The Immunological Basis of Asthma PDF

PREFACE

Our thinking on the pathogenesis of asthma has changed substantially over the last two decades, in large part because of the progress in invasive and noninvasive measurements of airway inflammation and lung function as well as in the fields of immunology and cell biology. It is currently believed that a dysregulated cellular and humoral immune response to allergen might be the basis for atopy. This immune response is already programmed in early life and is influenced by the genetic background of the individual as well as by environmental factors such as lifestyle, infections, and pollution. All these factors seem to influence the various cells and regulatory processes of the immune system in a complex and interrelated manner. Although atopy is a risk factor for the development of asthma, not all atopics develop bronchial hyperreactivity and symptoms of asthma. Additional factors, such as those derived from airway epithelial cells and tissue resident cells, may be of critical importance for the regulation of immune responses in the lung and the development of chronic self-perpetuating airway inflammation that leads to functional changes and, ultimately, to irreversible airway remodeling.

Along with this increasing knowledge about the natural evolution of asthma, there has been an explosion of research in which animal models of eosinophilic airway inflammation have been used to draw conclusions about the role of a particular cell or mediator in the pathogenesis of asthma. Although these models can only partly address the complex regulatory mechanisms in human asthma, they have elucidated the important functional roles of antigen-presenting cells, T lymphocytes, cytokines, chemokines, and neuropeptides and, at the same time, have cast some doubt on the most classic paradigms of allergy, such as the contribution of mast cells, IgE, and eosinophils to certain aspects of chronic airway inflammation and bronchial hyperreactivity.

In this book, data on the immunology of asthma obtained from human studies are presented in light of data obtained from animal models of the disease. In Part One, the various cells of the pulmonary immune system as well as the products they secrete will be discussed briefly. This will provide the nonimmunologist with the basic knowledge about these cells necessary to understand the subsequent chapters of this volume. In Part Two, the steady-state regulatory processes that operate within the immune system of the lung are discussed. The fundamental outcome of a first exposure to antigen can be tolerance or immunity. Tolerance to inhaled allergen can be the result of ignorance, anergy, or suppression, but is generally thought to be the result of an active, proliferative immune response to allergen. The induction of immunity results from a complex interaction between antigen-presenting cells and naive T cells that initially occurs in the central lymphoid organs. However, naive T cells eventually differentiate to become migratory memory/effector T cells that migrate through the lung and produce polarized sets of cytokines upon encounter with antigen. Part Three discusses the immunological aspects of airway inflammation and remodeling in atopic and nonatopic asthma. Whereas human biopsy studies only allow associations to be made between an observed cell or mediator and the asthmatic phenotype, animal models show cause and effect. Animal models of allergen- or virally induced eosinophilic airway inflammation have intensively highlighted the functional importance of dendritic cells, T cells, cytokines, and chemokines to the induction and maintenance of eosinophilic airway inflammation and bronchial hyperreactivity. In vitro studies of human material also show cause and effect of an immunological mediator on the pathophysiology of asthma.

The eventual goal for increasing our knowledge of the immunology of asthma is to devise new strategies aimed at reversing the spontaneous evolution and symptoms of asthma. In Part Four, the manner in which our current therapies already affect many of the immune cells and their regulatory processes within the lung is discussed. Newer, specifically designed therapeutics exploit the immune system more selectively to intervene in asthma. Increasing knowledge of the epidemiology of asthma also suggests that exploiting bacterial motifs to stimulate the innate immune system may hold promise for devising a preventive vaccine. Finally, newer techniques to screen the expression of immune-related genes in healthy and diseased tissues may allow identification of novel genes that interfere with asthma pathogenesis, with the ultimate goal of devising antagonists to block a disease-causing gene product or to introduce a novel gene (product) to protect against asthma.

This book will provide a guide to scientists, clinicians, and clinical pharmacologists who wish to understand the origins of asthma in greater detail and to devise new therapies for asthma based on immunological interventions that ultimately change the natural course of the disease. It has been an honor to be able to collaborate with the contributors to this volume and we would like to take this opportunity to thank them for their fine efforts. We would also like to acknowledge the interest and support of the staff at Marcel Dekker, Inc., and Dr. Claude Lenfant, Executive Editor of this series, which have made this volume possible.