022Alloimmune events such as the development of donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary... (Review)
Review
Alloimmune events such as the development of donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary contributors to kidney transplant failure in children. For decades, a creatinine-based estimated glomerular filtration rate (eGFR) has been the non-invasive gold standard biomarker for detecting clinically significant alloimmune events, but it suffers from low sensitivity and specificity, especially in smaller children and older allografts. Many clinically "stable" children (based on creatinine) will have alloimmune events known as "subclinical acute rejection" (based on biopsy) that merely reflect the inadequacy of creatinine-based estimates for alloimmune injury rather than a distinct phenotype from clinical rejection with allograft dysfunction. The poor biomarker performance of creatinine leads to many unnecessary surveillance and for-cause biopsies that could be avoided by integrating non-invasive biomarkers with superior sensitivity and specificity into current clinical paradigms. In this review article, we will present and appraise the current state-of-the-art in monitoring for alloimmune events in pediatric kidney transplantation. We will first discuss the current clinical standards for assessing the presence of alloimmune injury and predicting long-term outcomes. We will review principles of biomarker medicine and the application of comprehensive metrics to assess the performance of a given biomarker against the current gold standard. We will then highlight novel blood- and urine-based biomarkers (with special emphasis on pediatric biomarker studies) that have shown superior diagnostic and prognostic performance to the current clinical standards including creatinine-based eGFR. Finally, we will review some of the barriers to translating this research and implementing emerging biomarkers into common clinical practice, and present a transformative approach to using multiple biomarker platforms at different times to optimize the detection and management of critical alloimmune events in pediatric kidney transplant recipients.
PubMed: 36741087
DOI: 10.3389/fped.2022.1087841 -
Transfusion and Apheresis Science :... Dec 2019β-Thalassemia is considered one of the common hemoglobin disorders in the Arabian Peninsula. Red blood cell (RBC) transfusion is a crucial component of the management... (Review)
Review
BACKGROUND
β-Thalassemia is considered one of the common hemoglobin disorders in the Arabian Peninsula. Red blood cell (RBC) transfusion is a crucial component of the management of transfusion-dependent β-Thalassemia patients. Patients with Thalassemia Intermedia (TI), also known as non-transfusion dependent β-thalassemia, have a wide clinical presentation and variable transfusion dependence. Rates of RBC alloimmunization and its risk factors in transfusion-dependent β-thalassemia patients varied between different reports. Risk of alloimmunization is higher in TI patients.
MATERIAL AND METHODS
A literature review on existing reports on alloimmunization rates and risk factors in transfusion dependent and non-transfusion dependent β-thalassemia in the Eastern Mediterranean region was performed.
RESULTS
A total of 17 publications were found. Reported rates of alloimmunization among transfusion-dependent β-Thalassemia patients ranged between 2.87 and 30 % and between 6.8 and 19.5 % among TI patients. Most centers utilize ABO and RhD matched RBCs. The most common antibodies described are anti-K and anti-E. The risk factors described included age at onset of transfusion, gender, history of splenectomy, duration of transfusion and number of units transfused. Rate of autoantibody formation ranged between 0.1 and 45 %.
CONCLUSION
Our review showed variable alloimmunization rates and risk factors in thalassemia patients and scant data on TI patients. The commonest antibodies are anti-K and anti-E. Further studies are required in addressing the rate of alloimmunization, cross-match requirements and role of genotyping in this group of patients. Transfusion support of patients with thalassemia necessitates the availability of blood bank facilities and specialized expertise.
Topics: Blood Transfusion; Erythrocytes; Humans; Immunization; Mediterranean Region; beta-Thalassemia
PubMed: 31753776
DOI: 10.1016/j.transci.2019.102678