T Cell Costimulation In Anti Tumor Immunity And Autoimmunity
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| Author | : Kenneth F. May |
| Publisher | : |
| Total Pages | : |
| Release | : 2004 |
| Genre | : Autoimmunity |
| ISBN | : |
Abstract: Costimulatory molecules, including 4-1BB, CTLA-4, and B7, play a critical role in the activation, sustenance, and regulation of T cell immune responses. Manipulation of these pathways holds promise for the development of therapies for cancer and autoimmunity. Anti-4-1BB monoclonal antibody (mAb) has been demonstrated to boost anti-tumor immunity in animal models. Using a model of tumor-specific CD8 T cell adoptive immunotherapy, we demonstrate that anti-4-1BB mAb can mediate the rejection of large established tumors in the absence of CD4 T cell help. Anti-4-1BB mAb increases populations of tumor-specific CD8 T cells in peripheral blood by reduction of activation-induced cell death, but not increased T cell proliferation. The use of anti-CTLA-4 mAb has also been shown to enhance anti-tumor immunity. Here we employ two novel "humanized" mouse models to screen anti-human CTLA-4 mAb for translation to human cancer therapy. Using the hu-PBL-SCID model of Epstein-Barr virus (EBV)-associated lymphoproliferative disease, we show that anti-human CTLA-4 mAb promotes the in vivo expansion of human CD8 and CD4 T cells, and the generation of antigen specific CD8 T cell responses to EBV lymphoma. This correlates with reduced levels of the oncogenic EBV protein LMP-1, and increased survival in these mice. We also characterize the creation of a knock-in mouse model in which mouse T cells express the human CTLA-4 molecule. Preliminary testing in this mouse model supports the use of this model to screen anti-human CTLA-4 mAb for clinical use. Understanding the role of B7/CD28/CTLA-4 interaction in immune activation and tolerance in autoimmune disease is fundamental to successful intervention targeted at costimulatory molecules. We describe the spontaneous development of whole-body alopecia, lymphadenopathy, and skin disease in mice lacking B7 molecules. This disease is mediated by autoimmune CD4 T cells, which induce multi-organ inflammation when transferred to mice expressing B7 molecules. This disease may result from impaired development of CD4+CD25+ regulatory T cells (Treg) in B7-deficient mice. Since provision of Treg can abrogate the multi-organ inflammation despite lack of B7 molecules on the auto-pathogenic T cells, interaction between CTLA-4 on Treg and B7-1/2 on effector T cells is not essential for Treg function.
| Author | : Kenneth D. Lute |
| Publisher | : |
| Total Pages | : |
| Release | : 2006 |
| Genre | : Antigen-antibody reactions |
| ISBN | : |
Abstract: The results of numerous basic studies support the use of anti-CTLA-4 antibodies in human cancer therapy. To assist in the translation of this concept to the clinic it would be helpful to establish preclinical models to identify anti-human CTLA-4 antibodies that can induce anti-cancer immunity with acceptable autoimmune side effects. To that end we have produced a human CTLA-4 knock-in mouse in which murine CTLA-4 has been replaced with its human homolog. We used our knock-in mouse to screen a panel of anti-human CTLA-4 antibodies to determine whether our model was useful in discriminating the antibodies' therapeutic effects and autoimmune side-effects. Surprisingly, while all of the antibodies induced protection against cancer and demonstrated some autoimmune side effects, the antibody that induced the strongest protection also induced the least autoimmune side effects. These results suggest that anti-tumor immunity is not necessarily linked to autoimmunity, and that it may be possible to uncouple the two. Studies of neonatal tolerance have suggested that pre-existing antigens are tolerogenic to subsequently generated T cells. However whether the same is true in the adult host is not known. As the effect of tumor on developing T cells has not been tested, we analyzed the impact of resident tumor on the development of tumor-reactive T cells in the thymus and their immune competence in the periphery. Our results suggest that newly produced T cells with specificity for pre-existing tumor cells are activated rather than inactivated by tumor antigens in the host. The importance of B7:CD28 costimulation in Treg development is a widely accepted, yet poorly understood concept. As Treg have been shown to be produced in the periphery as well as intrathymically, it remains unclear as to whether costimulation plays a similar role and produces equivalent effects at each location. To further explore this matter we characterized the expansion of regulatory T cells within Treg-deficient mice following agonistic anti-CD28 antibody treatment. We show here, in the thymus costimulation promotes Treg expansion by licensing developing thymocytes, as Treg are generated de novo, in the absence of proliferation. In the periphery costimulation promotes Treg expansion primarily through enhanced proliferation.
| Author | : Priscilla Do |
| Publisher | : |
| Total Pages | : |
| Release | : 2017 |
| Genre | : Cancer |
| ISBN | : |
Immune suppression is a hallmark of cancer that has gained recent unprecedented attention following dramatic responses with new immune based therapies. Many therapeutic strategies are employed to reverse suppression and utilize our natural biological defense against cancerous cells. The beauty of which, is demonstrated as a non-chemotherapeutic method for durable clinical benefit and potentially, a cure. Attunement of anti-tumor immunity rests largely on provocation of adaptive immunity and the ability of T cells to remember non-self and self-dangerous signals. The naive to effector T cell transition, accomplished through stimulation of the T cell receptor and co-stimulation through CD28, is critical for the development of this response. Presented here are two strategies in a B cell malignancy, Chronic Lymphocytic Leukemia (CLL), aimed at attunement of this T cell co-stimulatory node by influencing surrounding biological players.
| Author | : Manzoor Ahmad Mir |
| Publisher | : Academic Press |
| Total Pages | : 320 |
| Release | : 2015-05-25 |
| Genre | : Medical |
| ISBN | : 0128026758 |
Developing Costimulatory Molecules for Immunotherapy of Diseases highlights the novel concept of reverse costimulation and how it can be effectively exploited to develop immunotherapy using either humanized antibodies against CD80, CD86, and other costimulatory molecules or CD28 fusinogenic proteins in the treatment of diseases, including allergies, asthma, rheumatoid arthritis, multiple sclerosis, lupus nephritis, severe psoriasis, vulgaris tuberculosis, thopoid, transplantation therapeutic, cancer, and inflammation. The text aims to provide the latest information on the complex roles and interactions within the CD28 and B7 costimulatory families, with the hope that targeting these families will yield new therapies for the treatment of inflammation, autoimmunity, transplantation, cancer, and other infectious diseases. Highlights the novel concept of reverse costimulation and how it can be effectively exploited to develop immunotherapy Provides the latest information on the complex roles and interactions within the CD28 and B7 costimulatory families Targets new therapies for the treatment of inflammation, autoimmunity, transplantation, cancer, and other infectious diseases
| Author | : Patrik Andersson |
| Publisher | : Frontiers Media SA |
| Total Pages | : 316 |
| Release | : 2019-12-27 |
| Genre | : |
| ISBN | : 2889631613 |
The immune system harbors great potential for controlling and eliminating tumors. Recent developments in the field of immuno-oncology has led to unprecedented clinical benefits for a broad spectrum of solid tumors. However, immunotherapy (IT) approaches currently have several limitations including (i) low response rate; (ii) development of resistance and (iii) causing severe immune-related adverse effects (IrAEs), which underline the importance of adequate patient selection. Importantly, IT holds promising synergistic potential when combined with standard-of-care chemotherapy, radiotherapy (RT) and anti-angiogenic therapy (AAT) as part of multi-modal oncologic treatment regimes. Published data suggest that there are potential synergy between RT and AAT, which ultimately could help potentiate the response to IT. However, the complex interactions between RT and IT and/or AAT remain poorly understood. Many research questions including optimal timing, scheduling and dosing, as well as patient selection and side effects of combined therapy approaches, remain to be addressed. This Research Topic aims to give a comprehensive overview of the current field with particular emphasis on the future outlook of RT and AAT as complementary approaches to improve IT in solid tumors.
| Author | : James H. Finke |
| Publisher | : Springer Science & Business Media |
| Total Pages | : 392 |
| Release | : 2003-11-24 |
| Genre | : Medical |
| ISBN | : 1592597432 |
Leading investigators and clinicians detail the different mechanisms used by tumors to escape and impair the immune system and then spell out possible clinical strategies to prevent or reverse tumor-induced immune dysfunction. The authors review the mechanisms of immune dysfunction and evasion mechanisms in histologically diverse human tumors, focusing on tumor-induced molecular defects in T cells and antigen-presenting cells (dendritic cells and tumors), that may serve as biomarkers for patient prognosis. They discuss the means by which these immune functions may be protected or restored in order to more effectively support the process of tumor rejection in situ. Cutting-edge techniques are outlined with the capacity to monitor the strength and quality of patients' immune responses using immunocytometry, MHC-peptide tetramers combined with apoptosis assay, ELISPOT assay, and detection of MHC-TAA peptide complexes on tumor cells.
| Author | : Jianxun Song |
| Publisher | : Bentham Science Publishers |
| Total Pages | : 283 |
| Release | : 2015-04-16 |
| Genre | : Medical |
| ISBN | : 1681080486 |
Clinicians, patients and scientists, alike, have been battling cancer for over several decades; however, patient outcomes have not significantly improved over the years with conventional therapies. In recent years, this has caused researchers to look for a change in the status quo, and, the awareness of the human immune system, which has an intrinsic mechanism to control microbial pathogens and dysfunctional self-tissues, has triggered scientists to look for new modes of cancer therapy. Cancer Immunotherapy has become a major research field as a result of these efforts, gaining some recognition for notable breakthroughs in cancer patient prognosis. Frontiers in Cancer Immunology collectively presents the methods which have been studied and used in cancer immunotherapy based on the different components of human immune system. The series will give clinicians and immunologists a roadmap of current trends in all branches of cancer immunology. This volume lists the major immune system components (such as T cells and NK cells and associated antigens/antibodies) which have been demonstrated to limit the growth of or kill tumor cells. Relevant applications in cancer therapy are also included in addition to a general introduction to engineered as well as targeted cancer immunotherapies (cancer vaccines).
| Author | : Kenneth Murphy |
| Publisher | : Garland Science |
| Total Pages | : |
| Release | : 2010-06-22 |
| Genre | : Medical |
| ISBN | : 9780815344575 |
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 | : Manzoor Ahmad Mir |
| Publisher | : |
| Total Pages | : 215 |
| Release | : 2013 |
| Genre | : Medical |
| ISBN | : 9781629482132 |
Cancer is one of the most prominent causes of mortality in children and adults causing about 9 million deaths annually, is a major health problem worldwide. The transformation of normal cells to cancer cells may arise due to dysregulation of oncogenes, tumor suppressors and/or stability genes. These transformed cells are sensed by the cells of the immune system, especially T cells, through specific receptors for an effective immune response. But unfortunately even after the interaction with T cells, an effective immune response is not generated. Considering the importance of costimulation in the regulation of immune responses against relapsed cancer, the manipulation of this pathway to increase immunity, regress the growth, augment the expression of pro-apoptotic molecules and induce the apoptosis of lymphomas represents a potential therapeutic approach. This novel strategy of costimuilation activation/inhibition can be effectively exploited to develop immunotherapy either using humanized antibodies against CD80, CD86 and CD40 or CD28 fusogenic proteins for the treatment of intracellular pathogens like M. tuberculosis, HIV, L. donovani, T. cruzi, etc. This strategy can also be used as an alternative strategy or in combination with the drugs. Since this approach is based on modulating the immune system of the hosts rather than targeting the pathogen; hence it significantly diminishes chance of emergence of drug resistant strains of pathogens and if applied properly, may overcome the rising menace of infectious diseases. The potent role of costimulatory molecules is aptly established in the optimum activation of T cells and APCs; the cells that play a cardinal role in curbing the infections. Hence, immunotherapy involving costimulatory molecules can be a breakthrough strategy to treat various diseases, minimizing side effects inflicted by drug therapies and in restricting the emergence of drug resistance.
| Author | : Masaki Terabe |
| Publisher | : Springer Science & Business Media |
| Total Pages | : 212 |
| Release | : 2011-09-22 |
| Genre | : Medical |
| ISBN | : 1461406137 |
This book will cover primary roles of NKT cells in immunity to cancer, in both mouse tumor models and cancer patients. There are several chapters describing general aspects of NKT cells.
