المؤلفون: Yohannes, Dawit A, Kaukinen, Katri, Kurppa, Kalle, Saavalainen, Päivi, Greco, Dario

مصطلحات موضوعية: TCR differential abudance analysis, Celiac disease associated TCR clonotypes, Immune repertoire analysis, TCR repertoire analysis, Immuno-informatics, Antigen-specific TCR identification, Computational antigen-specificity identification, TCR clustering

الوصف: Background Deep immune receptor sequencing, RepSeq, provides unprecedented opportunities for identifying and studying condition-associated T-cell clonotypes, represented by T-cell receptor (TCR) CDR3 sequences. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has mostly been limited to either “public” CDR3 sequences or to comparisons of CDR3 frequencies observed in a single individual. A methodology for the identification of condition-associated TCR CDR3s by direct population level comparison of RepSeq samples is currently lacking. Results We present a method for direct population level comparison of RepSeq samples using immune repertoire sub-units (or sub-repertoires) that are shared across individuals. The method first performs unsupervised clustering of CDR3s within each sample. It then finds matching clusters across samples, called immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. It finally ranks CDR3s in differentially abundant sub-repertoires for relevance to the condition. We applied the method on total TCR CDR3β RepSeq datasets of celiac disease patients, as well as on public datasets of yellow fever vaccination. The method successfully identified celiac disease associated CDR3β sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3β sequences with previously known CDR3βs specific to gluten in celiac disease. It also successfully recovered significantly high numbers of previously known CDR3β sequences relevant to each condition than would be expected by chance. Conclusion We conclude that immune sub-repertoires of similar immuno-genomic features shared across unrelated individuals can serve as viable units of immune repertoire comparison, serving as proxy for identification of condition-associated CDR3s.

وصف الملف: application/pdf

العلاقة: BMC Bioinformatics. 2021 Mar 25;22(1):159; http://hdl.handle.net/10138/328648Test

الإتاحة: http://hdl.handle.net/10138/328648Test

المؤلفون: Landoni, E., Fuca, G., Wang, J., Chirasani, V.R., Yao, Z., Dukhovlinova, E., Ferrone, S., Savoldo, B., Hong, L.K., Shou, P., Musio, S., Padelli, F., Finocchiaro, G., Droste, M., Kuhlman, B., Shamshiev, A., Pellegatta, S., Dokholyan, N.V., Dotti, G.

المصدر: Cancer Immunology Research, 9(4)

مصطلحات موضوعية: animal tissue, male, computer model, malignant neoplasm, human cell, amino acid substitution, animal experiment, glioblastoma, female, normal human, human, melanoma, controlled study, signal transduction, antigen specificity, nonhuman, mouse, antineoplastic activity, animal model, chimeric antigen receptor T-cell immunotherapy, data analysis software

الوصف: Chimeric antigen receptor (CAR) tonic signaling, defined as spontaneous activation and release of proinflammatory cytokines by CAR-T cells, is considered a negative attribute because it leads to impaired antitumor effects. Here, we report that CAR tonic signaling is caused by the intrinsic instability of the mAb single-chain variable fragment (scFv) to promote self-aggregation and signaling via the CD3z chain incorporated into the CAR construct. This phenomenon was detected in a CAR encoding either CD28 or 4-1BB costimulatory endodomains. Instability of the scFv was caused by specific amino acids within the framework regions (FWR) that can be identified by computational modeling. Substitutions of the amino acids causing instability, or humanization of the FWRs, corrected tonic signaling of the CAR, without modifying antigen specificity, and enhanced the antitumor effects of CAR-T cells. Overall, we demonstrated that tonic signaling of CAR-T cells is determined by the molecular instability of the scFv and that computational analyses of the scFv can be implemented to correct the scFv instability in CAR-T cells with either CD28 or 4-1BB costimulation.

العلاقة: https://doi.org/10.17615/6jyd-af65Test; https://cdr.lib.unc.edu/downloads/pk02cm48x?file=thumbnailTest; https://cdr.lib.unc.edu/downloads/pk02cm48xTest

الإتاحة: https://doi.org/10.17615/6jyd-af65Test
https://cdr.lib.unc.edu/downloads/pk02cm48x?file=thumbnailTest
https://cdr.lib.unc.edu/downloads/pk02cm48xTest

المؤلفون: Emily C. Cox, Joshua A. Walker, Christopher A. Alabi, Matthew P. DeLisa, Jacqueline B Plesset, Dana N. Thornlow, Michelle R. Sorkin

المصدر: Bioconjugate Chemistry. 30:1702-1710

مصطلحات موضوعية: Models, Molecular, Immunoconjugates, medicine.medical_treatment, Biomedical Engineering, Pharmaceutical Science, Antigen specificity, Bioengineering, 02 engineering and technology, Pharmacology, 01 natural sciences, Dual site, Targeted therapy, Antineoplastic Agents, Immunological, Cell Line, Tumor, medicine, Humans, Potency, Peptide Synthases, biology, 010405 organic chemistry, Chemistry, Organic Chemistry, Trastuzumab, 021001 nanoscience & nanotechnology, biology.organism_classification, 0104 chemical sciences, Drug Liberation, Specific antibody, biology.protein, Antibody, Peptides, 0210 nano-technology, Bacteria, Biotechnology, Conjugate

الوصف: Antibody-drug conjugates utilize the antigen specificity of antibodies and the potency of chemotherapeutic and antibiotic drugs for targeted therapy. However, as cancers and bacteria evolve to resist the action of drugs, innovative controlled release methods must be engineered to deliver multidrug cocktails. In this work, we engineer lipoate-acid ligase A (LplA) acceptor peptide (LAP) tags into the constant heavy and light chain of a humanized Her2 targeted antibody, trastuzumab. These engineered LAP tags, along with the glutamine 295 (Q295) residue in the heavy chain, were used to generate orthogonally cleavable site-specific antibody conjugates via a one-pot chemoenzymatic ligation with microbial transglutaminase (mTG) and LplA. We demonstrate orthogonal cargo release from these dual-labeled antibody bioconjugates via matrix metalloproteinase-2 and cathepsin-B-mediated bond cleavage. To the best of our knowledge, this is the first demonstration of temporal control on dual-labeled antibody conjugates, and we believe this platform will allow for sequential release and cooperative drug combinations on a single antibody bioconjugate.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::85a2705595ac426da997127e688678a5Test
https://doi.org/10.1021/acs.bioconjchem.9b00244Test

المؤلفون: T Al-Aubodah, Ciriaco A. Piccirillo, M Attias

المصدر: Clinical and Experimental Immunology

مصطلحات موضوعية: 0301 basic medicine, Review Article, medicine.disease_cause, T-Lymphocytes, Regulatory, regulatory T cells, Epigenesis, Genetic, Autoimmunity, Arthritis, Rheumatoid, Translational Research, Biomedical, Cell therapy, 0302 clinical medicine, Neoplasms, Immunology and Allergy, IL-2 receptor, Review Articles, education.field_of_study, Effector, Peripheral tolerance, FOXP3, Cell Differentiation, Forkhead Transcription Factors, Genetic Diseases, X-Linked, hemic and immune systems, Review Series: Regulatory T Cells, Immune System Diseases, Immunotherapy, Signal Transduction, Diarrhea, Immunology, Population, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, Biology, 03 medical and health sciences, Series Editor: Ciriaco A. Piccirillo, medicine, Humans, Cell Lineage, education, Transcription factor, Inflammation, human immunology, Peripheral Tolerance, Models, Immunological, regulatory T cell dysfunction, Diabetes Mellitus, Type 1, 030104 developmental biology, antigen specificity, cell therapy, 030215 immunology

الوصف: Summary Regulatory T (Treg) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage-defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non-suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers such as CD25 and FoxP3. Moreover, murine Treg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff) cells. However, this plasticity can also result in Treg cell lineage instability and acquisition of proinflammatory Teff cell functions. Consequently, these dysfunctional CD4+FoxP3+ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to Treg cell antigen-specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3+ Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ef58b6a8da846345f02202977e048e82Test
https://doi.org/10.1111/cei.13290Test

المؤلفون: Grant L.J. Keller, Jesus A. Alonso, Timothy P. Riley, Kendra C. Foley, Nishant K. Singh, Brian M. Baker, Lance M. Hellman, Craig W. Vander Kooi, Cory M. Ayres, Michael I. Nishimura, Jason R. Devlin, Yuting Zhang

المصدر: Molecular Therapy. 27:300-313

مصطلحات موضوعية: medicine.drug_class, Receptors, Antigen, T-Cell, Antigen specificity, T-Cell Antigen Receptor Specificity, chemical and pharmacologic phenomena, Computational biology, Adaptive Immunity, Biology, Monoclonal antibody, Protein Structure, Secondary, Epitope, 03 medical and health sciences, MART-1 Antigen, 0302 clinical medicine, Drug Discovery, Genetics, medicine, Humans, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, T-cell receptor, Antibodies, Monoclonal, hemic and immune systems, Surface Plasmon Resonance, Acquired immune system, Immune toxicity, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, Original Article, Antibody, Function (biology)

الوصف: T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a7a37434c6ee2c7a776772482ea1ddfTest
https://doi.org/10.1016/j.ymthe.2018.12.010Test

المؤلفون: Shoichi Iriguchi, Shin Kaneko

المصدر: Cancer Science

مصطلحات موضوعية: Pluripotent Stem Cells, 0301 basic medicine, Cancer Research, T-Lymphocytes, T cell, Induced Pluripotent Stem Cells, Adoptive immunotherapy, Cell, T cell differentiation, Review Article, Biology, iPS cell, Immunotherapy, Adoptive, T cell rejuvenation, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Humans, Transplantation, Homologous, Off the shelf, Induced pluripotent stem cell, Review Articles, Cell Engineering, T cell immunotherapy, Cell Differentiation, General Medicine, Chimeric antigen receptor, Cell biology, regenerative immunotherapy, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, antigen specificity

الوصف: Recent outstanding clinical results produced by engineered T cells, including chimeric antigen receptors, have already facilitated further research that broadens their applicability. One such direction is to explore new T cell sources for allogeneic “off‐the‐shelf” adoptive immunotherapy. Human pluripotent stem cells could serve as an alternative cell source for this purpose due to their unique features of infinite propagation ability and pluripotency. Here, we describe the current state of engineered T cell transfer with the focus on cell manufacturing processes and the potentials and challenges of induced pluripotent stem cell‐derived T cells as a starting material to construct off‐the‐shelf T‐cell banks.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::89db052c13f5fe122d9017f85b6c1329Test
https://doi.org/10.1111/cas.13892Test

المؤلفون: Herrera, Daniel, Rojas, Olga L., Duarte-Rey, Carolina, Mantilla, Rubén D., Ángel, Juana, Franco, Manuel A.

المصدر: instname:Universidad del Rosario

مصطلحات موضوعية: Rotavirus, Linfocitos B, Rituximab, Tetanus Toxoid, Rheumatoid Factor, Methylprednisolone, Middle Aged, Monoclonal Antibody, Specificity, Species, Lymphocyte Depletion, Immunologic Memory, Immunoglobulin M, B-Lymphocytes, B-Lymphocyte Subsets, Autoantigens, Antibodies, Aged, Species Difference, Procedures, Drug Effects, Systemic Lupus Erythematosus, Rheumatoid Arthritis, Nephelometry, Erythematosus Nephritis, Kinetic Nephelometry, Lupus, Cd27 Antigen, Double Stranded Dna Antibody, Antigen Specificity

الوصف: The mechanisms that contribute to the maintenance of serological memory are still unclear. Rotavirus (RV) memory B cells (mBc) are enriched in IgM + and CD27- subpopulations, which are associated with autoimmune diseases pathogenesis. In patients with autoimmune diseases treated with Rituximab (RTX), some autoantibodies (auto-Abs) decrease after treatment, but other auto-Abs and pathogen-specific IgG Abs remain unchanged. Thus, maintenance of autoimmune and pathogenspecific serological memory may depend on the type of antigen and/or Ab isotype evaluated. Antigen-specific mBc and antigen-specific Abs of different isotypes have not been simultaneously assessed in patients after RTX treatment. To study the relationship between mBc subpopulations and serological memory we characterized total, RV- and tetanus toxoid (TT)-specific mBc by flow cytometry in patients with autoimmune diseases before and after treatment with RTX. We also measured total, RV- and TT-Abs, and some auto-Abs by kinetic nephelometry, ELISA, and EliA tests, respectively. Minor differences were observed between the relative frequencies of RV-mBc in healthy controls and patients with autoimmune disease. After RTX treatment, naïve Bc and total, RV- and TT-specific mBc [IgM+, switched (IgA+/IgG+), IgM+ only, IgD+ only, and CD27- (IgA+/IgG+/IgM+)] were significantly diminished. An important decrease in total plasma IgM and minor decreases in total IgG and IgA levels were also observed. IgM rheumatoid factor, IgG anti-CCP, and IgG anti-dsDNA were significantly diminished. In contrast, RV-IgA, RV-IgG and RV-IgG1, and TT-IgG titers remained stable. In conclusion, in patients with autoimmunity, serological memory against RV and TT seem to be maintained by long-lived plasma cells, unaffected by RTX, and an important proportion of total IgM and serological memory against some auto-antigens seem to be maintained by short-lived plasma cells, dependent on mBc precursors depleted by RTX. © 2014 Herrera et al.

وصف الملف: application/pdf

العلاقة: http://repository.urosario.edu.co/handle/10336/18703Test; https://doi.org/10.1371/journal.pone.0097087Test

الإتاحة: https://doi.org/10.1371/journal.pone.0097087Test
http://repository.urosario.edu.co/handle/10336/18703Test

المؤلفون: Torres-Morales, Elizabeth, Taborda, Laura, Cardona, Nestor, de-la-Torre, Alejandra, Sepulveda-Arias, Juan Carlos, Gomez-Marin, Jorge Enrique, Patarroyo, Manuel A.

المصدر: instname:Universidad del Rosario

مصطلحات موضوعية: CD3 antigen, CD4 antigen, CD8 antigen, Gamma interferon, Interleukin 10, Protein p30, ROP18 protein, Tumor necrosis factor alpha, Unclassified drug, Virulence factor, Cytokine, Leukocyte antigen, Parasite antigen, Protein serine threonine kinase, Protozoal protein, Adult, Antigen specificity, Article, Asymptomatic disease, Carboxy terminal sequence, CD4+ T lymphocyte, CD8+ T lymphocyte, Child, Clinical article, Controlled study, Cytokine production, Ex vivo study, Female, Human, Human cell

الوصف: We determined the specific lymphocyte proliferative response and cytokine profile production regarding Toxoplasma P30 (2017 from virulent and non-virulent strain) and ROP18 protein-derived peptides (from clonal lineages I, II and III) in 19 patients having ocular toxoplasmosis, five suffering chronic asymptomatic infection, nine with congenital toxoplasmosis and eight Toxoplasma negative people. A Beckman Coulter FC500 flow cytometer was used for determining antigen-specific T cells (CD3+ CD4+ or CD3+ CD8+ cells) in peripheral blood culture. IFN ? and IL10 levels were determined in culture supernatants. Specific CD4+ and CD8+ T cell response to total antigen and P30- and ROP18-derived peptides was observed in infected people. Ocular toxoplasmosis patients had a preferential Th2 response after antigenic stimulation. Non-virulent peptide 2017 was able to shift response toward Th1 in congenitally infected children and virulent peptide 2017 induced a Th2 response in chronically infected, asymptomatic people. An immune response in human toxoplasmosis after ex vivo antigenic stimulation was Th1- or Th2-skewed, depending on a patient’s clinical condition. Colombian ocular toxoplasmosis patients’ immune response was Th2-skewed, regardless of the nature of antigen stimulus. © 2014, Springer-Verlag Berlin Heidelberg.

وصف الملف: application/pdf

العلاقة: https://repository.urosario.edu.co/handle/10336/22571Test; https://doi.org/10.1007/s00430-014-0339-0Test

الإتاحة: https://doi.org/10.1007/s00430-014-0339-0Test
https://repository.urosario.edu.co/handle/10336/22571Test

المؤلفون: Dennis Wolf, Seble Kassaye, Klaus Ley, Howard D. Strickler, Kevin Tse, Melanie Vassallo, Marc K. Jenkins, Thamotharampillai Dileepan, Stephen J. Gange, William W. Kwok, Alan L. Landay, Christian Ryden, Kouji Kobiyama, Marco Orecchioni, Roksana Karim, Robert C. Kaplan, John Sidney, Phyllis C. Tien, Jacqueline Miller, Takayuki Kimura, Holger Winkels, Eddie A. James, Alessandro Sette, David B. Hanna, Helen G. Durkin

المصدر: Circulation. 138:1130-1143

مصطلحات موضوعية: 0301 basic medicine, chemistry.chemical_classification, Major Histocompatibility Complex Class II, Apolipoprotein B, biology, business.industry, Antigen specificity, Peptide, 030204 cardiovascular system & hematology, Virology, Epitope, Vaccination, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, chemistry, Immunization, Physiology (medical), biology.protein, Low density, Medicine, Cardiology and Cardiovascular Medicine, business

الوصف: Background: CD4 + T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules. Methods: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E–deficient ( Apoe −/− ) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined. Results: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4 + T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3 + regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe −/− mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4 + T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-A b -p18 tetramer identified the expansion of p18-specific CD4 + T cells on vaccination, which were enriched for interleukin-10–producing Tregs. Conclusions: These findings show that APOB p18–specific CD4 + T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::3677a4f45f7d205f5d597acd5b4a2f39Test
https://doi.org/10.1161/circulationaha.117.031420Test

المؤلفون: Kyla S. Ost, June L. Round

المصدر: Annu Rev Microbiol

مصطلحات موضوعية: Mammals, 0301 basic medicine, Host immunity, Microbiota, Antigen specificity, Context (language use), Computational biology, Adaptive Immunity, Biology, Acquired immune system, Pathogenicity, Microbiology, Immunity, Innate, Article, 03 medical and health sciences, 030104 developmental biology, Immune system, Immunity, Host-Pathogen Interactions, Animals, Humans

الوصف: Mammalian immune systems evolved within a diverse world dominated by microbes, making interactions between these two life-forms inevitable. Adaptive immunity protects against microbes through antigen-specific responses. In classical studies, these responses were investigated in the context of pathogenicity; however, we now know that they have significant effects on our resident microbes. In turn, microbes employ an arsenal of mechanisms to influence development and specificity of host immunity. Understanding these complex reactions will be necessary to develop microbiota-based strategies to prevent or treat disease. Here we review the literature detailing the cross talk between resident microbes with a focus on the specificity of host responses and the microbial molecules that influence them.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1e8eefd63320f53fa75d50d71acb4c08Test
https://doi.org/10.1146/annurev-micro-090817-062307Test