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IL-21-producing effector Tfh cells promote B cell alloimmunity in lymph nodes and kidney allografts.JCI Insight Oct 2023Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins, and functions of...
Follicular helper T (Tfh) cells have been implicated in controlling rejection after allogeneic kidney transplantation, but the precise subsets, origins, and functions of Tfh cells in this process have not been fully characterized. Here we show that a subset of effector Tfh cells marked by previous IL-21 production is potently induced during allogeneic kidney transplantation and is inhibited by immunosuppressive agents. Single-cell RNA-Seq revealed that these lymph node (LN) effector Tfh cells have transcriptional and clonal overlap with IL-21-producing kidney-infiltrating Tfh cells, implicating common origins and developmental trajectories. To investigate the precise functions of IL-21-producing effector Tfh cells in LNs and allografts, we used a mouse model to selectively eliminate these cells and assessed allogeneic B cell clonal dynamics using a single B cell culture system. We found that IL-21-producing effector Tfh cells were essential for transplant rejection by regulating donor-specific germinal center B cell clonal dynamics both systemically in the draining LN and locally within kidney grafts. Thus, IL-21-producing effector Tfh cells have multifaceted roles in Ab-mediated rejection after kidney transplantation by promoting B cell alloimmunity.
Topics: Mice; Animals; T Follicular Helper Cells; T-Lymphocytes, Helper-Inducer; Lymph Nodes; Kidney; Allografts
PubMed: 37870962
DOI: 10.1172/jci.insight.169793 -
Seminars in Hematology Oct 2019Red cell genotyping has become widely available and now contributes to support transfusion of patients with hematologic diseases. This technology has facilitated the... (Review)
Review
Red cell genotyping has become widely available and now contributes to support transfusion of patients with hematologic diseases. This technology has facilitated the immunohematologic approach to antibody prevention, detection and identification. Donors, particularly rare donors, are most efficiently screened and identified by red cell genotyping. In transfused patients with challenging serologic reactivity, antibodies are more reliably identified when molecular typing information is available. Red cell genotyping of both donors and patients augments the selection of blood components. This technology, serving at the core of a real-time database inventory, is resulting in blood supply efficiencies. However, there is limited published evidence on the extent to which red cell genotyping has translated into improved clinical outcomes. Red cell alloimmunized patients may benefit the most in enhanced safety. For patients with antibodies to high-prevalence antigens, other than Rh, blood centers realized supply-chain efficiencies in the past decade. Prospective clinical trials and cost-effectiveness studies would contribute to further clarifying the optimal role of molecular testing in providing transfusion support for patients with hematologic diseases.
Topics: Erythrocyte Transfusion; Genomics; Humans; Prospective Studies
PubMed: 31836029
DOI: 10.1053/j.seminhematol.2019.11.001 -
BMJ Sexual & Reproductive Health Jul 2022The aim of this review was to systematically review the outcome of routine anti-D administration among unsensitised rhesus (RhD)-negative individuals who have an... (Meta-Analysis)
Meta-Analysis Review
AIM
The aim of this review was to systematically review the outcome of routine anti-D administration among unsensitised rhesus (RhD)-negative individuals who have an abortion. This review is registered with Prospero.
METHODS
A search for all published and ongoing studies, without restrictions on language or publication status, was performed using the following databases from their inception: EBM Reviews Ovid - Cochrane Central Register of Controlled Trials, MEDLINE Ovid (Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily), Embase.com, Popline and Google Scholar. Study types included: randomised controlled trials, controlled trials, cohort and case-control studies from 1971 onwards. The population included women who undergo an abortion (induced, incomplete, spontaneous or septic abortion), medical or surgical <12 weeks, and isoimmunisation in a subsequent pregnancy. The primary outcomes were: (1) development of a positive Kleihauer-Betke test and (2) development of Rh alloimmunisation in a subsequent pregnancy.
RESULTS
A total of 2652 studies were screened with 105 accessed for full-text review. Two studies have been included with high bias appreciated. Both studies found few women to be sensitised in forming antibodies after an abortion. The limited studies available and heterogeneity prevent the conduction of a meta-analysis.
CONCLUSIONS
Rh immunoglobulin has well-documented safety. However, it is not without risks and costs, is a possible barrier to delivering efficient services, and may have limited availability in some countries. The evidence base and quality of studies are currently limited. There is unclear benefit from the recommendation for Rh testing and immunoglobulin administration in early pregnancy. More research is needed as clinical practice guidelines are varied, based on expert opinions and moving away from testing and administration at time of abortion.
IMPLICATIONS
There is limited evidence surrounding medical benefit of Rh testing and immunoglobulin administration in early pregnancy. Further research is needed to define alloimmunisation and immunoglobulin benefit to update standards of care. Additionally, other factors should be considered in forming clinical policies and guidelines such as costs, feasibility and impact on access to care for patients.
Topics: Abortion, Induced; Abortion, Spontaneous; Cohort Studies; Female; Humans; Pregnancy; Rh Isoimmunization
PubMed: 34819315
DOI: 10.1136/bmjsrh-2021-201225 -
International Journal of Molecular... Sep 2023Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is...
Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is the main limitation of transfusion, which can worsen anaemia and lead to delayed haemolytic transfusion reaction or transfusion deadlock. Although biological risk factors have been identified for immunisation, patient alloimmunisation remains difficult to predict. We aimed to characterise genetic alloimmunisation factors to optimise the management of blood products compatible with extended antigen matching to ensure the self-sufficiency of labile blood products. Considering alloimmunisation in other clinical settings, like pregnancy and transplantation, many studies have shown that HLA Ib molecules (HLA-G, -E, and -F) are involved in tolerance mechanism; these molecules are ligands of immune effector cell receptors (LILRB1, LILRB2, and KIR3DS1). Genetic polymorphisms of these ligands and receptors have been linked to their expression levels and their influence on inflammatory and immune response modulation. Our hypothesis was that polymorphisms of genes and of their receptors are associated with alloimmunisation susceptibility in SCD patients. The alloimmunisation profile of thirty-seven adult SCD patients was analysed according to these genetic polymorphisms and transfusion history. Our results suggest that the alloimmunisation of SCD patients is linked to both and genetic polymorphisms located in their regulatory region and associated with their protein expression level.
Topics: Adult; Female; Pregnancy; Humans; Leukocyte Immunoglobulin-like Receptor B1; Ligands; Genes, MHC Class I; Anemia, Sickle Cell; Anemia, Hemolytic, Autoimmune; Antigens, CD
PubMed: 37686397
DOI: 10.3390/ijms241713591 -
Clinics in Laboratory Medicine Mar 2021Red blood cell (RBC) transfusion is critical in managing acute and chronic complications of sickle cell disease. Alloimmunization and iron overload remain significant... (Review)
Review
Red blood cell (RBC) transfusion is critical in managing acute and chronic complications of sickle cell disease. Alloimmunization and iron overload remain significant complications of transfusion therapy and are minimized with prophylactic Rh and K antigen RBC matching and iron chelation. Matched sibling donor hematopoietic stem cell transplant (HSCT) is a curative therapeutic option. Autologous hematopoietic stem cell (HSC)-based gene therapy has recently shown great promise, for which obtaining sufficient HSCs is essential for success. This article discusses RBC transfusion indications and complications, transfusion support during HSCT, and HSC mobilization and collection for autologous HSCT with gene therapy.
Topics: Anemia, Sickle Cell; Blood Group Antigens; Blood Transfusion; Cell- and Tissue-Based Therapy; Erythrocyte Transfusion; Humans
PubMed: 33494879
DOI: 10.1016/j.cll.2020.10.007 -
Current Opinion in Hematology Nov 2020The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC)... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC) transfusion, the formation of alloantibodies following RBC alloantigen exposure, and the development of hyperhemolysis in patients with sickle cell disease (SCD).
RECENT FINDINGS
Recent studies demonstrate that complement can accelerate alloantibody-mediated removal of target alloantigens from the RBC surface following incompatible transfusion. Complement also influences alloantigen availability during developing alloimmune responses and serves as a unique mediator of CD4 T-cell-independent alloantibody formation following RBC alloantigen exposure. Finally, alternative complement pathway activation appears to play a key role in the development of acute hemolytic episodes in patients with SCD, providing a potential druggable target to prevent acute complications in patients with this disease.
SUMMARY
Recent studies suggest that complement can regulate a wide variety of processes germane to hematology, from transfusion complications to baseline hemolysis in patients with SCD. As the role of complement in various disease processes becomes more fully understood, the ability to leverage recently developed complement modulating drugs will only continue to enhance providers' ability to favorably intervene in many hematological diseases.
Topics: Anemia, Hemolytic, Autoimmune; Animals; Blood Group Incompatibility; Complement System Proteins; Erythrocyte Transfusion; Erythrocytes; Hemolysis; Humans; Isoantibodies; Isoantigens
PubMed: 32889827
DOI: 10.1097/MOH.0000000000000610 -
Current Opinion in Organ Transplantation Dec 2019The microbiota in mammalian hosts can affect maturation and function of the immune system and has been associated with health and disease. We will review new findings on... (Review)
Review
PURPOSE OF REVIEW
The microbiota in mammalian hosts can affect maturation and function of the immune system and has been associated with health and disease. We will review new findings on how this dynamic environmental factor impacts alloimmunity and therapy in transplant hosts.
RECENT FINDINGS
The microbiota changes after transplantation and immunosuppressive therapy. New data indicate that different microbial community structures have distinct impact on graft outcome, from promoting, to inhibiting or being neutral to transplant survival. In addition, we will address reciprocal interactions between the microbiota and immunosuppressive drugs, as well as the suitability of the microbiota as a predictive biomarker and its utility as adjunct therapy in transplantation.
SUMMARY
Advances in microbiome sequencing and wider availability of gnotobiotic facilities are enabling mechanistic investigations into the commensal communities and pathways that modulate allograft outcome, responsiveness to immunosuppression and side effects of drugs. A better understanding of the functions of the microbiota may help mitigate drug toxicity, predict drug dosage and dampen alloimmunity in transplant patients.
Topics: Graft Survival; Humans; Microbiota; Organ Transplantation
PubMed: 31577594
DOI: 10.1097/MOT.0000000000000702 -
World Journal of Gastroenterology Jul 2019The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago.... (Review)
Review
The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart. The liver has a unique architecture and is home to many cells involved in immunity and inflammation. After transplantation, these cells migrate from the liver into the recipient. Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system. Recent studies on human T-cell subtypes, cytokine expression, and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation. In this article, we discuss the privileged state of liver transplantation compared to other solid organ transplantation, the liver allograft's role in multivisceral transplantation, various cells in the liver involved in immune responses, and the potential mechanisms underlying immunomodulation of host alloresponses.
Topics: Allografts; Graft Rejection; Graft Survival; Humans; Immune Tolerance; Liver; Organ Transplantation; Transplantation, Homologous
PubMed: 31333306
DOI: 10.3748/wjg.v25.i25.3123 -
Current Opinion in Organ Transplantation Jun 2021Immune responses following lung transplantation continue to result in high rates of allograft failure and rejection, and current immunosuppression does not address the... (Review)
Review
PURPOSE OF REVIEW
Immune responses following lung transplantation continue to result in high rates of allograft failure and rejection, and current immunosuppression does not address the unique immunologic properties of the lung. Here, we review recent studies on lung allograft tolerance and alloimmunity and discuss implications for immunosuppression.
RECENT FINDINGS
Processes governing tolerance and alloimmunity in lung allografts differ from other solid organs. Recent studies have suggested that allorecognition is regulated at the level of the lung graft. Furthermore, certain cell populations essential for lung allograft tolerance may facilitate rejection in other organs. Induction of lung allograft tolerance is associated with the formation of tertiary lymphoid organs, which are enriched in regulatory T cells and play an important role in preventing rejection.
SUMMARY
Recent discoveries regarding alloactivation and the regulation of tolerance following lung transplantation have introduced exciting potential avenues for the development of lung-specific immunosuppression.
Topics: Allografts; Graft Rejection; Graft Survival; Humans; Immune Tolerance; Immunity; Immunosuppression Therapy; Lung; Lung Transplantation
PubMed: 33782247
DOI: 10.1097/MOT.0000000000000871 -
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