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Cell Metabolism Jun 2024Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of...
Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1R T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1R and GLP-1R CD3 T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1R are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.
Topics: Animals; Glucagon-Like Peptide-1 Receptor; Mice; Mice, Inbred C57BL; Islets of Langerhans Transplantation; T-Lymphocytes; Male; Heart Transplantation; Mice, Inbred BALB C; CD8-Positive T-Lymphocytes; Graft Survival
PubMed: 38838642
DOI: 10.1016/j.cmet.2024.05.001 -
The Journal of Clinical Investigation Jun 2024Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA]...
Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for this currently hard-to-treat clinical entity that has several etiologies but a potentially focused mechanism.
Topics: Humans; Immunoglobulin G; Acute Lung Injury; Complement Activation; Animals; Isoantibodies; Protein Multimerization; Histocompatibility Antigens Class I; Antigen-Antibody Complex
PubMed: 38828725
DOI: 10.1172/JCI181137 -
Clinical Hematology International 2024Hematopoietic stem cell transplantation (HSCT) is a cornerstone of modern medical practice, and can only be performed safely and effectively with appropriate transfusion... (Review)
Review
Hematopoietic stem cell transplantation (HSCT) is a cornerstone of modern medical practice, and can only be performed safely and effectively with appropriate transfusion medicine support. Patients undergoing HSCT often develop therapy-related cytopenia, necessitating differing blood product requirements in the pre-, peri-, and post-transplant periods. Moreover, ensuring optimal management for patients alloimmunized to human leukocyte antigens (HLA) and/or red blood cell (RBC) antigens, as well as for patients receiving ABO-incompatible transplants, requires close collaboration with transfusion medicine and blood bank professionals. Finally, as updated transfusion guidelines and novel blood product modifications emerge, the options available to the transplant practitioner continue to expand. Herein, we detail contemporary blood transfusion and transfusion medicine practices for patients undergoing HSCT.
PubMed: 38817704
DOI: 10.46989/001c.94135 -
American Journal of Perinatology Jun 2024Mainstay therapy for fetuses affected by maternal red cell alloimmunization is serial intrauterine transfusion (IUT). Testing to determine when fetal red cells have...
OBJECTIVE
Mainstay therapy for fetuses affected by maternal red cell alloimmunization is serial intrauterine transfusion (IUT). Testing to determine when fetal red cells have been replaced with donor cells historically involves the use of the Kleihauer-Betke (KB) test. Hemoglobin (Hgb) electrophoresis testing may be more rapid with a reduced cost of analysis. We aimed to determine the correlation between fetal Hgb electrophoresis versus the traditional KB test.
STUDY DESIGN
This is a retrospective analysis of all alloimmunized singleton pregnancies undergoing IUT between January 1, 2021, and July 1, 2023. Maternal and fetal characteristics were collected along with the indication for IUT. A final fetal blood sample was obtained at the conclusion of each transfusion and sent for KB testing and Hgb electrophoresis. The primary outcome was the assessment of these parameters in their ability to predict the replacement of the fetal circulating red cell population with donor cells. Linear regression analysis and repeated measures analysis of variance were performed, and -values less than 0.05 were considered significant.
RESULTS
A total of 56 IUTs were performed in 16 patients. There were 39 (69.6%) final KB test values collected and compared with 30 (53.6%) final Hgb electrophoresis values. Hgb electrophoresis when compared with the KB test demonstrated a significant correlation ( = 0.93; 95% confidence interval, 0.61-0.76; < 0.001). This same finding held true when examining the correlation at each individual IUT as well. The final KB test and Hgb electrophoresis values significantly decreased with each transfusion ( = 0.003). A predominance of adult donor blood was noted by the third transfusion for both laboratory indices.
CONCLUSION
Fetal Hgb electrophoresis obtained at the time of IUT demonstrates a significant correlation with the traditional KB test.
KEY POINTS
· Fetal Hgb electrophoresis following IUT is underexplored. · Hgb electrophoresis is an automated evaluation. · The traditional KB test is a manual evaluation. · These two tests demonstrate significant correlation.
PubMed: 38806157
DOI: 10.1055/a-2334-6990 -
Transfusion Medicine (Oxford, England) May 2024Antibodies against blood group antigens play a key role in the pathophysiology of haemolytic transfusion reactions (HTRs) and haemolytic disease of the fetus and newborn...
BACKGROUND
Antibodies against blood group antigens play a key role in the pathophysiology of haemolytic transfusion reactions (HTRs) and haemolytic disease of the fetus and newborn (HDFN). This study aimed to determine the frequencies of alleles, genotypes, and risk of alloimmunisation of clinically significant blood group systems in ethnic northeastern Thais.
METHODS
In total, 345 unrelated, healthy, ethnic northeastern Thais were tested using the in-house PCR-sequence specific primers (PCR-SSP) method for simultaneously genotyping of RHCE, Kell, Duffy, Kidd, Diego and MNS glycophorin hybrids and results confirmed by Sanger sequencing.
RESULTS
In this cohort, the alleles RHCE*C (81.0%) and RHCE*e (84.8%) were more prevalent than RHCE*c (19.0%) and RHCE*E (15.2%). The most common predicted haplotype combinations of the RHCE alleles were C+c-E-e+(RR) (59.4%) followed by the C+c+E+e+ (RR) (20.6%) and C+c+E-e+ (Rr) (11.3%). The KEL*01 allele was not found in this study. The frequencies of FY*01 and FY*02 were 88.3% and 11.7%, respectively. The genotype FY*02/02 was found in four samples (1.2%). The frequencies of JK*01 and JK*02 were 52.5% and 47.5%, respectively. Homozygous JK*02/02 was found in 81 samples (23.5%). The frequencies of DI*01 and DI*02 were 0.6% and 99.4%, respectively. In total, 64 samples (18.6%) were found to carry the MNS glycophorin hybrids.
CONCLUSIONS
Our results indicated a possible high risk of c, E, Fy, Jk, Jk and Mi alloimmunisation in these populations. Moreover, methods established for genotyping clinically significant blood groups in this study can now be utilised in routine clinical application.
PubMed: 38804163
DOI: 10.1111/tme.13055 -
Frontiers in Immunology 2024Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA)....
Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APCs), particularly dendritic cells (DCs), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DCs (cDCs) and APCs on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation. By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. Notably, the skin component exhibited heightened immunogenicity when compared to the entire VCA, evidenced by increased frequencies of pan (CD11bCD11c), mature (CD11bCD11cMHCII) and active (CD11bCD11cCD40) DCs and cDC2 subset (CD11bCD11c MHCII) in the lymphoid tissues and the blood of skin transplant recipients. While donor depletion of cDC and APC reduced frequencies, maturation and activation of DCs in all analyzed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4IL-17) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APCs and cDCs mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.
Topics: Animals; Dendritic Cells; Skin Transplantation; Mice; Hindlimb; Graft Rejection; Mice, Inbred C57BL; Mice, Inbred BALB C; Composite Tissue Allografts; Vascularized Composite Allotransplantation; CD8-Positive T-Lymphocytes; Male; Tissue Donors; Skin
PubMed: 38799435
DOI: 10.3389/fimmu.2024.1395945 -
Biomedical Journal May 2024After transplantation of allogeneic tissues and organs, recognition by recipient T cells of donor MHC molecules initiates the pro-inflammatory adaptive immune response...
After transplantation of allogeneic tissues and organs, recognition by recipient T cells of donor MHC molecules initiates the pro-inflammatory adaptive immune response leading to allograft rejection. T cell allorecognition has long been known to be mediated via two distinct pathways: the direct pathway in which T cells recognize intact allogeneic MHC molecules displayed on donor cells and the indirect pathway whereby T cells recognize donor MHC peptides processed and presented by recipient antigen-presenting cells (APCs). It is believed that direct allorecognition is the driving force behind early acute allograft rejection while indirect allorecognition is involved in chronic allograft rejection, a progressive condition characterized by graft vasculopathy and tissue fibrosis. Recently, we and others have reported that after transplantation of allogeneic skin and organs, donor MHC molecules are transferred from donor cells to the host's APCs via trogocytosis or extracellular vesicles. Recipient APCs having captured donor MHC molecules can either present them to T cells in the intact form on their surface (semi-direct pathway) or the form of peptides bound to self-MHC molecules (indirect pathway). The present article provides an overview of recent studies evaluating the role of intercellular exchange of MHC molecules in T cell alloimmunity and its contribution to allograft rejection and tolerance.
PubMed: 38797478
DOI: 10.1016/j.bj.2024.100749 -
Bone Marrow Transplantation May 2024In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to...
In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to transfuse red blood cells (RBC) in the donor's Rh phenotype from the day of transplantation, leading to a risk of allo-immunization, either of donor or recipient origin. In this single-center retrospective study, the incidence of donor/recipient Rh incompatibility was 7.1% over an 8-year period including 1012 alloHSCT. Six of 58 evaluable patients (10.3%) developed alloantibodies to RBC antigens within one year of alloHSCT. None of these allo-immunizations were directed against the donor-mismatched Rh antigens and none could have been prevented by the transfusion of recipient and donor Rh-compatible RBC units. None of these allo-immunizations led to immune-mediated hemolytic anemia. We observed a statistically significant higher incidence of chronic GVHD among patients with anti-RBC allo-immunization. In the context of donor/recipient Rh incompatibility, the transfusion of packed RBC units in the donor's Rh phenotype from the day of alloHSCT is feasible and not associated with a high risk of allo-immunization. The generalization of this strategy could be discussed even when donor and recipient Rh phenotypes could be respected, to allow the preservation of units of infrequent phenotypes for other indications.
PubMed: 38796632
DOI: 10.1038/s41409-024-02316-0 -
Cells May 2024Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor...
Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCs). Pig lungs were placed on EVLP for 6 h and randomized to control ( = 7), intravascular delivery of 20 × 10 ( = 5, low dose) or 40 × 10 human MSCs ( = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSC therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSC delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSC dose resulting in inflammation and cytotoxic CD8 T cell activation. MSC therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.
Topics: Lung Transplantation; Animals; Interleukin-10; Mesenchymal Stem Cells; Swine; Immunomodulation; Mesenchymal Stem Cell Transplantation; Humans; Genetic Engineering; Lung
PubMed: 38786082
DOI: 10.3390/cells13100859