Immunology and Medicine – serie

Immunotherapy began in 1774 when the Dorset farmer Benjamin Jesty inoculated his wife and two sons with the pus from the teat of a cow suffering from cow pox, using his wife's knitting needle as a vaccinating implement. It has made slow progress. Meanwhile the science of Immunology has burgeoned so much that if all immunologists read every page of the Journal of Immunology, let alone the other Immunology journals, then they would have no time left to write for it. I am pleased that some of them have found the time to write for this volume. In spite of the rapid expansion in immuno­ logical knowledge and the undreamt of complexity of the immune system that has been unravelled, immunologists have remained until recently erudite but therapeutically effete. Indeed anyone purporting to treat disease by immuno­ logical methods has been in danger of being labelled a quack or a crackpot. Happily things are changing. The nine chapters of this volume detail nine quite different approaches to manipulating the immune system for therapeutic benefit. All are experimental and they have been attended with greater or lesser degrees of success. In some cases their main effect has been to elucidate the complexity of the problem. On the other hand, there are people alive and well today as a result of these approaches who would otherwise have perished. Immunotherapy is here to stay and it can only get better.

Antibodies are crucial to the fine specificity of the immune system. An effective functioning of these molecules requires interaction with immune cells. Receptors for antibodies, Fc receptors, provide this critical link between the humoral and cellular branches of the immune system. This book presents a comprehensive overview of the different Fc receptors recognized. The first part of the book contains state-of-the-art overviews on the biological role of FcR. The latest information on FcR heterogeneity, FcR physiology, FcR-ligand recognition, their crucial co-ordinating role in immunity, interactions with other immunoreceptors, and the role of FcR in immunoglobulin transport and catabolism are discussed. The clinical importance of FcR is developed in the second part of the book. The well-recognized roles of FcR in allergy, inflammation, infectious diseases, autoimmune disorders, and immunotherapeutic importance are reviewed. The information in this book is easily accessible and should be helpful for researchers and clinical specialists as a convenient overview of the field, as well as a comprehensive introduction for students starting in this area of research.

Infection with the human immunodeficiency virus is characterized by the destruction of the host immune system as also reflected by a progressive loss of CD4-positive T-cells. This finally results in the host's incapacity to deal with opportunistic infections and the immune surveillance of tumours, a clinical status known as the Acquired Immunodeficiency Syndrome (AIDS). Providing a complete overview of the clinical course of HIV-1 infection, this text describes the clinical aspects of primary infection, the different clinical outcomes of HIV-1 infection, and strategies for anti-viral treatment. In addition, more fundamental aspects of HIV-1 infection are reviewed. These include the biology of the virus and the novel insights in AIDS pathogenesis. Not only is the significance of an HIV-specific cellular and humoral immune response discussed, but also the possible incapacity of the adult human host to deal with T-cell destruction. Finally, the book discusses the laboratory markers being used in 2000 that allow for monitoring of the clinical course of infection.

This work has broad applications in clinical medicine, ranging from prevention and treatment of organ and bone marrow transplant rejection, management of various autoimmune disorders (for example, rheumatoid arthritis), skin disease and asthma. Whereas traditionally only a small repertoire of immunosuppressive agents was available for clinical use, recent discoveries have significantly increased the number of approved agents, resulting in numerous trials to further evaluate their potential. There is also considerable interest in the potential of cell-based therapies (particularly hematopoietic stem and dendritic cell therapy) of allo- and autoimmunity. Important recent advances in the immunotherapy of allergic diseases are also covered in this book. This volume is intended both for practising physicians and surgeons and for biomedical scientists at the graduate/postdoctoral levels, and is designed to provide the theory behind these various approaches to immunosuppression, and to provide state-of-the-art reviews of current developments in each area.

CYTOTOXIC T LYMPHOCYTES-INDUCTION AND ACTIVATION ...124 EPSTEIN BARR VIRUS ASSOCIATED TUMOURS ...125 Immunoblastic lymphomas ...126 Burkitt's lymphoma ...127 NPC and Hodgkin's lymphoma ...127 Vaccines for EBV associated malignancies ...128 HUMAN PAPILLOMA VIRUS (HPV) ASSOCIATED TUMOURS ...129 T cell responses against HPV ...130 Cytotoxic T cell responses in HPV infection ...130 Vaccines and clinical trials ...132 Recombinant viral vaccines ...132 Peptide vaccines ...133 Bacterial fusion protein vaccines ...134 Potential Pitfalls for CTL based immunotherapy of CaCX ...134 PROSPECTS FOR OTHER VIRALL Y ASSOCIATED CANCERS ...135 Hepatitis viruses and primary liver cancer ...135 Human herpes virus 8 and Kaposi's sarcoma ...136 Human T lymphotropic virus and adult T cell leukaemia ...136 Emerging tumour viruses ...137 CONCLUDING REMARKS ...137 ACKNOWLEDGEMENTS ...138 REFERENCES ...139 Chapter 8 ...147 The immune response to oncogenic fusion proteins LORENA PASSONI & CARLO GAMBACORTI-PASSERINI xiii INTRODUCTION ...147 BCRlABL ...149 CML immunotherapy ...150 Specific recognition of the bcr/abl protein ...150 CML vaccination ...152 FUSION PROTEINS AND TUMOUR ESCAPE ...152 CONCLUDING REMARKS ...154 REFERENCES ...154 Chapter 9 ...157 Immunological significance ofhsp70 in tumor rejection ANTOINE MENORET INTRODUCTION ...157 PROGRESSOR AND REGRESSOR TUMORS ...157 CO-SEGREGATION OF EXPRESSION OF THE INDUCIBLE HSP70, BUT NOT OF THE CONSTITUTIVE HSC70, WITH A REGRESSIVE PHENOTYPE ...159 IMMUNIZATION WITH TUMOR-DERIVED HEAT SHOCK PROTEIN OF 70 KDA (HSP70IHSC70), NA TURALL Y OR ARTIFICIALLY COMPLEXED WITH ANTIGENIC PEPTIDES ...161 DIFFERENCE OF PEPTIDE BINDING DOMAINS BETWEEN THE INDUCIBLE HSP70 AND CONSTITUTIVE HSC70 ...163 XIV IMPLICATION FOR IMMUNOTHERAPY OF CANCER AND BEYOND ...165 ACKNOWLEDGMENTS ...166 REFERENCES ...166 Chapter 10 ...

Diseases of the gastrointestinal tract are common. There is increasing appreciation of the importance of the immune system in the pathogenesis of a number of these diseases. This book covers basic aspects of innate and adaptive immunity in the gastrointestinal tract, oral tolerance, and cellular and molecular mechanisms of acute and chronic inflammation. Specific disease covered include bacterial infections, human immunodeficiency virus (HIV) infection, coeliac disease, and inflammatory bowel disease. Other topics include mucosal immunisation and intestinal transplantation immunology. The readership of this book includes clinicians, scientists, and students interested in the gastrointestinal tract.

The complement system plays a major role in the host's defence against infections and in immune complex diseases. Although it is known to consist of a number of serum and membrane proteins that interact through a cascade, there is still a poor understanding of the exact nature of the components and their complex interaction. Many of the biological consequences of complement activation also await elucidation. This fully revised edition of "Complement in Health and Disease" provides an up-to-date account of how the system works and its effects on the host. Key topics covered include the history, phylogeny and evolution of the system; genetics and biochemistry; deficiency states and infection; immune complex diseases; complement and angioedema; anaphylatoxins; and diseases of the nervous system. The book is valuable both for those wanting an introduction to this complex area of immunology as well as those requiring a more detailed update on developments in specific topics.

The neuromuscular diseases comprise the disorders of peripheral nerves, the neuromuscular junction, and muscle. Both pre- and post-synaptic elements of the neuromuscular junction may become targets of autoimmune attack in different diseases. This book addresses the immunologically-mediated neuromuscular diseases, including Guillain-Barre syndrome and other autoimmune neuropathies, the Lambert-Eaton myasthenic syndrome, myasthenia gravis, and the autoimmune diseases of muscle. Two chapters are devoted to the vasculitic and HIV-mediated neuromuscular diseases. The experimental models of neuritis and myasthenia gravis are addressed in separate chapters. An introductory chapter provides a general background to autoimmunity. This book aims to be a useful overview for all neurologists, rheumatologists and immunologists both in research and clinical practice.

The eye can become involved in immune-mediated diseases that affect it alone or as part of a multi-organ disease process. Much immunological attention has been focused on other organs affected by these processes and the subject of the immunology of eye diseases is a relatively new one. Many of these diseases that involve the eye are not life-threatening but can result in devastat­ ing loss of sight that if bilateral, will have major effects on the patient's life. Systemic immunological investigations are generally unhelpful in these patients and one of the major problems in this field has been the lack of diseased tissue available for examination to determine the pathological processes involved. Our poor understanding of basic mechanisms of disease in the eye has meant that treatment of many of these conditions is often inadequate. It has become possible to apply in the eye many ofthe techniques used to investigate the role of the immune system in other systems. Animal models of many of the disease processes have also allowed dissection of the immune response both within and outside the eye. It is my belief that a greater understanding of the mechanisms by which the structures in the eye become damaged will allow more specific and effective therapeutic strategies to be devised.

This volume highlights the areas in which immunological mechanisms are now known to be involved in disorders of the ears, nose and throat. These include the normal defence mechanisms of the upper respiratory tract, the immunology of the tonsils and failures of immunity, such as fungal infections, granulomatous disorders and malignancies. Disorders of the middle and inner ear are considered, as are nasal polyposis and various aspects of allergy: allergic rhinitis, and food sensitivity in relation to the nose and allergy. A final chapter deals with the future prospects for immunological involvement in ENT disorders. The volume provides insights, with possible novel therapeutic approaches, not only to otorhinolaryngologists, but also to audiologists, allergists and respiratory physicians. It also provides an up-to-date background for any immunological researcher in this field.

Gastrointestinal diseases present a considerable problem in human medicine in terms of both morbidity and mortality. The aim of this book is to cover the different immunological disorders of the gut with special reference to immunopathological and protective mechanisms. It will be of general interest to clinicians, scientists and students concerned with the gastrointestinal tract. Topics covered include: the current status of research into toxin-secreting pathogens, Campylobacter, Giardia and HIV; the immunological features of idiopathic inflammatory gut diseases such as Crohn's disease and intractable diarrhoea; the genesis of the flat mucosa; the iatrogenic diseases of the gut such as graft-versus-host disease and small bowel allografts; the immune mechanisms and lesions in the gut of patients with parasitic nematode infections (very important in the tropics). Basic background on the immune apparatus in the intestine is also discussed, as are the effects of inflammation on intestinal permeability.

It is now 10 years since the first AIDS cases were reported in the USA. In that relatively short period of time, study of the disease has moved from the level of early clinical description to exhaustive and extensive laboratory characterization of the human immunodeficiency virus (HIV), the immune responses directed towards it and reasons for their failure. This volume provides contributions from clinical and basic scientists who are actively involved in research in a number of areas of current interest and controversy. Further progress in the clinical management of the HIV-infected patient will undoubtedly build on the basic knowledge about HIV and its modes of pathogenesis. The intimate relationship between HIV and the human immune system provides observations and questions that are relevant to viral immunopathogenesis in general. In the first chapter the clinical features of HIV immunodeficiency are re­ viewed, and aspects of its changing face are discussed. Dr Tersmette then presents evidence for changing viral characteristics at different stages of the disease. This view of close competition for ascendancy between HIV and the host immune response raises questions about current approaches to therapy.

The immune system has evolved in large part to enable organisms to resist microbial infection. Micro-organisms have long been used as experimental tools by immunologists, and the study of the immune response to viruses and bacteria has contributed much to our understanding of basic immunological mechanisms. There are also important practical and clinical reasons for attempting to understand the immunology of infections. These include the rational design of vaccines, the pathogenesis of infectious diseases, the advent of AIDS, the rise in drug-resistant mycobacterial infections and the recognition of the infectious aetiology of peptic ulcer disease. The contributors to this book are all chosen for their active involvement and expertise in the fields. It bridges the divide between basic immunological research and clinical practice.

The contributions to this book examine the role of the immune response in liver disease. The book is divided into three sections and there are two introductory chapters: one discussing viral immunopathology and the other autoimmune disease. Three chapters are devoted to viral hepatitis infections, the immune responses engendered by each virus and the pathogenesis of the diseases they cause. One author reviews the use of immunotherapy in hepatocellular carcinoma. Two chapters then review the recent advances in the identification and characterization of autoantibodies and their cytoplasmic antigens. These concentrate on current experimental approaches using molecular biological techniques to identify the structures recognized by disease-specific autoantibodies. The third section has a chapter reviewing the immune mechanisms in alcoholic liver disease and a chapter examining the immune reactions provoked by hepatotoxic drugs.

Our understanding of inflammation has increased rapidly in recent years, due in large part to the impact of molecular biology and gene identification and cloning. This book brings together ideas from a number of different biochemical disciplines which are frequently not integrated. The first chapter gives a visual overview of the subject; the remaining chapters are organized into three themes: the affector molecules, the regulatory components and the processes of inflammation itself. This book is aimed at the busy physician or pathologist who wants to be up-to-date with recent developments in immunology as they affect the diagnosis and treatment of many conditions.

Connective tissue diseases demand study because of their frequency, morbidity and mortality. These dieases present challenges in the fields of diagnosis, management and research. Their range has now expanded enormously so that no individual can master the whole subject, particularly as this relates to their immunological basis. This book has been written by experts who are either clinical or basic scientists. It presents reviews of the immunological basis of connective tissue diseases as it impacts on diagnosis, pathogenetic concepts, disease monitoring and management. The book is aimed at physicians interested in understanding the immunological basis of these diseases, and at immunologists who are either entering this field for the first time and would like to have a convenient state-of-the-art account of its status, or who are researching in one area and would like to acquaint themselves with the developments which have taken place in others.

Infection with the human immunodeficiency virus is characterized by the destruction of the host immune system as also reflected by a progressive loss of CD4-positive T-cells. This finally results in the host's incapacity to deal with opportunistic infections and the immune surveillance of tumors, a clinical status known as the Acquired Immunodeficiency Syndrome (AIDS). The book AIDS Pathogenesis provides the reader with a complete overview of the clinical course of HIV-1 infection. It describes the clinical aspects of primary infection, the different clinical outcomes of HIV-1 infection, and strategies for anti-viral treatment. In addition, more fundamental aspects of HIV-1 infection are reviewed. These include the biology of the virus and the novel insights in AIDS pathogenesis. Not only is the significance of an HIV-specific cellular and humoral immune response discussed, but also the possible incapacity of the adult human host to deal with T-cell destruction. Finally, the book discusses the currently used laboratory markers that allow for monitoring of the clinical course of infection.

CYTOTOXIC T LYMPHOCYTES-INDUCTION AND ACTIVATION ...124 EPSTEIN BARR VIRUS ASSOCIATED TUMOURS ...125 Immunoblastic lymphomas ...126 Burkitt's lymphoma ...127 NPC and Hodgkin's lymphoma ...127 Vaccines for EBV associated malignancies ...128 HUMAN PAPILLOMA VIRUS (HPV) ASSOCIATED TUMOURS ...129 T cell responses against HPV ...130 Cytotoxic T cell responses in HPV infection ...130 Vaccines and clinical trials ...132 Recombinant viral vaccines ...132 Peptide vaccines ...133 Bacterial fusion protein vaccines ...134 Potential Pitfalls for CTL based immunotherapy of CaCX ...134 PROSPECTS FOR OTHER VIRALL Y ASSOCIATED CANCERS ...135 Hepatitis viruses and primary liver cancer ...135 Human herpes virus 8 and Kaposi's sarcoma ...136 Human T lymphotropic virus and adult T cell leukaemia ...136 Emerging tumour viruses ...137 CONCLUDING REMARKS ...137 ACKNOWLEDGEMENTS ...138 REFERENCES ...139 Chapter 8 ...147 The immune response to oncogenic fusion proteins LORENA PASSONI & CARLO GAMBACORTI-PASSERINI xiii INTRODUCTION ...147 BCRlABL ...149 CML immunotherapy ...150 Specific recognition of the bcr/abl protein ...150 CML vaccination ...152 FUSION PROTEINS AND TUMOUR ESCAPE ...152 CONCLUDING REMARKS ...154 REFERENCES ...154 Chapter 9 ...157 Immunological significance ofhsp70 in tumor rejection ANTOINE MENORET INTRODUCTION ...157 PROGRESSOR AND REGRESSOR TUMORS ...157 CO-SEGREGATION OF EXPRESSION OF THE INDUCIBLE HSP70, BUT NOT OF THE CONSTITUTIVE HSC70, WITH A REGRESSIVE PHENOTYPE ...159 IMMUNIZATION WITH TUMOR-DERIVED HEAT SHOCK PROTEIN OF 70 KDA (HSP70IHSC70), NA TURALL Y OR ARTIFICIALLY COMPLEXED WITH ANTIGENIC PEPTIDES ...161 DIFFERENCE OF PEPTIDE BINDING DOMAINS BETWEEN THE INDUCIBLE HSP70 AND CONSTITUTIVE HSC70 ...163 XIV IMPLICATION FOR IMMUNOTHERAPY OF CANCER AND BEYOND ...165 ACKNOWLEDGMENTS ...166 REFERENCES ...166 Chapter 10 ...

Therapeutic immunosuppression has very broad applications in clinicalmed- icine, ranging from prevention and treatment of organ and bone marrow transplant rejection, management of various autoimmune disorders (e. g. rheumatoid arthritis) skin disease, and asthma. Whereas traditionally, only a small repertoire of immunosuppressive agents was available for clinical use, recent discoveries have significantly increasedthe number ofapproved agents, resulting in numerous trials to further evaluate their potential. In addition, products of the biotechnology industry, - monoclonal antibodies, cytokines, cytokine antagonists and other products of genetic engineering that target key molecular pathways in disease pathogenesis, have either already made, or are on the verge of making an important impact on treat- ment. There is also considerable interest in the potential ofcell-based thera- pies (particularly hematopoietic stem and dendritic celltherapy) ofallo-and autoimmunity. Important recent advances in the immunotherapy of allergic diseases are also covered in this book.Gene therapy offers considerable promise for suppressing pathogenic processes in either transplantation or autoimmune disorders. The possibility of combining these important new advances to maximize benefit to the patient, and to minimize possible untoward effects (that are also given extensive coverage in this book)is one ofthe most exciting challenges ofcontemporary medicine. This volume is intended both forpracticing physicians and surgeons and for biomedical scientists at the graduate/postdoctoral levels, and is designed to provide the theory behind these various approaches to immunosuppres- sion, and to provide state-of-the-artreviews ofcurrent developments in each area. Each chapter is contributed by an expert(s) in the field.

Diseases of the gastrointestinal tract are common. There is increasing appreciation of the importance of the immune system in the pathogenesis of a number of these diseases. This book covers basic aspects of innate and adaptive immunity in the gastrointestinal tract, oral tolerance, and cellular and molecular mechanisms of acute and chronic inflammation. Specific disease covered include bacterial infections, human immunodeficiency virus (HIV) infection, coeliac disease, and inflammatory bowel disease. Other topics include mucosal immunisation and intestinal transplantation immunology. The readership of this book includes clinicians, scientists, and students interested in the gastrointestinal tract.

The neuromuscular diseases comprise the disorders of peripheral nerve, neuromuscular junction, and muscle (Figure 1). This book addresses the immunologically mediated neuromuscular diseases, including Guillain-Barre syndrome and other autoimmune neuropathies, the Lambert-Eaton myas- thenic syndrome, myasthenia gravis, and the autoimmune diseases of muscle. Two chapters are devoted to the vasculitis and human immunodeficiency virus-mediated neuromuscular diseases. The experimental models of neuritis and myasthenia gravis are addressed in separate chapters. An introductory chapter provides a general background to autoimmunity. I wish to thank my contributing colleagues, all of whom are recognized experts in their respective fields, for their willingness to cooperate in this project. Furthermore, I am grateful to Dr Bill Hoffman of Stanford University who generously assisted in the editing of several chapters during his time spent with us on a sabbatical. I am also indebted to the editor and editorial staff of Kluwer Academic Publishers for their help and advice during preparation of this book.Munich/ Martinsried Reinhard Hohlfeld March 1994 ix IMMUNOLOGY OF NEUROMUSCULAR DISEASE Myelin; Guillain Barre syndrome NERVE TERMINAL ..

The role of the immune response in both the pathology of liver disease and in the modulation ofliver injury has been the subject of intense research. Further chapters are devoted to the three major autoimmune liver diseases which are thought to be the result of loss of tolerance to autologous liver tissue.

The immune system has evolved in large part to enable organisms to resist microbial infeetion. Given this very fundamental relationship between the immune system and infeetious microbial agents it is entirely appropriate that avolume in this series should be devoted to the immunology of infeetion. Mieroorganisms have long been used as experimental tools by immunologists, and the study of the immune response to viruses and baeteria has eontributed mueh to our understanding of basie immunologieal meehanisms (for example of the meehanism by whieh non-self determinants on eells are reeognized). However there are of eourse important praetieal and elinical reasons for attempting to understand the immunology of infeetions - these inelude the needs for rational design of vaeeines and to understand the pathogenesis of human infeetious diseases.The last deeade or so has seen a resurgenee of interest in infeetious diseases and a reeognition that they remain of importanee and pertinenee to all areas of medicineo This is not just beeause of the advent of AIDS, although that has been a major faetor - the rise in drug-resistant myeobaeterial infeetions and the reeognition of the infeetious aetiology of peptie uleer disease are other illustrations. It should be made elear that this volume deals with aspeets of the immunolgy of baeteria, viruses and fungi - but it does not deal with parasite immunology which it is planned to eover in a separate volume in the series.

Connective tissue diseases demand study because of their frequency, morbidity and mortality. The book presents up-to-date reviews of the immunological basis of connective tissue diseases as it impacts on diagnosis, pathogenetic concepts, disease monitoring and management.

Until recently, the contribution of immunological knowledge to the under­ standingand management ofENTdisorders was slight, being largely confined to the appreciation that many rhinitic patients were allergic. Happily, this situation is rapidly changing: the immunological basis of many disorders of the ears, nose and throat is becoming recognized and the mechanisms of the reactions involved are being elucidated. From this, rational therapy should evolve. This book aims to highlight some of the areas in which immunological mechanisms are involved in otorhinolaryngology. It is written by experts in their respective fields of immunology and allergy, otology, rhinology and pathology. It opens with an overview ofthe pathways ofthe immune response and the cells and molecules involved, leading to an appreciation of the normal defence mechanisms of the upper respiratory tract and possible areas offailure. There is then a chapter on HIV infection and how this may present to otorhinolaryngologists. The normal function of the tonsil and the immunological effects oftonsillectomy are then considered. The varying roles of fungi in ENT disorders ranging from commensal through allergen to invasive organisms is assessed by Professor R. J. Hay. Perhaps the most obvious immunological contribution to management thus far lies in the immunocytochemical diagnosis of pathological conditions of the ears, nose and throat and this is covered in a chapter by Professor Leslie Michaels.

Since the first edition of Complement in Health and Disease was published in 1986, significant advances have been made. The cDNAs for all of the components and some of the receptors have been cloned and sequenced. The chromosomal localization and the structural organization of a number of these genes have now been determined. These advances are now facilitating research into the structure of the complement proteins, the nature of the complement deficiency syndromes, the regulation of complement gene expression and the role of complement in different diseases. This edition contains contributions from both basic and clinical scientists in a format which we hope will appeal to both immunologists and physicians who wish to know more about this fascinating and important host defence system. The introductory chapter by John Weiler presents a historical background to research on the complement system and describes the biochemical events occurring during activation of the system. In Chapter 2 Alastair Dodds and Tony Day discuss the phylogeny and evolution of the complement system. The techniques of protein chemistry and molecular biology have provided powerful insights into the modular structure of complement proteins and the evolution of the complement system. The structure and organisation of the complement genes is described in Chapter 3 by Ken Reid and Duncan Campbell. This chapter describes the modular structure of the complement proteins and some of the mutations which are responsible for deficiencies of individual components.

Gastrointestinal diseases present a considerable problem in human medicine in terms of both morbidity and mortality. The aim of this book is to cover the different immunological disorders of the gut with special reference to immunopathological and protective mechanisms. It will be of general interest to clinicians, scientists and students concerned with the gastrointestinal tract. Topics covered include: the current status of research into toxin-secreting pathogens, Campylobacter, Giardia and HIV; the immunological features of idiopathic inflammatory gut diseases such as Crohn's disease and intractable diarrhoea; the genesis of the flat mucosa; the iatrogenic diseases of the gut such as graft-versus-host disease and small bowel allografts; the immune mechanisms and lesions in the gut of patients with parasitic nematode infections (very important in the tropics). Basic background on the immune apparatus in the intestine is also discussed, as are the effects of inflammation on intestinal permeability.