-
Research (Washington, D.C.) 2023Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various...
Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell-Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4 regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.
PubMed: 37808178
DOI: 10.34133/research.0236 -
Immunity Jul 2023Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5) can cure HIV, yet mechanisms remain speculative. To...
Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4 T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; HIV Infections; Macaca fascicularis; Hematopoietic Stem Cell Transplantation; Viral Load
PubMed: 37236188
DOI: 10.1016/j.immuni.2023.04.019 -
Haematologica Jun 2024Patients with severe aplastic anemia (SAA) are at high risk of morbidity and mortality due to severe infections. We aimed to characterize the role of granulocyte...
Patients with severe aplastic anemia (SAA) are at high risk of morbidity and mortality due to severe infections. We aimed to characterize the role of granulocyte transfusions (GT) in SAA. Primary outcomes were survival after the first GT, including overall survival (OS) at last follow up, survival to discharge, and receipt of a hematopoietic stem cell transplant (HSCT) Secondary outcomes included evaluation of clinical response at 7 and 30 days after initiation of GT, using a clinical scoring system incorporating microbiological and radiographic response. Twenty-eight SAA patients underwent 30 GT courses with a per-dose median of 1.28x109 granulocytes/kilogram (range, 0.45-4.52x109). OS from initial GT to median last follow up (551 days) was 50%, with 39% (11/28) alive at last follow up. Sixty-four percent (18/28) of all patients survived to hospital discharge. Patients with a complete or partial response, or stable infection, at 30 days had significantly better OS compared to non-responders (P=0.0004). Eighty-six percent (18/21) of patients awaiting HSCT during GT underwent a transplant and 62% (13/21) survived to post-HSCT discharge. Sex, type of infection, and percentage of days with absolute neutrophil count >0.2x109/L during the course of GT were not predictive of survival (P=0.52, P=0.7 and P=0.28, respectively). Nine of 28 (32%) patients developed new or increased human leukocyte antigen alloimmunization during their GT course. GT in SAA may have an impact on survival in those patients with improvement or stabilization of their underlying infection. Alloimmunization can occur and OS in this population remains poor, but GT may be a useful tool to bridge patients to curative treatment with HSCT.
Topics: Humans; Anemia, Aplastic; Granulocytes; Male; Female; Adult; Middle Aged; Adolescent; Leukocyte Transfusion; Hematopoietic Stem Cell Transplantation; Young Adult; Treatment Outcome; Child; Severity of Illness Index; Aged; Follow-Up Studies; Retrospective Studies
PubMed: 38058170
DOI: 10.3324/haematol.2023.283826 -
Transfusion and Apheresis Science :... Oct 2023Several autoimmune disorders have been reported to be related with COVID infection. In continuation to these autoimmune phenomenon, autoimmune hemolytic anaemia (AIHA)... (Observational Study)
Observational Study
BACKGROUND
Several autoimmune disorders have been reported to be related with COVID infection. In continuation to these autoimmune phenomenon, autoimmune hemolytic anaemia (AIHA) also has been noted in COVID infected patients. The aim of the study was to find out the prevalence of red cell alloimmunization, ABO discrepancy and positive direct antiglobulin test (DAT) results in COVID infected patients hospitalised in a tertiary care centre in North India.
METHODOLOGY
This was a retrospective observational study done from July 2020 to June 2021. All symptomatic patients admitted to ICU tested positive for SARS CoV-2 whose blood samples were received in the immunohematology laboratory of department of Transfusion Medicine for determination of blood group and issue of packed red cells, and found to have positive antibody screen, blood group discrepancy and positive DAT results, were included in the study.
RESULTS
A total of 10,568 tests were run, out of which 4437 were for determination of blood group, 5842 were for antibody screen and 289 were for direct antiglobulin test. Included in this study were 146 patients who either had blood group discrepancy, or had a positive antibody screen or had a positive DAT. Out of 115 positive antibody screen, 66 patients had only alloantibodies, 44 patients had only autoantibodies while only 5 patients had both auto as well as alloantibodies. Total number of positive DAT cases was 50 (50/289 = 17.3 %). There were 26 ABO discrepancies (26/4437 =0.58 %) found.
CONCLUSION
Our results also indicate that there is rise in rate of alloimmunization and DAT positivity among COVID patients.
Topics: Humans; Isoantibodies; COVID-19; Anemia, Hemolytic, Autoimmune; Erythrocytes; Coombs Test; Blood Group Antigens
PubMed: 37286441
DOI: 10.1016/j.transci.2023.103729 -
Frontiers in Immunology 2023Acute myeloid leukemia (AML) is one of the commonest hematologic disorders. Due to the high frequency of disease- or treatment-related thrombocytopenia, AML requires...
INTRODUCTION
Acute myeloid leukemia (AML) is one of the commonest hematologic disorders. Due to the high frequency of disease- or treatment-related thrombocytopenia, AML requires treatment with multiple platelet transfusions, which can trigger a humoral response directed against platelets. Some, but not all, AML patients develop an anti-HLA immune response after multiple transfusions. We therefore hypothesized that different immune activation profiles might be associated with anti-HLA alloimmunization status.
METHODS
We tested this hypothesis, by analyzing CD4+ T lymphocyte (TL) subsets and their immune control molecules in flow cytometry and single-cell multi-omics.
RESULTS
A comparison of immunological status between anti-HLA alloimmunized and non-alloimmunized AML patients identified differences in the phenotype and function of CD4+ TLs. CD4+ TLs from alloimmunized patients displayed features of immune activation, with higher levels of CD40 and OX40 than the cells of healthy donors. However, the most notable differences were observed in non-alloimmunized patients. These patients had lower levels of CD40 and OX40 than alloimmunized patients and higher levels of PD1. Moreover, the Treg compartment of non-alloimmunized patients was larger and more functional than that in alloimmunized patients. These results were supported by a multi-omics analysis of immune response molecules in conventional CD4+ TLs, Tfh circulating cells, and Tregs.
DISCUSSION
Our results thus reveal divergent CD4+ TL characteristics correlated with anti-HLA alloimmunization status in transfused AML patients. These differences, characterizing CD4+ TLs independently of any specific antigen, should be taken into account when considering the immune responses of patients to infections, vaccinations, or transplantations.
Topics: Humans; Blood Platelets; T-Lymphocytes, Helper-Inducer; CD4-Positive T-Lymphocytes; Thrombocytopenia; Anemia, Hemolytic, Autoimmune; CD40 Antigens; Leukemia, Myeloid, Acute
PubMed: 37701444
DOI: 10.3389/fimmu.2023.1165973 -
Frontiers in Molecular Biosciences 2023Regulatory T cells (Tregs) adoptive immunotherapy is emerging as a viable treatment option for both autoimmune and alloimmune diseases. However, numerous challenges... (Review)
Review
Regulatory T cells (Tregs) adoptive immunotherapy is emerging as a viable treatment option for both autoimmune and alloimmune diseases. However, numerous challenges remain, including limitations related to cell number, availability of target-specific cells, stability, purity, homing ability, and safety concerns. To address these challenges, cell engineering strategies have emerged as promising solutions. Indeed, it has become feasible to increase Treg numbers or enhance their stability through Foxp3 overexpression, post-translational modifications, or demethylation of the Treg-specific demethylated region (TSDR). Specificity can be engineered by the addition of chimeric antigen receptors (CARs), with new techniques designed to fine-tune specificity (tandem chimeric antigen receptors, universal chimeric antigen receptors, synNotch chimeric antigen receptors). The introduction of B-cell targeting antibody receptor (BAR) Tregs has paved the way for effective regulation of B cells and plasma cells. In addition, other constructs have emerged to enhance Tregs activation and function, such as optimized chimeric antigen receptors constructs and the use of armour proteins. Chimeric antigen receptor expression can also be better regulated to limit tonic signaling. Furthermore, various opportunities exist for enhancing the homing capabilities of CAR-Tregs to improve therapy outcomes. Many of these genetic modifications have already been explored for conventional CAR-T therapy but need to be further considered for CAR-Tregs therapies. This review highlights innovative CAR-engineering strategies that have the potential to precisely and efficiently manage immune responses in autoimmune diseases and improve transplant outcomes. As these strategies are further explored and optimized, CAR-Treg therapies may emerge as powerful tools for immune intervention.
PubMed: 37900916
DOI: 10.3389/fmolb.2023.1267762 -
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 -
Current Opinion in Organ Transplantation Oct 2023The implementation of highly sensitive immune assays measuring anti-human leukocyte antigen (HLA) antibodies has modified alloimmune risk stratification and diagnosis of... (Review)
Review
PURPOSE OF REVIEW
The implementation of highly sensitive immune assays measuring anti-human leukocyte antigen (HLA) antibodies has modified alloimmune risk stratification and diagnosis of rejection. Nonetheless, anti-HLA antibodies represent the downstream effector mechanism of the B-cell response. Better characterizing the cellular components of the humoral immune response (including memory B cells (mBCs) and long-lived plasma cells) could help to further stratify the alloimmune risk stratification and enable discovery of new therapeutic targets. Several tests that characterize HLA-specific mBCs, either functionally or phenotypically, have been developed in the last years, showing promising applications as well as some limitations.
RECENT FINDINGS
Functional assays involving ex vivo polyclonal activation of mBC have been refined to allow the detection of HLA-specific mBC capable of producing anti-HLA Abs, using different and complementary detection platforms such as multiplex Fluorospot and single antigen bead assay on culture supernatants. Detection of circulating HLA-specific B cells by flow cytometry remains hindered by the very low frequency of HLA-specific mBC.
SUMMARY
Technological refinements have allowed the development of tests detecting HLA-specific mBC. Further evaluation of these assays in clinical trials, both for immune risk stratification and to assess treatment efficacy (desensitization strategies, rescue therapies for ABMR) are now urgently needed.
Topics: Humans; B-Lymphocytes; Flow Cytometry; Immunity, Humoral
PubMed: 37678170
DOI: 10.1097/MOT.0000000000001097 -
The Veterinary Clinics of North... Jun 2024Alloimmune disorders occur in foals when pregnant mares produce antibodies against antigens on the foal's cells or tissues, and concentrate them within colostrum. Once... (Review)
Review
Alloimmune disorders occur in foals when pregnant mares produce antibodies against antigens on the foal's cells or tissues, and concentrate them within colostrum. Once foals nurse and absorb colostral antibodies, they can develop hematologic or cutaneous manifestations that can occur individually or in combination. These include neonatal isoerythrolysis, a hemolytic anemia directed against factors on the foal's erythrocytes, alloimmune thrombocytopenia when the antibodies are directed against platelet antigens, alloimmune neutropenia when they are directed against neutrophil antigens, and a combination of suspected alloimmune ulcerative dermatitis, neutropenia and thrombocytopenia. Foals can also develop neutrophilic dermatitis which is suspected to be alloimmune.
PubMed: 38852013
DOI: 10.1016/j.cveq.2024.05.001