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Cureus Mar 2024Patients with myelodysplastic syndrome (MDS) often need platelet transfusions to address thrombocytopenia. The risk of alloimmunization, particularly in Rhesus (Rh)...
Patients with myelodysplastic syndrome (MDS) often need platelet transfusions to address thrombocytopenia. The risk of alloimmunization, particularly in Rhesus (Rh) incompatibility between donors and recipients during platelet transfusions, is heightened, especially with whole blood-derived pooled platelets as opposed to apheresis platelets. Although the occurrence of alloimmunization from platelet transfusions is minimal, there is an ongoing debate about whether Rh immune globulin (RhIg) should be administered to Rhesus D (RhD)-negative recipients of RhD-positive platelet units. We present a unique case of anti-D alloimmunization in a 56-year-old patient with underlying MDS following multiple platelet transfusions but never received packed cell transfusion or anti-D immunoglobulin. Some studies advocate for RhIg administration in specific scenarios and for certain patient populations. This case underscores the importance of considering Rhesus compatibility or administering anti-D immunoglobulin in cases where frequent platelet transfusions are required.
PubMed: 38681415
DOI: 10.7759/cureus.57165 -
Journal of Clinical Medicine Apr 2024The novel coronavirus disease 2019 (COVID-19) has led to significant morbidity and mortality among kidney transplant recipients. SARS-CoV-2 has been hypothesized to...
The novel coronavirus disease 2019 (COVID-19) has led to significant morbidity and mortality among kidney transplant recipients. SARS-CoV-2 has been hypothesized to cause an unusual immunological dysregulation triggering alloimmunity and leading to graft rejection. This prospective observational cohort study assessed 321 kidney transplant recipients who had COVID-19 infection. After the infection, patients' sera were tested for the presence of anti-HLA de novo DSA and non-DSA specificities. Logistic regression analysis and a stepwise multivariable logistic regression analysis were used to analyze the independent risk factors associated with the development of antibodies, adjusting for known confounders. The variables evaluated were acute COVID-19 characteristics (i.e., presentation, and need for hospitalization), demographic characteristics (i.e., age, gender, and primary renal disease), clinical characteristics (i.e., various comorbidities), and post-COVID-19 sequelae. Anti-HLA de novo DSA developed in 18.7% of patients, while anti-HLA class I and class II non-DSA antibodies developed de novo in 84 (26.3%) and 83 (25.9%) patients, respectively. The development of DSA, HLA-DQ, and HLA-DR antibodies was predicted by the history of graft rejection. Obesity appeared to be protective against the emergence of de novo DSA. De novo DSA and HLA-DR antibody formation was positively linked with intravenous immunoglobulin use, CMV-hyperimmune globulin use, and decreased doses of immunosuppression during acute infection. Better allograft function during the acute disease was a protective factor against the formation of HLA-DQ and HLA-DR antibodies. Positive predictors of de novo DSA development were graft biopsy and the reactivation of EBV after infection. These findings suggest that the SARS-CoV-2 virus has an immunomodulatory effect and may be associated with an increased mortality in this population.
PubMed: 38673655
DOI: 10.3390/jcm13082383 -
Pathologie (Heidelberg, Germany) Jul 2024The Banff Foundation produces recommendations for classifying various lesions in renal allografts. Experts gather to update the classification every other year based on... (Review)
Review
BACKGROUND
The Banff Foundation produces recommendations for classifying various lesions in renal allografts. Experts gather to update the classification every other year based on new scientific and clinical evidence.
OBJECTIVES
This article presents the most important changes incorporated into the new recommendations after the last Banff conference.
MATERIALS AND METHODS
The author of this article personally took part in the Banff conference and the subsequent survey, reported on the activities of a Banff working group (peritubular capillaritis) on-site, and contributed to drafting the recently published meeting report.
RESULTS
Lesions of antibody-mediated kidney allograft rejection (AMR), especially microvascular inflammation, have been part of the diagnostic algorithm for over 20 years. Experts advocated for a simplified AMR algorithm and mindful inclusion of molecular pathological data in the clinicopathological reflection regarding therapeutic decision. A new, more descriptive diagnostic entity-microvascular inflammation, C4d negative and DSA negative-has been introduced into the AMR category to acknowledge this histological constellation and motivate research into this pathophysiologically and immunologically probably different phenotype.
CONCLUSIONS
The Banff classification provides a structure for diagnosing kidney transplant pathology. Regular updates serve to adapt to ever-growing knowledge about alloimmunity. Particular challenges are capturing the complexity of various immunological scenarios and ensuring an understandable representation of these in a pathology report.
Topics: Kidney Transplantation; Humans; Graft Rejection; Allografts; Inflammation; Kidney; Microvessels
PubMed: 38649466
DOI: 10.1007/s00292-024-01328-3 -
BioRxiv : the Preprint Server For... Apr 2024Regulatory T cells (Tregs) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using an HLA-A2-specific chimeric antigen...
Regulatory T cells (Tregs) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using an HLA-A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR Tregs limited anti-HLA-A2 alloimmunity. However, it was unknown if A2-CAR Tregs could also limit immunity to autoantigens. Using a model of HLA-A2 islet transplantation into immunodeficient non-obese diabetic mice, we investigated if A2-CAR Tregs could control diabetes induced by islet-autoreactive (BDC2.5) T cells. In mice transplanted with HLA-A2 islets, A2-CAR Tregs reduced BDC2.5 T cell engraftment, proliferation and cytokine production, and protected mice from diabetes. Tolerance to islets was systemic, including protection of the HLA-A2 endogenous pancreas. In tolerant mice, a significant proportion of BDC2.5 T cells gained FOXP3 expression suggesting that long-term tolerance is maintained by Treg generation. Thus, A2-CAR Tregs mediate linked suppression and infectious tolerance and have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation.
PubMed: 38645184
DOI: 10.1101/2024.04.06.588414 -
African Journal of Laboratory Medicine 2024The Kell blood group system is clinically important in transfusion medicine, particularly in patients with antibodies specific to Kell antigens. To date, genetic...
BACKGROUND
The Kell blood group system is clinically important in transfusion medicine, particularly in patients with antibodies specific to Kell antigens. To date, genetic variations of the Kell metallo-endopeptidase () gene among Thai populations remain unknown.
OBJECTIVE
This study aimed to determine the frequencies of and alleles among Thai blood donors using an in-house polymerase chain reaction-sequence-specific primer (PCR-SSP) method.
METHODS
Blood samples obtained from 805 unrelated central Thai blood donors at a blood bank in Pathumthani, Thailand, from March 2023 to June 2023, were typed for Kp and Kp antigens using the column agglutination test, and the results for 400 samples were confirmed using DNA sequencing. A PCR-SSP method was developed to detect the and alleles, and genotyping results were validated using known DNA controls. DNA samples obtained from Thai donors in central ( = 2529), northern ( = 300), and southern ( = 427) Thailand were also genotyped using PCR-SSP for comparison.
RESULTS
All 805 (100%) donors had the Kp(a-b+) phenotype. The PCR-SSP genotyping results agreed with the column agglutination test and DNA sequencing. All 3256 Thai blood donors had the homozygous genotype. Frequencies of the and alleles among Thai donors differed significantly from those of Japanese, Native American, South African, Brazilian, Swiss, and German populations.
CONCLUSION
This study found a 100% allele frequency in three Thai populations. These data could provide information on and allele frequencies to estimate the risk of alloimmunisation in Thai populations.
WHAT THIS STUDY ADDS
This study demonstrates that in-house PCR-SSP can be used to determine and alleles to predict Kp and Kp antigens. Even though only homozygous genotypes were found among Thai donor populations, the established PCR-SSP method may be useful for estimating the risk of alloimmunisation in other populations.
PubMed: 38629087
DOI: 10.4102/ajlm.v13i1.2294 -
The Journal of Clinical Investigation Apr 2024Administration of anti-RhD immunoglobulin (Ig) to decrease maternal alloimmunization (antibody-mediated immune suppression [AMIS]) was a landmark clinical development....
Administration of anti-RhD immunoglobulin (Ig) to decrease maternal alloimmunization (antibody-mediated immune suppression [AMIS]) was a landmark clinical development. However, IgG has potent immune-stimulatory effects in other settings (antibody-mediated immune enhancement [AMIE]). The dominant thinking has been that IgG causes AMIS for antigens on RBCs but AMIE for soluble antigens. However, we have recently reported that IgG against RBC antigens can cause either AMIS or AMIE as a function of an IgG subclass. Recent advances in mechanistic understanding have demonstrated that RBC alloimmunization requires the IFN-α/-β receptor (IFNAR) and is inhibited by the complement C3 protein. Here, we demonstrate the opposite for AMIE of an RBC alloantigen (IFNAR is not required and C3 enhances). RBC clearance, C3 deposition, and antigen modulation all preceded AMIE, and both CD4+ T cells and marginal zone B cells were required. We detected no significant increase in antigen-specific germinal center B cells, consistent with other studies of RBC alloimmunization that show extrafollicular-like responses. To the best of our knowledge, these findings provide the first evidence of an RBC alloimmunization pathway which is IFNAR independent and C3 dependent, thus further advancing our understanding of RBCs as an immunogen and AMIE as a phenomenon.
Topics: Animals; Mice; Complement C3; Lymphoid Tissue; B-Lymphocytes; Erythrocytes; Immunoglobulin G; Interferon-alpha
PubMed: 38618959
DOI: 10.1172/JCI167665 -
International Journal of Molecular... Mar 2024Immunodominant alloantigens in pig sperm membranes include 15 known gene products and a previously undiscovered r 20,000 sperm membrane-specific protein (SMA20). Here we...
Immunodominant alloantigens in pig sperm membranes include 15 known gene products and a previously undiscovered r 20,000 sperm membrane-specific protein (SMA20). Here we characterize SMA20 and identify it as the unannotated pig ortholog of PMIS2. A composite SMA20 cDNA encoded a 126 amino acid polypeptide comprising two predicted transmembrane segments and an N-terminal alanine- and proline (AP)-rich region with no apparent signal peptide. The Northern blots showed that the composite SMA20 cDNA was derived from a 1.1 kb testis-specific transcript. A BLASTp search retrieved no SMA20 match from the pig genome, but it did retrieve a 99% match to the gene product in warthog. Sequence identity to predicted PMIS2 orthologs from other placental mammals ranged from no more than 80% overall in Cetartiodactyla to less than 60% in Primates, with the AP-rich region showing the highest divergence, including, in the extreme, its absence in most rodents, including the mouse. SMA20 immunoreactivity localized to the acrosome/apical head of methanol-fixed boar spermatozoa but not live, motile cells. Ultrastructurally, the SMA20 AP-rich domain immunolocalized to the inner leaflet of the plasma membrane, the outer acrosomal membrane, and the acrosomal contents of ejaculated spermatozoa. Gene name search failed to retrieve annotated from most mammalian genomes. Nevertheless, individual pairwise interrogation of loci spanning - identified in all placental mammals, but not in marsupials or monotremes. We conclude that the gene encoding sperm-specific SMA20/PMIS2 arose de novo in Eutheria after divergence from Metatheria, whereupon rapid molecular evolution likely drove the acquisition of a species-divergent function unique to fertilization in placental mammals.
Topics: Male; Female; Pregnancy; Swine; Animals; Mice; DNA, Complementary; Placenta; Semen; Spermatozoa; Eutheria; Alanine; Isoantigens; Fertilization
PubMed: 38612464
DOI: 10.3390/ijms25073652 -
Science Advances Apr 2024Allograft rejection is common following clinical organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive. Calcineurin...
Allograft rejection is common following clinical organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive. Calcineurin inhibitor dose escalation, corticosteroids, and/or lymphocyte depleting antibodies have remained the primary options for treatment of clinical rejection episodes. Here, we developed a highly multiplexed imaging mass cytometry panel to study the immune response in archival biopsies from 79 liver transplant (LT) recipients with either no rejection (NR), acute T cell-mediated rejection (TCMR), or chronic rejection (CR). This approach generated a spatially resolved proteomic atlas of 461,816 cells (42 phenotypes) derived from 96 pathologist-selected regions of interest. Our analysis revealed that regulatory (HLADR T) and PD1 T cell phenotypes (CD4 and CD8 subsets), combined with variations in M2 macrophage polarization, were a unique signature of active TCMR. These data provide insights into the alloimmune microenvironment in clinical LT, including identification of potential targets for focused immunotherapy during rejection episodes and suggestion of a substantial role for immune exhaustion in TCMR.
Topics: Immune System Exhaustion; Liver Transplantation; Proteomics; Biopsy; Immunotherapy
PubMed: 38608023
DOI: 10.1126/sciadv.adm8841 -
Clinical Kidney Journal Apr 2024Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the... (Review)
Review
Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have a 2- to 4-fold higher risk of developing cancer compared to the general population and post-transplant malignancy is the third most common cause of death in KTR. Moreover, it is well known that certain cancer types are overrepresented after transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, with remarkable survival benefit in a subgroup of patients. ICI are monoclonal antibodies that block the binding of specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand programmed cell death ligand 1 (PD-L1) are the main targets of ICI. Solid organ transplant recipients (SOTR) have been excluded from clinical trials owing to concerns about tumor response, allo-immunity, and risk of transplant rejection. Indeed, graft rejection has been estimated as high as 48% and represents an emerging problem. The underlying mechanisms of organ rejection in the context of treatment with ICI are poorly understood. The search for restricted antitumoral responses without graft rejection is of paramount importance. This review summarizes the current knowledge of the use of ICI in KTR, the potential mechanisms involved in kidney graft rejection during ICI treatment, potential biomarkers of rejection, and how to deal with rejection in clinical practice.
PubMed: 38606169
DOI: 10.1093/ckj/sfae061 -
Journal of Clinical Medicine Feb 2024This study aimed to describe the historical experience of a single reference center in Brazil with intrauterine transfusion (IUT) for Rhesus (Rh) alloimmunization,...
This study aimed to describe the historical experience of a single reference center in Brazil with intrauterine transfusion (IUT) for Rhesus (Rh) alloimmunization, evaluating the major complications and the perinatal outcomes of this procedure. This retrospective cohort study evaluated data from medical records of pregnant women between 20 and 34 weeks of gestation whose fetuses underwent IUT by cordocentesis between January 1991 and June 2021. The same experienced examiner performed all procedures. Univariate and multivariate logistic regression was used to assess the effect of fetal hydrops, duration of IUT, post-transfusion cord bleeding time, and bradycardia on death (fetal or neonatal). We analyzed data from 388 IUTs in 169 fetuses of alloimmunized pregnant women with a mean age of 29.3 ± 5.1 years. Death and fetal hydrops were significantly associated at first IUT ( < 0.001). We had two cases of emergency cesarean section (mean of 0.51% per IUT) and three cases of premature rupture of the ovular membranes (mean of 0.77% per procedure). Thirty-six deaths were recorded, including 14 intrauterine and 22 neonatal. A higher percentage of neonatal deaths was observed in the group with post-transfusion cord bleeding time > 120 s (45.8%). The odds of neonatal death were 17.6 and 12.9 times higher in cases with hydrops and bradycardia than in cases without hydrops and bradycardia, respectively. The odds of death (fetal and neonatal) were 79.9 and 92.3 times higher in cases with hydrops and bradycardia than in cases without hydrops and bradycardia, respectively. The most common complications of IUT for Rh alloimmunization were post-transfusion cord bleeding, fetal bradycardia, premature rupture of ovular membranes, and emergency cesarean section. The IUT complication most associated with death (fetal and neonatal) was bradycardia, and the perinatal outcomes were worse in fetuses with hydrops.
PubMed: 38592667
DOI: 10.3390/jcm13051362