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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 -
Transplantation Apr 2022Antibody-mediated rejection (AMR) is a major barrier to long-term graft survival following solid organ transplantation (SOT). Major histocompatibility antigens... (Review)
Review
Antibody-mediated rejection (AMR) is a major barrier to long-term graft survival following solid organ transplantation (SOT). Major histocompatibility antigens mismatched between donor and recipient are well-recognized targets of humoral alloimmunity in SOT and thought to drive most cases of AMR. In contrast, the implication of minor histocompatibility antigens (mHAs) in AMR has not been fully investigated, and their clinical relevance remains controversial. Recent technological advances, allowing for genome-wide comparisons between donors and recipients, have uncovered novel, polymorphic mHA targets with potential influence on the graft outcome following SOT. Here, we review these latest studies relating to mHAs and discuss their clinical significance.
Topics: Antibody Formation; Graft Rejection; HLA Antigens; Histocompatibility; Minor Histocompatibility Antigens; Organ Transplantation
PubMed: 34699457
DOI: 10.1097/TP.0000000000003969 -
Transplantation Nov 2021Humoral allogeneic immunity driven by anti-HLA donor-specific antibodies and antibody-mediated rejection (AMR) significantly impede prolonged survival of organ... (Review)
Review
Humoral allogeneic immunity driven by anti-HLA donor-specific antibodies and antibody-mediated rejection (AMR) significantly impede prolonged survival of organ allografts after transplantation. Although the importance of T follicular helper (TFH) cells in controlling antibody responses has been long established, their role in directing donor-specific antibody generation leading to AMR was only recently appreciated in the clinical setting of organ transplantation. In this review, we provide a comprehensive summary of the current knowledge on the biology of human TFH cells as well as their circulating counterparts and describe their pivotal role in driving humoral alloimmunity. In addition, we discuss the intrinsic effects of current induction therapies and maintenance immunosuppressive drugs as well as of biotherapies on TFH cells and provide future directions and novel opportunities of biotherapeutic targeting of TFH cells that have the potential of bringing the prophylactic and curative treatments of AMR toward personalized and precision medicine.
Topics: Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Immunity, Humoral; Organ Transplantation; T Follicular Helper Cells; T-Lymphocytes, Helper-Inducer
PubMed: 33909968
DOI: 10.1097/TP.0000000000003776 -
Journal of Clinical Medicine Feb 2023Red cell (RC) alloantibodies occur on exposure to non-self RC antigens in transfusion and pregnancy (typically IgG and clinically significant) or in association with...
A Retrospective Cohort Study of Red Cell Alloimmunisation in Rural, Remote, and Aboriginal and Torres Strait Islander Peoples Admitted to Intensive Care in the Northern Territory, Australia.
Red cell (RC) alloantibodies occur on exposure to non-self RC antigens in transfusion and pregnancy (typically IgG and clinically significant) or in association with non-RC immune environmental factors (typically IgM and not clinically significant). In Australia, the risk of RC alloimmunisation in First Nations peoples is unknown. We assessed the epidemiology, specificity, and antecedents of RC alloimmunisation via a data linkage retrospective cohort study of Northern Territory (NT) intensive care unit (ICU) patients (2015-2019). Of 4183 total patients, 50.9% were First Nations. In First Nations versus non-First Nations patients, the period prevalence of alloimmunisation was 10.9% versus 2.3%, with 390 versus 72 prevalent alloantibodies detected in 232 versus 48 alloimmunised patients, of which 135 (34.6%) versus 52 (72.2%) were clinically significant specificities. Baseline and follow-up alloantibody testing were available for 1367 patients, in whom new incident clinically significant alloantibodies developed in 4.5% First Nations versus 1.1% non-First Nations patients. On Cox proportional hazards modelling, adjusted hazard ratios (HR) showed First Nations status (HR 2.67 (95% CI 1.05-6.80), = 0.04) and cumulative RC unit transfusion exposure (HR 1.03 (95% CI 1.01-1.05), = 0.01) were independent predictors of clinically significant alloimmunisation. First Nations Australian patients are at increased risk of alloimmunisation due to RC transfusion, underscoring the importance of very judicious use of RC transfusions and shared decision-making with patients. Further studies are recommended to explore the role of other (non-RC) immune host factors, given the relative high prevalence of non-clinically significant IgM alloantibodies within alloimmunised First Nations patients.
PubMed: 36836141
DOI: 10.3390/jcm12041606 -
International Journal of Molecular... Oct 2020Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell... (Review)
Review
Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.
Topics: Animals; Autoimmune Diseases; Cell Movement; Homeostasis; Humans; Immune Tolerance; Lymph Nodes; Neoplasms; Stromal Cells; T-Lymphocytes; Transplantation Immunology; Virus Diseases
PubMed: 33096748
DOI: 10.3390/ijms21207785 -
Kidney International Reports Jun 2022Human leukocyte antigens (HLAs) are the primary determinants of alloimmunity. A crossmatch test is a test that determines the immunologic risk of a recipient with a... (Review)
Review
Human leukocyte antigens (HLAs) are the primary determinants of alloimmunity. A crossmatch test is a test that determines the immunologic risk of a recipient with a potential donor by ensuring that there are no transplant-relevant circulating antibodies in the recipient directed against donor antigens. Physical crossmatch (PXM) tests, such as complement-dependent cytotoxicity crossmatch (CDCXM) and flow cytometry crossmatch (FCXM), require mixing of patient serum and donor cells, are labor intensive, and are logistically challenging. Virtual crossmatch (VXM) test assesses immunologic compatibility between recipient and potential donor by analyzing the results of 2 independently done physical laboratory tests-patient anti-HLA antibody and donor HLA typing. The goal of VXM is pretransplant risk stratification-though there is no consensus on whether such risk assessment involves predicting the PXM result or the posttransplant outcome. Although the concept of VXM is not new, the advent of solid-phase assays for detecting circulating antibodies in the recipient directed against individual HLA and DNA-based methods for typing donor HLA specificities at a higher resolution makes the routine use of VXM a reality. Accordingly, VXM may be applied at different scenarios-both for sensitized and nonsensitized patients. Implementation of VXM-based approach has resulted in statistically significant reduction in cold ischemia time without an increase in hyperacute rejection episodes. Though there are considerable challenges, VXM is expected to be used more often in the future, depending on the transplant center's tolerance of immunologic risk.
PubMed: 35685330
DOI: 10.1016/j.ekir.2022.03.006 -
Journal of Clinical Medicine May 2022Hemolytic disease of the fetus and newborn (HDFN), as well as fetal and neonatal alloimmune thrombocytopenia (FNAIT), represent two important disease entities that are... (Review)
Review
Hemolytic disease of the fetus and newborn (HDFN), as well as fetal and neonatal alloimmune thrombocytopenia (FNAIT), represent two important disease entities that are caused by maternal IgG antibodies directed against nonmaternally inherited antigens on the fetal blood cells. These antibodies are most frequently directed against the RhD antigen on red blood cells (RBCs) or the human platelet antigen 1a (HPA-1a) on platelets. For optimal management of pregnancies where HDFN or FNAIT is suspected, it is essential to determine the RhD or the HPA-1a type of the fetus. Noninvasive fetal RhD typing is also relevant for identifying which RhD-negative pregnant women should receive antenatal RhD prophylaxis. In this review, we will give an overview of the clinical indications and technical challenges related to the noninvasive analysis of fetal RBCs or platelet types. In addition, we will discuss the ethical implications associated with the routine administration of antenatal RhD to all pregnant RhD-negative women and likewise the ethical challenges related to making clinical decisions concerning the mother that have been based on samples collected from the (presumptive) father, which is a common practice when determining the risk of FNAIT.
PubMed: 35629001
DOI: 10.3390/jcm11102877 -
Frontiers in Immunology 2022Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation.... (Review)
Review
Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.
Topics: Humans; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Immune Reconstitution; Antilymphocyte Serum; Lymphocyte Depletion
PubMed: 36505500
DOI: 10.3389/fimmu.2022.1057694 -
Transplantation Dec 2021Immunological mechanisms linking undernutrition to infection and the alloimmune response are poorly understood in transplantation. We aimed to determine how...
BACKGROUND
Immunological mechanisms linking undernutrition to infection and the alloimmune response are poorly understood in transplantation. We aimed to determine how undernutrition and hypoleptinemia impact T-cell allospecific and cytomegalovirus (CMV) viral-specific immunity in a murine model.
METHODS
Fed, fasted for 48 h (model of undernutrition), and fasted with leptin injections (leptin rescue), C57BL/6 mice received skin grafts from either C57BL/6 (syngeneic) or BALB/c (allogeneic) mice donors. Allograft rejection and survival were monitored. Fed, fasted, and leptin rescue C57BL/6 mice were inoculated with murine cytomegalovirus (mCMV). Mouse spleens were retrieved for T-cell flow cytometry analysis, mCMV DNA extraction, and quantitative polymerase chain reaction. Serum leptin levels were measured with ELISA.
RESULTS
Fasted mice had prolonged rejection-free and graft survival compared with fed mice (P = 0.0002 and P = 0.043). Leptin administration did not alter rejection-free survival or allograft failure. CD8+ central memory T cell and CD8+ effector T cell proportions were significantly lower in fasted mice receiving allogeneic skin transplants compared with fed mice (P = 0.0009 and P = 0.0015). Fasted mice had higher viral loads (P = 0.0028) and impaired mCMV-specific interferon-gamma-producing CD8+ T cells (P = 0.0007), which improved with leptin rescue (P = 0.032).
CONCLUSIONS
Undernutrition and its associated hypoleptinemia correlated with impaired allospecific and viral-specific immunities. Leptin administration decreased mCMV viral burden and increased mCMV-specific T-cell immunity, however, it did not increase rejection or worsen graft survival in complete major histocompatibility complex-mismatched skin allografts. Leptin may be a potential adjunctive therapy for CMV viremia in undernourished transplant recipients.
Topics: Animals; CD8-Positive T-Lymphocytes; Cytomegalovirus; Cytomegalovirus Infections; Graft Rejection; Malnutrition; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL
PubMed: 33724247
DOI: 10.1097/TP.0000000000003743 -
Transfusion Medicine and Hemotherapy :... Feb 2023Antibodies to human neutrophil alloantigens (HNA) are involved in the pathophysiology of several clinical conditions including transfusion-related acute lung injury...
BACKGROUND
Antibodies to human neutrophil alloantigens (HNA) are involved in the pathophysiology of several clinical conditions including transfusion-related acute lung injury (TRALI), alloimmune and autoimmune neutropenia, and febrile nonhemolytic transfusion reactions leading to neutropenia. The cognate antigens are polymorphic structures expressed on several glycoproteins on the neutrophils, i.e., antigens HNA-1a, -1b, -1c, and -1d on Fc-γ-receptor IIIb; HNA-2 on CD177; HNA-3a and -3b on choline transporter-like protein 2; HNA-4a and -4b on CD11b/αM subunit of the αMβ2-integrin (CD11b/CD18, Mac-1, CR3); and HNA-5a and -5b on αL-subunit (CD11a) of the αLβ2 integrin (CD11a/CD18), leukocyte function associated molecule (LFA)-1. Currently, there is a lacuna of diagnostic methods for detection of HNA in India. This study aimed to determine the HNA frequencies in Indians, estimate the risk of alloimmunization, and prepare typed neutrophil panels, which can be used to detect HNA antibodies in neutropenia cases.
MATERIAL AND METHODS
EDTA blood samples were collected from random 1,054 blood donors. HNA-2 was phenotyped on fresh EDTA samples using FITC labelled monoclonal anti-CD177 by flowcytometry. HNA-1 () genotyping was carried out by DNA sequencing and PCR-RFLP. Antigens of HNA-3 () and HNA-5 () were genotyped by PCR-RFLP using and restriction enzymes, respectively, while HNA-4 () was genotyped by PCR-SSP.
RESULTS
Allele frequencies of *, *, and * were found to be 0.433, 0.444, and 0.087, respectively. FCGR3B*01+*02+*03- was the most common genotype (33.78%). Ten individuals showed deficiency of FCGR3B individuals, while 23 showed hyperexpression, i.e., ***. *and * occurred with a frequency of 0.002 and 0.024. HNA-2 was found to be a high frequency antigen occurring in 98.8% population. Four percent individuals showed atypical expression of CD177 on their neutrophils. Allele frequencies of * and *were 0.812 and 0.188, respectively, and that of *, *, *, and * were 0.9546, 0.0454, 0.2372, and 0.7628, respectively.
CONCLUSION
This is the first study in India to report the frequencies of HNA among blood donors. Typed neutrophil panels identified in the present study will enable us to investigate suspected cases of immune neutropenia in future.
PubMed: 36818775
DOI: 10.1159/000525654