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Immunogenetics Jun 2023Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural... (Review)
Review
Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural selection by pathogens. Of these pathogens, human herpesviruses have a uniquely ancient relationship with our species, where coevolution likely has reciprocating impact on HLA and viral genomic diversity. Consistent with this notion, genetic variation at multiple HLA loci is strongly associated with modulating immunity to herpesvirus infection. Here, we synthesize published genetic associations of HLA with herpesvirus infection and disease, both from case/control and genome-wide association studies. We analyze genetic associations across the eight human herpesviruses and identify HLA alleles that are associated with diverse herpesvirus-related phenotypes. We find that whereas most HLA genetic associations are virus- or disease-specific, HLA-A*01 and HLA-A*02 allotypes may be more generally associated with immune susceptibility and control, respectively, across multiple herpesviruses. Connecting genetic association data with functional corroboration, we discuss mechanisms by which diverse HLA and cognate receptor allotypes direct variable immune responses during herpesvirus infection and pathogenesis. Together, this review examines the complexity of HLA-herpesvirus interactions driven by differential T cell and Natural Killer cell immune responses.
Topics: Humans; Genome-Wide Association Study; HLA Antigens; Polymorphism, Genetic; Herpesviridae Infections; HLA-A Antigens
PubMed: 36595060
DOI: 10.1007/s00251-022-01288-z -
ACS Synthetic Biology Oct 2022The Notch pathway converts receptor-ligand interactions at the cell surface into a transcriptional response in the receiver cell. In recent years, synthetic Notch...
The Notch pathway converts receptor-ligand interactions at the cell surface into a transcriptional response in the receiver cell. In recent years, synthetic Notch systems (synNotch) that respond to different inputs and transduce different transcriptional responses have been engineered. One class of synNotch systems uses antibody-antigen interactions at the cell surface to induce the proteolytic cleavage cascade of the endogenous Notch autoregulatory core and the consequent release of a synNotch intracellular domain (ICD), converting surface antigen detection into a cellular response. While the activation of endogenous Notch requires ubiquitylation and subsequent endocytosis of the ligand ICD, these synNotch systems do not seem to have such a requirement because the synNotch ligands completely lack an ICD. This observation raises questions about existing models for the synNotch activation mechanism. Here, we test how different structural and biochemical factors affect the dependence of endogenous and synthetic Notch activation on ligand ICD. We compare the behavior of antibody-antigen synNotch (aa-synNotch) to that of endogenous Notch, and to a synNotch system that uses rapamycin induced dimerization of FK506 binding protein (FKBP) and FKBP rapamycin binding (FRB) domaindimerization domains (ff-synNotch), which still requires a ligand ICD. We found that differences in receptor-ligand affinity, in the identity of the transmembrane domain, or in the presence or absence of extracellular epidermal growth factor repeats cannot explain the differences in ligand ICD requirement that distinguishes aa-synNotch from endogenous Notch or ff-synNotch. We also found that unlike endogenous Notch and ff-synNotch, the aa-synNotch system does not exhibit trans-endocytosis of the receptor extracellular domain into the sender cell. These findings suggest that the aa-synNotch systems bypass the ligand ICD requirement because antigen-antibody pairs are able to promote other adhesive cell-cell interactions that provide the mechanical tension needed for ligand activation.
Topics: Ligands; Signal Transduction; Epidermal Growth Factor; Tacrolimus Binding Proteins; Sirolimus; Antigens, Surface
PubMed: 36107643
DOI: 10.1021/acssynbio.2c00247 -
Molecules (Basel, Switzerland) Oct 2021(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and...
(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA.SA.KuE and AAZTA.SA.KuE were synthesized. DATA.SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated and using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA.SA.KuE was synthesized successfully. AAZTA.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA.SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [Ga]Ga-DATA.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA.SA.KuE and DATA.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. and studies of [Lu]Lu-AAZTA.SA.KuE, [Sc]Sc-AAZTA.SA.KuE and [Ga]Ga-DATA.SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially allowing for translational theranostic use.
Topics: Animals; Antigens, Surface; Chelating Agents; Chemistry Techniques, Synthetic; Diagnostic Imaging; Disease Models, Animal; Glutamate Carboxypeptidase II; Heterografts; Humans; Isotope Labeling; Kinetics; Mice; Molecular Structure; Neoplasms; Protein Binding; Radiopharmaceuticals; Translational Research, Biomedical
PubMed: 34770742
DOI: 10.3390/molecules26216332 -
International Journal of Molecular... Jan 2022In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy.... (Review)
Review
In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [Ga]Ga-PSMA-11 and [F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.
Topics: Antigens, Surface; Glutamate Carboxypeptidase II; Humans; Male; Positron-Emission Tomography; Precision Medicine; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 35163083
DOI: 10.3390/ijms23031158 -
Experimental Hematology Jun 2020The CD34 cell surface antigen is widely expressed in tissues on cells with progenitor-like properties and on mature vascular endothelia. In adult human bone marrow, CD34... (Review)
Review
The CD34 cell surface antigen is widely expressed in tissues on cells with progenitor-like properties and on mature vascular endothelia. In adult human bone marrow, CD34 marks hematopoietic stem and progenitor cells (HSPCs) starting from the bulk of hematopoietic stem cells with long-term repopulating potential (LT-HSCs) throughout expansion and differentiation of oligopotent and unipotent progenitors. CD34 protein surface expression is typically lost as cells mature into terminal effectors. Because of this expression pattern of HSPCs, CD34 has had a central role in the evaluation or selection of donor graft tissue in HSC transplant (HSCT). Given its clinical importance, it is surprising that the biological functions of CD34 are still poorly understood. This enigma is due, in part, to CD34's context-specific role as both a pro-adhesive and anti-adhesive molecule and its potential functional redundancy with other sialomucins. Moreover, there are also critical differences in the regulation of CD34 expression on HSPCs in humans and experimental mice. In this review, we highlight some of the more well-defined functions of CD34 in HSPCs with a focus on proposed functions most relevant to HSCT biology.
Topics: Animals; Antigens, CD34; Bone Marrow; Cell Differentiation; Gene Expression Regulation; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Mice
PubMed: 32422232
DOI: 10.1016/j.exphem.2020.05.004 -
Molecular Cancer Therapeutics Nov 2022New targeted chemotherapeutics are urgently needed to minimize off-target toxicity and reduce the high-mortality rate associated with metastatic prostate cancer. Herein,...
New targeted chemotherapeutics are urgently needed to minimize off-target toxicity and reduce the high-mortality rate associated with metastatic prostate cancer. Herein, we report on the modular synthesis, pharmacokinetics, and efficacy of two small-molecule-drug conjugates (SMDC) targeted to prostate-specific membrane antigen (PSMA) incorporating either: (i) a cathepsin-B-cleavable valine-citrulline (Val-Cit), or (ii) an acid-cleavable phosphoramidate linker. Crucial components used in the design of the conjugates include: (i) CTT1298, a nanomolar affinity ligand that binds irreversibly to PSMA and has proven in past studies to rapidly internalize and shuttle payloads into PSMA-expressing prostate cancer cells, (ii) MMAE, a known potent cytotoxic payload, and (iii) an albumin-binder, proven to improve residence time of drug conjugates. At dose of 0.8 mg/kg (∼250 nmol/kg), the two SMDCs showed significant efficacy in a PSMA(+) PC3-PIP mouse model of human prostate cancer compared with controls, without inducing systemic toxicity. Though localization of the SMDCs was observed in tissues apart from the tumor, release of MMAE was observed predominantly in tumor tissue, at levels that were 2-3 orders of magnitude higher than non-target tissues. Furthermore, SMDC2, which incorporated a novel pH-responsive phosporamidate linker, demonstrated significantly improved efficacy over SMDC1 that has a Val-Cit linker, with a 100% survival over 90 days and 4 out of 8 mice showing complete tumor growth inhibition after 6 weekly doses of 0.8 mg/kg (244 nmol/kg). Our findings demonstrate the potential of irreversible PSMA inhibitors combined with pH-responsive linkers as a way to specifically deliver chemotherapeutic drugs to prostate cancer tumors with minimal toxicity.
Topics: Male; Animals; Humans; Mice; Cell Line, Tumor; Glutamate Carboxypeptidase II; Antigens, Surface; Prostatic Neoplasms; Antineoplastic Agents; Albumins
PubMed: 35999662
DOI: 10.1158/1535-7163.MCT-22-0160 -
Nuclear Medicine and Biology 2022Prostate specific membrane antigen (PSMA) is an attractive target for molecular imaging of prostate cancer and several other solid tumors because of its overexpression... (Review)
Review
Prostate specific membrane antigen (PSMA) is an attractive target for molecular imaging of prostate cancer and several other solid tumors because of its overexpression in prostate carcinoma and tumor neovasculature, respectively. While currently most commonly used PSMA PET radioligands are Ga-labeled compounds, the short half-life and relatively low available radioactivity of gallium-68 have led to a steep increase in the development of F-labeled PSMA ligands. Several F-PSMA tracers such as [F]DCFPyL and [F]PSMA-1007 are already established in clinical practice, but there are still several drawbacks to be considered. Radiofluorination is often a multistep and time-consuming process requiring harsh labeling conditions. The limited sensitivity in the lower PSA ranges raises the need for improving the binding affinity of the ligands. Due to the metallic character of therapeutic radionuclides, there is very limited experience with F-PSMA tracers that can be applied for a theranostic approach. However, developments in the past few years have brought forward several improvements in these fields. These include the application of new radiosynthesis pathways for radiofluorination that reduces the process complexity, new approaches for the design of the pharmacophore, improving target interaction and the introduction of radiohybrid ligands, allowing labeling of the ligand with both diagnostic and therapeutic radionuclides. In this review, we will give an overview of these recent advancements of F-labeled PSMA PET radioligands.
Topics: Antigens, Surface; Gallium Radioisotopes; Glutamate Carboxypeptidase II; Humans; Ligands; Male; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 34998217
DOI: 10.1016/j.nucmedbio.2021.12.005 -
Genes Sep 2021Avian coccidiosis is a disease caused by members of the genus . Huge economic losses incurred by the global poultry industry due to coccidiosis have increased the need...
Avian coccidiosis is a disease caused by members of the genus . Huge economic losses incurred by the global poultry industry due to coccidiosis have increased the need for cost-effective and easily available recombinant vaccines. Microneme protein 2 (MIC2) and surface antigen 1 (SAG1) of have been recognised as potential vaccine candidates. However, the genetic diversity of the antigens in field isolates, which affects vaccine efficacy, has yet to be largely investigated. Here, we analysed genetic diversity and natural selection of and in Korean isolates. Both genes exhibited low levels of genetic diversity in Korean isolates. However, the two genes showed different patterns of nucleotide diversity and amino acid polymorphism involving the isolates obtained from different countries including China and India. These results underscore the need to investigate the genetic diversity of the vaccine candidate antigens and warrant monitoring of genetic heterogeneity and evolutionary aspects of the genes in larger numbers of field isolates from different geographical areas to design effective coccidial vaccines.
Topics: Animals; Antigens, Protozoan; Antigens, Surface; Chickens; Coccidiosis; Eimeria tenella; Female; Genetic Variation; Microneme; Poultry Diseases; Protozoan Proteins; Selection, Genetic
PubMed: 34573400
DOI: 10.3390/genes12091418 -
Clinical and Experimental Immunology May 2021Peptides that bind to and are presented on the cell surface by human leucocyte antigen (HLA) molecules play a critical role in adaptive immunity. For a long time it was... (Review)
Review
Peptides that bind to and are presented on the cell surface by human leucocyte antigen (HLA) molecules play a critical role in adaptive immunity. For a long time it was believed that all the HLA-bound peptides were generated through simple proteolysis of linear sequences of cellular proteins, and therefore are templated in the genome and proteome. However, evidence for untemplated peptide ligands of HLA molecules has accumulated during the last two decades, with a recent global analysis of HLA-bound peptides suggesting that a considerable proportion of HLA-bound peptides are potentially generated through splicing/fusion of discontinuous peptide segments from one or two distinct proteins. In this review, we will evaluate recent discoveries and debates on the contribution of spliced peptides to the HLA class I immunopeptidome, consider biochemical rules for splicing and the potential role of these spliced peptides in immune recognition.
Topics: HLA Antigens; Histocompatibility Antigens Class I; Humans; Peptides; Proteolysis
PubMed: 33644851
DOI: 10.1111/cei.13589 -
The Journal of Allergy and Clinical... Jan 2023Mast cells (MC) and basophils are effector cells of allergic reactions and display a number of activation-linked cell surface antigens. Of these antigens, however, only...
BACKGROUND
Mast cells (MC) and basophils are effector cells of allergic reactions and display a number of activation-linked cell surface antigens. Of these antigens, however, only a few are functionally relevant and specifically expressed in these cells.
OBJECTIVE
We sought to identify MC- and basophil-specific surface molecules and to study their cellular distribution and regulation during cytokine-induced and IgE-dependent activation.
METHODS
Multicolor flow cytometry was performed to recognize surface antigens and to determine changes in antigen expression upon activation.
RESULTS
We identified Siglec-6 (CD327) as a differentially regulated surface antigen on human MC and basophils. In the bone marrow, Siglec-6 was expressed abundantly on MC in patients with mastocytosis and in reactive states, but it was not detected on other myeloid cells, with the exception of basophils and monocytes. In healthy individuals, allergic patients, and patients with chronic myeloid leukemia (CML), Siglec-6 was identified on CD203c blood basophils, a subset of CD19 B lymphocytes, and few CD14 monocytes, but not on other blood leukocytes. CML basophils expressed higher levels of Siglec-6 than normal basophils. IL-3 promoted Siglec-6 expression on normal and CML basophils, and stem cell factor increased the expression of Siglec-6 on tissue MC. Unexpectedly, IgE-dependent activation resulted in downregulation of Siglec-6 in IL-3-primed basophils, whereas in MC, IgE-dependent activation augmented stem cell factor-induced upregulation of Siglec-6.
CONCLUSIONS
Siglec-6 is a dynamically regulated marker of MC and basophils. Activated MC and basophils exhibit unique Siglec-6 responses, including cytokine-dependent upregulation and unique, cell-specific, responses to IgE-receptor cross-linking.
Topics: Humans; Antigens, CD; Basophils; Chronic Disease; Immunoglobulin E; Interleukin-3; Mast Cells; Sialic Acid Binding Immunoglobulin-like Lectins; Stem Cell Factor
PubMed: 35953001
DOI: 10.1016/j.jaci.2022.07.018