Immunodeficiency and Generation of the Human T Cell Receptor Repertoire PDF Download
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Author: Christopher Pickard
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages :
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Author: Christopher Pickard
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages :
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Author: Tak W. Mak
Publisher: Springer Science & Business Media
ISBN: 1468454064
Category : Medical
Languages : en
Pages : 243
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The importance of thymus-dependent cells, or T cells, in the generation of a successful immune response was first realized in the early sixties. In the follow ing two decades, a succession of elegant experiments established the antigen specificity of T cells and their ability to perform both as regulatory and effector cells. T cells were shown to be essential in most immune reactions, playing a crucial role in augmenting the activity of effector T and B cells against 'foreign' antigen, as well as in the suppression of effector activity against self antigens. The means by which T cells differentiate 'foreign' from 'self' antigens is based on their recognition of antigen almost exclusively in the context of self major histocompatibility complex products, unlike B cells, which recognize an tigen alone. It is this recognition, mediated by the T-cell receptor, that sets into motion the diverse cell-cell interactions, which control the differentiation and regulation of the immune response. Although its importance was well established, the molecular nature of the T-cell receptor remained elusive for two decades. Many hypotheses as to its structure and precise function were put forward, using immunoglobulin as a basis for conjecture, but "the Holy Grail of Immunology" remained ephemeral until three years ago. In the ensuing years, both immunologists and molecular biologists have contributed to an explosion of data unsurpassed by any previous period in the field.
Author: David H. Aggen
Publisher:
ISBN:
Category :
Languages : en
Pages :
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The alpha-beta T cell receptor (TCR) is responsible for mediating T cell recognition of self and non-self tissues, through recognition between a complex of a peptide and a product of the major histocompatibility complex (pepMHC) on target cells. In the immune response to cancerous tissue, the immune repertoire of T cells is often insufficient to target pepMHC complexes associated with cancer cells, as these tumor antigens have often induced tolerance or the tumor microenvironment promotes immunosuppression of T cells. To improve the response to tumors, gene therapy with tumor specific T cell receptors provides an attractive approach to effectively arm patient0́9s T cells for cancer cell destruction. An inherent difficulty, however, is generation of T cell receptors of sufficient affinity to redirect both CD4+ and CD8+ T cells. This thesis describes the development of engineering strategies for human single-chain T cell receptor variable fragments (scTv), with the goal of understanding the properties that allow scTv to be expressed and deployed in a therapeutic mode. Stable scTv receptors can be used to generate high-affinity TCRs specific for disease-associated pepMHC complexes and produced in soluble expression systems for subsequent biochemical and biophysical characterization. This work also develops scTv and scFv (antibody variable fragments) as fusion proteins, collectively called chimeric antigen receptors, for cell mediated therapies to redirect T cells to specific antigens In chapter 2, two human Valpha2+ T cell receptors specific for human immunodeficiency virus and human T cell lymphotrophic virus derived pepMHC complexes were engineered for improved stability as scTv proteins, consisting of only the variable domains of the T cell receptor attached by a flexible linker. High-affinity, stabilized scTv proteins could be expressed as soluble proteins in E. coli and used for detection of low levels of HIV pepMHC antigens, suggesting that these receptors have potential diagnostic applications for the detection of HIV infected cells. Finally, the results suggest that other V1̐Ł2+ TCRs with different specificities can be engineered for enhanced affinity by yeast display. Chapter 3 describes the development of chimeric antigen receptors, that consist of scTv-fusion proteins, for T cell targeting of tumor antigens. scTv proteins engineered for improved stability by yeast display were fused to the intracellular signaling domains of CD28,CD3zeta, and LCK and introduced into murine T cells. The high affinity scTv, called m33, that is specific for the pepMHC SIY/Kb was used to redirect T cells with similar antigen sensitivity to the full-length m33 TCR. An inherent problem with full-length TCR gene therapy is the generation of receptors of unknown specificity through mispairing between introduced and endogenous TCR, leading to graft versus host disease or autoimmunity. I show that the scTv-fusions avoided mispairing with endogenous alpha-beta TCRs and allowed for endogenous TCR surface expression at high levels. A human HIV-specific scTv (chapter 2) was also expressed as a fusion to intracellular signaling domains and it also mediated antigen specific T cell activity. In chapter 4, the murine m33 scTv fusion was compared to an antibody derived chimeric antigen receptor called 237. The 237 antibody single-chain fragment variable (scFv) is specific for a tumor antigen resulting from a glycopeptide defect that is created by a mutant chaperone protein. Fusion of the 237 scFv to intracellular domains, as with the m33 scTv, mediated T cell activity against tumor cells that expressed the glycopeptide defect. Results with T cells transduced with chimeric antigen receptor in the absence or presence of coreceptor CD8, showed that CD8 could contribute to target cell recognition, presumably through its interactions with MHC molecules that are proximal to the antigen epitope. Chapter 5 describes the engineering of a murine T cell receptor, called 3D, for enhanced affinity to the model Wilm0́9s tumor antigen (WT-1/Db). Using a novel T cell display system, mutated TCR libraries were displayed on the surface of T cell hybridomas in the absence of the coreceptor CD8. Selection with fluorescently labeled dimers of WT-1/Db resulted in the isolation of two high affinity 3D TCR variants, one which mediated T cell activity in the absence of CD8. Analysis of the TCR residues used by human and murine TCRs specific for the identical WT-1 peptide suggested that there is homology between human and mouse TCR CDR3 sequences, indicating that these residues have strong selective pressures to bind to the identical peptide epitope. Thus, one may be able to engineer high-affinity TCRs in the human TCR based on knowledge from the mouse TCRs.
Author: Bruce Alberts
Publisher:
ISBN: 9780815332183
Category : Cytology
Languages : en
Pages : 0
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Author: Kenneth Murphy
Publisher: Garland Science
ISBN: 9780815344575
Category : Medical
Languages : en
Pages :
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The Janeway's Immunobiology CD-ROM, Immunobiology Interactive, is included with each book, and can be purchased separately. It contains animations and videos with voiceover narration, as well as the figures from the text for presentation purposes.
Author: Mark M. Davis
Publisher:
ISBN:
Category : Medical
Languages : en
Pages : 488
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Book Description
Animal models of some autoimmune diseases have indicated restricted T-cell receptor use and have suggested therapies based on those data. Patients with naturally occurring diseases have not shown a consistent picture of receptor utilisation. This volume discusses the spectrum of T-cell receptor use in human disease, the relationship between the human and animal findings, and the biological and therapeutic implications of the former.
Author: Jayajit Das
Publisher: CRC Press
ISBN: 1498717411
Category : Science
Languages : en
Pages : 355
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"Taken together, the body of information contained in this book provides readers with a bird’s-eye view of different aspects of exciting work at the convergence of disciplines that will ultimately lead to a future where we understand how immunity is regulated, and how we can harness this knowledge toward practical ends that reduce human suffering. I commend the editors for putting this volume together." –Arup K. Chakraborty, Robert T. Haslam Professor of Chemical Engineering, and Professor of Physics, Chemistry, and Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA New experimental techniques in immunology have produced large and complex data sets that require quantitative modeling for analysis. This book provides a complete overview of computational immunology, from basic concepts to mathematical modeling at the single molecule, cellular, organism, and population levels. It showcases modern mechanistic models and their use in making predictions, designing experiments, and elucidating underlying biochemical processes. It begins with an introduction to data analysis, approximations, and assumptions used in model building. Core chapters address models and methods for studying immune responses, with fundamental concepts clearly defined. Readers from immunology, quantitative biology, and applied physics will benefit from the following: Fundamental principles of computational immunology and modern quantitative methods for studying immune response at the single molecule, cellular, organism, and population levels. An overview of basic concepts in modeling and data analysis. Coverage of topics where mechanistic modeling has contributed substantially to current understanding. Discussion of genetic diversity of the immune system, cell signaling in the immune system, immune response at the cell population scale, and ecology of host-pathogen interactions.
Author: Donjetë Simnica
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Author: Pedro A. de Alarcón
Publisher: Cambridge University Press
ISBN: 1108488986
Category : Medical
Languages : en
Pages : 501
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Book Description
An essential guide to the pathogenesis, diagnosis and management of hematologic problems in the neonate, covering erythrocyte disorders, leukocyte disorders, immunologic disorders and hemostatic disorders. Guidance is practical, including blood test interpretation, advice on transfusions and reference ranges for hematological values.
Author: Ann Arvin
Publisher: Cambridge University Press
ISBN: 1139461648
Category : Medical
Languages : en
Pages : 1325
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Book Description
This comprehensive account of the human herpesviruses provides an encyclopedic overview of their basic virology and clinical manifestations. This group of viruses includes human simplex type 1 and 2, Epstein–Barr virus, Kaposi's Sarcoma-associated herpesvirus, cytomegalovirus, HHV6A, 6B and 7, and varicella-zoster virus. The viral diseases and cancers they cause are significant and often recurrent. Their prevalence in the developed world accounts for a major burden of disease, and as a result there is a great deal of research into the pathophysiology of infection and immunobiology. Another important area covered within this volume concerns antiviral therapy and the development of vaccines. All these aspects are covered in depth, both scientifically and in terms of clinical guidelines for patient care. The text is illustrated generously throughout and is fully referenced to the latest research and developments.
