Tcr Affinity And Negative Regulation Limit Autoimmunity Microform

Cytotoxic T lymphocytes (CTLs) represent a subset of lymphocytes that are important for effective immune responses to a variety of pathogens including viruses. However, these cells have also been implicated in the development of various autoimmune diseases. This thesis investigates some of the factors that are important during the development of autoimmunity and immune responses. In one study presented here, the importance of high affinity interactions between TCR of naive, autoreactive T cells and peptide/MHC for the development of autoimmunity was evaluated. It was found that high affinity interactions are important for disease development, unless the T cell negative regulatory molecule Cbl-b was missing. The second study was different in that the importance of affinity of self-reactive T cells for peptide/MHC on the tissue was assessed. Surprisingly, high affinity interactions at the target recognition stage were crucial for T cell infiltration into the tissue and disease development. In the final study, the role of the E3 ubiquitin ligase Cbl-b in autoimmunity was evaluated. Using gene deficient animals and a transgenic model of diabetes, it was found that Cbl-b plays a variety of roles in the immune system. It is required to maintain immunological ignorance in vivo and its absence circumvents the need for APC maturation signals to break tolerance and induce autoimmunity. Furthermore, Cbl-b is important in limiting pathogen-induced immune responses. Together, these results contribute to the understanding of factors that regulate the development of autoimmunity.

The immune system has been known to be capable of distinguishing self from non-self since the pioneering work of Paul Erhlich more than a century ago. Originally described in experiments studying blood transfusion comp- ibility, the principle of “horror autotoxicus” is still valid, although today the phenomenon is usually described in terms of tolerance or ignorance. A great deal has been learned about the various processes preventing self-reactivity normally. These include processes that operate during immune cell ontogeny and subsequently on reactivity of mature lymphocytes in the periphery. They encompass mechanisms that are intrinsic to potentially reactive lymphocytes and can result in central or peripheral deletion or the alteration of functional potential. In addition, there are in?uences that are extrinsic to potentially auto-reactive lymphocytes, including the function of regulatory cells, d- ferentiation state of antigen-presenting cells, availability of self-antigen, the cytokine and chemokine milieu, as well as the traf?cking patterns involved in generating productive immune interactions. It is clear that the immune system devotes a considerable effort to the avoidance of the development of potentially pathogenic self-reactivity. Despite this, the development of self-reactivity is relatively common. - though the development of autoimmune disease is less frequent, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus e- thematosus, psoriasis, thyroiditis, and myasthenia gravis, are all too common, and can cause considerable morbidity and even mortality.

Knowledge about diagnostic procedures in melanoma has in creased rapidly within the past few years. Single tumor cells have been identified in normal tissue such as sentinel lymph nodes, as well as in bone marrow, peripheral blood, and other bodily fluids and cells, by molecular technologies. The introduction of polymerase chain reaction-based methods can be regarded as a prototype of this dramatic development towards molecular approaches in new diagnostic procedures. This fact opens up the possibility of clinical use in patients and of influencing treatment strategies. Considerable discrepancies have been described, how ever, in the success rates of these new techniques for the detec tion of minimal residual disease in cancer patients. Despite fav orable results reported by different groups of investigators, it will take several years to define the clinical and pathophysiological relevance of new diagnostic procedures. The 1st International Symposium "Minimal Residual Disease in Melanoma: Biology, Detection and Clinical Relevance of Microme tastases", held in September 1999 in Homburg/Saar, Germany, fo cused on recent developments in this particular area of cancer re search. The purpose of the meeting was to stimulate discussion and exchange of new data and ideas by renowned international scientists. The aim of this volume is to summarize major topics of basic research and clinical investigations presented by invited experts in this fascinating but still. controversial field of melanoma re search.

I entered the gene therapy field in the mid-1990s, being fascinated by the immense potential of genes as drugs for the treatment of human disease. Since then, I have experienced the ups and downs of this discipline, and tried to contribute with my work and that of my laboratory to the development of innovative approaches to the treatment of cardiovascular disorders. During these years, I have had several opp- tunities to speak on gene therapy at lectures and academic lessons, and have often noticed that the field is very attractive to scientists of all disciplines. However, as yet no comprehensive book on the subject has been published. Indeed, most books in the field are either a collection of gene transfer laboratory protocols or deal with the subject in a rather superficial manner. Hence the idea to write a gene therapy textbook that is broad and comprehensive, but at the same time provides sufficient molecular and clinical detail to be of interest to students, professors, and specialists in the various disciplines that contribute to gene therapy. I have tried to keep the language plain and, whenever possible, non-technical. Since the book is intended to be a textbook in the field of gene therapy in both the basic science and clinical areas, whenever technical descriptions are required, they are provided.

The interplay between tumors and their immunologic microenvironment is complex, difficult to decipher, but its understanding is of seminal importance for the development of novel prognostic markers and therapeutic strategies. The present review discusses tumor-immune interactions in several human cancers that illustrate various aspects of this complexity and proposes an integrated scheme of the impact of local immune reactions on clinical outcome. Current active immunotherapy trials have shown durable tumor regressions in a fraction of patients. However, clinical efficacy of current vaccines is limited, possibly because tumors skew the immune system by means of myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of cancer vaccines in patients with metastatic disease, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment.

- Based on multidisciplinary knowledge and written by leading clinicians and scientists. - Includes chapters on classification and clinical aspects, pathologic features, and treatment and management of lupus erythematosus. - Although the lupus erythematosus is primarily a skin disease, because it can affect other areas such as joints, kidneys, lungs, heart, liver, brain, and blood vessels this book is also useful to specialists in internal medicine.

Easy to understand and easy to use, this essential book reflects the rapid progress in one of the most intriguing fields of medicine. It offers state-of-the-art information on basic immunology, fetal-neonatal immunology, and many more fascinating areas.