scholarly journals Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance

2021 ◽  
Author(s):  
Mepur H. Ravindranath ◽  
Fatiha E.L. Hilali
Keyword(s):  
Amino Acid ◽  
Nk Cells ◽  
Major Histocompatibility Complex Gene ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Amino Acid Sequences ◽  
Leukocyte Antigens ◽  
Hla Class I Molecules ◽  
Specific Localization ◽  
High Degree

A monoclonal antibody (mAb) binds to an antigen recognizing an epitope (a sequence of amino acids). A protein antigen may carry amino acid sequence unique to that antigen as well as sequences found in other proteins. Human leukocyte antigens (HLA), a family of proteins expressed by the Major Histocompatibility Complex gene family represent a special case, in that it displays a high degree of polymorphism. Every HLA molecule possesses both specific (private) epitopes and epitopes shared (public) with other HLA class Ia and class Ib molecules. HLA-E is overexpressed in cancer cells more than any other HLA Class I molecules. Therefore specific localization of HLA-E with mAbs is pivotal for developing targeted therapy against cancer. However, the commercially available mAbs for immunodiagnosis are polyreactive. We have developed anti-HLA-E mAbs and distinguished monospecific from polyreactive mAbs using Luminex multiplex single antigen bead (SAB) assay. HLA-E-binding of monospecific-mAbs was also inhibited by E-restricted epitopes. The amino acid sequences in the region of the epitopes bind to CD94/NKG2A receptors on CD8+ T cells and NK cells and block their antitumor functions. Monospecific-HLA-E mAbs recognizing the epitopes sequences can interfere with the binding to restore the anti-tumor efficacy of NK cells. Also, monospecific-mAbs augment the proliferation of CD4-/CD+ cytotoxic T-lymphocytes. Therefore, anti-HLA-E monospecific-mAb can serve as a double-edged sword for eliminating tumor cells.

Does the interaction of KIR and HLA affect the development of non-infectious uveitis?

2021 ◽  
Vol 21 ◽  
Author(s):  
Jutaro Nakamura ◽  
Masaki Takeuchi ◽  
Masao Ota ◽  
Nobuhisa Mizuki ◽  
Shigeaki Ohno
Keyword(s):  
Nk Cells ◽  
Immune Tolerance ◽  
Immune Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Leukocyte Antigen ◽  
Hla Class I Molecules ◽  
Essential Components ◽  
Infectious Uveitis

: Immune tolerance is established in the eye to prevent permanent blindness associated with destructive damage to the cornea and retina caused by immune cell infiltration; hence, the immune responses and subsequent inflammations are strongly suppressed. While non-infectious uveitis develops from a disruption of immune tolerance in the eye, its onset is a result of accumulating etiologic factors, including genetic predisposition, environmental factors, and aging. Many non-infectious uveitis cases are genetically predisposed to human leukocyte antigen (HLA) as the most substantial disease susceptibility region. HLA class I molecules are critical for natural killer (NK) cells to distinguish between self and non-self. The killer cell Ig-like receptor (KIR) family is one of the essential components of these receptors. Evidence has accumulated that NK cells are involved in innate and acquired immunity by interacting with other immunocompetent cells to develop several autoimmune diseases. This review summarizes the possible role of KIR in the development of non-infectious uveitis.

scholarly journals The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

2021 ◽  
Vol 28 (2) ◽  
pp. 1077-1093
Author(s):  
Synat Kang ◽  
Xuefeng Gao ◽  
Li Zhang ◽  
Erna Yang ◽  
Yonghui Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Tumor Development ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Clinical Applications ◽  
Therapeutic Approaches ◽  
Leukocyte Antigens ◽  
Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

scholarly journals Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000410
Author(s):  
Jonathan S Cebon ◽  
Martin Gore ◽  
John F Thompson ◽  
Ian D Davis ◽  
Grant A McArthur ◽  
...  
Keyword(s):  
New York ◽  
High Risk ◽  
Phase Ii ◽  
Immune Escape ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Double Positive ◽  
Double Blind ◽  
Hla Class I Molecules

BackgroundTo compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.MethodsParticipants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.ResultsThe ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+and CD8+responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.ConclusionsThe vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.

scholarly journals Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update

2020 ◽  
Vol 21 (13) ◽  
pp. 4756
Author(s):  
Chiara Tersigni ◽  
Federica Meli ◽  
Caterina Neri ◽  
Azzurra Iacoangeli ◽  
Rita Franco ◽  
...  
Keyword(s):  
Immune System ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Immune Recognition ◽  
Protective Mechanisms ◽  
Maternal Immune System ◽  
Hla Class I Molecules ◽  
Classical Pattern ◽  
Hla Molecules

The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman’s immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal–fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies.

scholarly journals HATK: HLA analysis toolkit

2020 ◽  
Author(s):  
Wanson Choi ◽  
Yang Luo ◽  
Soumya Raychaudhuri ◽  
Buhm Han
Keyword(s):  
Amino Acid ◽  
Fine Mapping ◽  
Disease Susceptibility ◽  
Human Leukocyte ◽  
Amino Acid Sequences ◽  
Hla Typing ◽  
Amino Acid Residues ◽  
Leukocyte Antigen ◽  
Mapping Analysis ◽  
Visualization Tools

Abstract Summary Fine-mapping human leukocyte antigen (HLA) genes involved in disease susceptibility to individual alleles or amino acid residues has been challenging. Using information regarding HLA alleles obtained from HLA typing, HLA imputation or HLA inference, our software expands the alleles to amino acid sequences using the most recent IMGT/HLA database and prepares a dataset suitable for fine-mapping analysis. Our software also provides useful functionalities, such as various association tests, visualization tools and nomenclature conversion. Availability and implementation https://github.com/WansonChoi/HATK.

Carnivora: The Amino Acid Sequence of the Adult European Polecat (Mustela putorius, Mustelidae) Hemoglobins

1989 ◽  
Vol 44 (7) ◽  
pp. 817-824 ◽  
Author(s):  
Aftab Ahmed ◽  
Meeno Jahan ◽  
Gerhard Braunitzer ◽  
Helmut Pechlaner
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Gas Phase ◽  
Primary Structure ◽  
Amino Acid Sequences ◽  
Mustela Putorius ◽  
Globin Chains ◽  
The Family ◽  
High Degree ◽  
Β Chain

The complete amino acid sequences of the hemoglobins from the adult European polecat (Mustela putorius) are presented. The erythrocytes contain two hemoglobin components and three globin chains (α I, α II and β). The primary structure of globin chains and of the tryptic peptides determined in liquid- and gas-phase sequantors. Comparing the sequences of the globin chains of the polecat with that of human Hb-A, 17 (23.9%) substitutions were recognized in the α I, 16 (22.5%) in the α II and 14 (20.4%) in the β chain. A high degree of homology observed with other representatives of the family Mustelidae.

scholarly journals Human natural killer cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles.

1994 ◽  
Vol 180 (2) ◽  
pp. 545-555 ◽  
Author(s):  
A Moretta ◽  
M Vitale ◽  
S Sivori ◽  
C Bottino ◽  
L Morelli ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Hla Class I ◽  
Cytolytic Activity ◽  
Class I ◽  
Target Cells ◽  
Human Natural Killer Cell ◽  
Ligand Interaction ◽  
Hla Class I Molecules

GL183 or EB6 (p58) molecules have been shown to function as receptors for different HLA-C alleles and to deliver an inhibitory signal to natural killer (NK) cells, thus preventing lysis of target cells. In this study, we analyzed a subset of NK cells characterized by a p58-negative surface phenotype. We show that p58-negative clones, although specific for class I molecules do not recognize HLA-C alleles. In addition, by the use of appropriate target cells transfected with different HLA-class I alleles we identified HLA-B7 as the protective element recognized by a fraction of p58-negative clones. In an attempt to identify the receptor molecules expressed by HLA-B7-specific clones, monoclonal antibodies (mAbs) were selected after mice immunization with such clones. Two of these mAbs, termed XA-88 and XA-185, and their F(ab')2 fragments, were found to reconstitute lysis of B7+ target cells by B7-specific NK clones. Both mAbs were shown to be directed against the recently clustered Kp43 molecule (CD94). Thus, mAb-mediated masking of Kp43 molecules interferes with recognition of HLA-B7 and results in target cell lysis. Moreover, in a redirected killing assay, the cross-linking of Kp43 molecules mediated by the XA185 mAb strongly inhibited the cytolytic activity of HLA-B7-specific NK clones, thus mimicking the functional effect of B7 molecules. Taken together, these data strongly suggest that Kp43 molecules function as receptors for HLA-B7 and that this receptor/ligand interaction results in inhibition of the NK-mediated cytolytic activity. Indirect immunofluorescence and FACS analysis of a large number of random NK clones showed that Kp43 molecules (a) were brightly expressed on a subset of p58-negative clones, corresponding to those specific for HLA-B7; (b) displayed a medium/low fluorescence in the p58-negative clones that are not B7-specific as well as in most p58+ NK clones; and (c) were brightly expressed as in the p58+ clone ET34 (GL183-/EB6+, Cw4-specific). Functional analysis revealed that Kp43 functioned as an inhibitory receptor only in NK clones displaying bright fluorescence. These studies also indicate that some NK clones (e.g., the ET34) can coexpress two distinct receptors (p58 and Kp43) for different class I alleles (Cw4 and B7). Finally, we show that Kp43 molecules function as receptors only for some HLA-B alleles and that still undefined receptor(s) must exist for other HLA-B alleles including B27.

Is CD94/NKG2A a Novel Target for Lymphoid Malignancies Immunotherapy?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4650-4650
Author(s):  
Donata Urbaniak-Kujda ◽  
Jaroslaw Dybko ◽  
Iwona Prajs ◽  
Marek Kielbinski ◽  
Beata Tomaszewska-Toporska ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cd8 T Cells ◽  
Hla Class I ◽  
Treated Group ◽  
Target Cells ◽  
Healthy Controls ◽  
Nkg2d Ligands ◽  
Lymphoid Malignancies ◽  
Nkg2d Expression ◽  
Hla Class I Molecules

Abstract Background: Natural killer (NK)-cell receptors (NKRs) on CD8+ T cells can modulate antigen-specific T cell activity but their function and rules that govern their expression remain unclear. Among NKRs heterodimers CD94-NKG2 form either an inhibitory or an activating receptor, depending on whether CD94 associates with NKG2A or NKG2C, E or H, respectively. NKG2D is expressed on all naïve and activated CD8+ T cells. NKG2D ligands are distantly related to HLA class I molecules and up-regulated in virally infected cells, tumour cells or otherwise stressed cells. The expression of NKG2D ligands by target cells potently induces NK cells cytotoxicity. Although specific immunity mediated by cytolitic T-lymphocytes might have an anti-cancer role, tumours escape from T-cell-based immune surveillance using various mechanisms, such as downregulation, mutation, or loss of HLA class I molecules. Aims: In this study we tried to establish the expression significance of molecules stimulating (NKG2D) and inhibiting (CD94/NKG2A) NK cells cytotoxicity in lymphoid malignancies. Our aim was also to explore whether any influence of this expression on treatment response exists. It could be useful as remission predictive factor or a future target for therapeutic approaches. Patients: 23 patients (F/M -13/10, median age 57) with lymphoid malignancies (Non-Hodgkin Lymphoma (NHL), Myeloma multiplex (MM) and Hodgkin disease (HD) in 19, 3 and 1 case respectively) diagnosed in our unit in two recent years and 8 healthy volunteers were included. Eight patients were still untreated while involved into the study. In the previously treated group 4 of 15 patients achieved complete remission (CR), 5-partial remission (PR) and in 6 cases there were no response (NR) for chemotherapy. In all cases first line treatment was used. Methods: Mononuclear cells (MNC) were isolated from blood samples in Ficoll gradient. All used antibodies were conjugated: CD8 (DAKO Cytomation), CD94/NKG2A PE (Becton Dickinson) and NKG2D PE (Immunotech). MNC were stained for co-expression of CD8/NKG2D and CD8/CD94/NKG2A populations and then performed for flow cytometry. Results: We evaluated the diffreneces in CD94/NKG2A and NKG2D expression in blood deriving CD8+ population between lymphoid malignancies patients and healthy volunteers. There were no statistically significant difference in CD94/NKG2A and NKG2D expression between treated and untreated patients. CD94/NKG2A expression was significantly higher in the treated group than in healthy controls (p=0,01). In reverse, NKG2D expression was significantly higher in previously untreated group than in healthy controls (p=0,04). The only significant correlation we found was positive CD94/NKG2A and NKG2D correlation among the whole group of patients (r=0,57, p=0,004). Conclusions: As the expression of NKG2D ligands by target cells potently induces NK cells cytotoxicity and we have found NKG2D to be overexpressed in lymphoid malignancies comparing to healthy controls it may be just another proof for a natural anti tumour surveillance. On the other hand the opposite role of CD94/NKG2A heterodimer may be a premise for antiNKG2A immunotherapy of lymphoid malignancies to support the natural surveillance especially in the light of our results: CD94/NKG2A expression was significantly higher in the treated group than in healthy controls.

scholarly journals Associations between HLA Class I Alleles and Escape Mutations in the Hepatitis B Virus Core Gene in New Zealand-Resident Tongans

2009 ◽  
Vol 84 (1) ◽  
pp. 621-629 ◽  
Author(s):  
William G. H. Abbott ◽  
Peter Tsai ◽  
Euphemia Leung ◽  
Alex Trevarton ◽  
Malakai Ofanoa ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hepatitis B ◽  
Selection Pressure ◽  
Hla Class I ◽  
Core Gene ◽  
Class I ◽  
Positive Selection Pressure ◽  
Hla Class I Molecules ◽  
B Virus ◽  
Chronic Hbv

ABSTRACT The full repertoire of hepatitis B virus (HBV) peptides that bind to the common HLA class I molecules found in areas with a high prevalence of chronic HBV infection has not been determined. This information may be useful for designing immunotherapies for chronic hepatitis B. We identified amino acid residues under positive selection pressure in the HBV core gene by phylogenetic analysis of cloned DNA sequences obtained from HBV DNA extracted from the sera of Tongan subjects with inactive, HBeAg-negative chronic HBV infections. The repertoires of positively selected sites in groups of subjects who were homozygous for either HLA-B*4001 (n = 10) or HLA-B*5602 (n = 7) were compared. We identified 13 amino acid sites under positive selection pressure. A significant association between an HLA class I allele and the presence of nonsynonymous mutations was found at five of these sites. HLA-B*4001 was associated with mutations at E77 (P = 0.05) and E113 (P = 0.002), and HLA-B*5602 was associated with mutations at S21 (P = 0.02). In addition, amino acid mutations at V13 (P = 0.03) and E14 (P = 0.01) were more common in the seven subjects with an HLA-A*02 allele. In summary, we have developed an assay that can identify associations between HLA class I alleles and HBV core gene amino acids that mutate in response to selection pressure. This is consistent with published evidence that CD8+ T cells have a role in suppressing viral replication in inactive, HBeAg-negative chronic HBV infection. This assay may be useful for identifying the clinically significant HBV peptides that bind to common HLA class I molecules.

scholarly journals A Viral, Transporter Associated with Antigen Processing (TAP)-independent, High Affinity Ligand with Alternative Interactions Endogenously Presented by the Nonclassical Human Leukocyte Antigen E Class I Molecule

2012 ◽  
Vol 287 (42) ◽  
pp. 34895-34903 ◽  
Author(s):  
Elena Lorente ◽  
Susana Infantes ◽  
David Abia ◽  
Eilon Barnea ◽  
Ilan Beer ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Antigen Processing ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Structural Motif ◽  
Leukocyte Antigen ◽  
High Affinity ◽  
Hla Class I Molecules ◽  
Infected Cells

The transporter associated with antigen processing (TAP) enables the flow of viral peptides generated in the cytosol by the proteasome and other proteases to the endoplasmic reticulum, where they complex with nascent human leukocyte antigen (HLA) class I. Later, these peptide-HLA class I complexes can be recognized by CD8+ lymphocytes. Cancerous cells and infected cells in which TAP is blocked, as well as individuals with unusable TAP complexes, are able to present peptides on HLA class I by generating them through TAP-independent processing pathways. Here, we identify a physiologically processed HLA-E ligand derived from the D8L protein in TAP-deficient vaccinia virus-infected cells. This natural high affinity HLA-E class I ligand uses alternative interactions to the anchor motifs previously described to be presented on nonclassical HLA class I molecules. This octameric peptide was also presented on HLA-Cw1 with similar binding affinity on both classical and nonclassical class I molecules. In addition, this viral peptide inhibits HLA-E-mediated cytolysis by natural killer cells. Comparison between the amino acid sequences of the presenting HLA-E and HLA-Cw1 alleles revealed a shared structural motif in both HLA class molecules, which could be related to their observed similar cross-reactivity affinities. This motif consists of several residues located on the floor of the peptide-binding site. These data expand the role of HLA-E as an antigen-presenting molecule.

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