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Follicular dendritic cells (FOe) are unique among cells of the immune system. While their morphological characteristics re sulted in their inclusion as a 'dendritic cell type', tt1ey differ quite significantly from the other members of the dendritic cell family. In contrast to T-cell-associated dendritic cells or the Langerhans cells found in the skin, FOe reside in highly organized B cell follicles within secondary lymphoid tissues. This site of resi dence provided a nomenclature committee in 1982 with the second descriptive factor for the derivation of their name. The cardinal feature of FOe is to trap and retain antigen on the surface of their dendritic processes for extended amounts of time and it is this feature that provides the conceptual compo nent for the title of this book. In response to an antigenic challenge, primary B cell follicles undergo dynamic events, giving rise to germinal centers which are associated with activation, expansion, and differentiation processes of B cells. The interactions of B cells with Foe and T cells in the germinal centers are essential for generating the complete repertoire of antibody isotypes obtained during an antibody response. In addition, stimuli either initiated or main tained during the germinal center reponse leads to production of high affinity antibodies through the processes of somatic muta tion and clonal selection. In this context, FOe act as a pivotal source of antigen. They accumulate foreign proteins (e. g.
These proceedings contain selected contributions from the participants to the Fourth International Symposium on Dendritic cells that was held in Venice (Lido) Italy, from Oc tober 5 to 10, 1996. The symposium was attended by more than 500 scientists coming from 24 different countries. Studies on dendritic cells (DC) have been greatly hampered by the difficulties in preparing sufficient cell numbers and in a reasonable pure form. At this meeting it has been shown that large quantities of DC can be generated from precursors in both mice and humans, and this possibility has enormously encouraged studies aimed to characterize DC physiology and DC-specific genes, and to employ DC therapeutically as adjuvants for im munization. The possibility of generating large numbers of autologous DC that can be used in the manipulation of the immune response against cancer and infectious diseases has tremendously boosted dendritic cell research and the role of DC in a number of medi cal areas has been heatedly discussed.
These Proceedings contain the contributions of the partIcIpants of the Third International Symposium on Dendritic Cells that was held in Annecy, France, from June 19 to June 24, 1994. This symposium represented a follow-up of the first and second international symposia that were held in Japan in 1990 and in the Netherlands in 1992. Dendritic cells are antigen-presenting cells, and are found in all tissues and organs of the body. They can be classified into: (1) interstitial dendritic cells of the heart, kidney, gut, and lung;(2) Langerhans cells in the skin and mucous membranes; (3) interdigitating dendritic cells in the thymic medulla and secondary lymphoid tissue; and (4) blood dendritic cells and lymph dendritic cells (veiled cells). Although dendritic cells in each of these compartments are all CD45+ leukocytes that arise from the bone marrow, they may exhibit differences that relate to maturation state and microenvironment. Dendritic cells are specialized antigen-presenting cells for T lymphocytes: they process and present antigens efficiently in situ, and stimulate responses from naive and memory T cells in the paracortical area of secondary lymphoid organs. Recent evidence also demonstrates their role in induction of tolerance. By contrast, the primary and secondary B-cell follicles contain follicular dendritic cells that trap and retain intact antigen as immune complexes for long periods of time. The origin of follicular dendritic cells is not clear, but most investigators believe that these cells are not leukocytes.
Antigen presentation is central to the immune response, and is instrumental in ensuring that the response mounted is that best suited to the eradication of the particular microbe faced. In this volume, experts in the field provide state-of-the-art descriptions of the antigen presentation pathways. How do viruses disrupt these critical pathways, and to what effect? Do all tissues present antigen in the same way? If not, why? What are the consequences of dysfunctional antigen presentation, seen in certain genetic disorders? This book considers not only the molecular details, but also their relevance to the whole organism.
Discrimination of self from nonself is the major function of the immune system and understanding the mechanism(s) involved a main employer of immunologists. Hence, the age-old puzzle of why a fetus that contains a panel of major histocompatibility (MHC) antigens derived from its mother and its father is not rejected (spontaneously aborted) by lymphocytes from its mother who should theoretically recognize foreign MHC molecules from the father has remained of great interest. This dilemma has enticed immunologists and developmental biologists for many years. This volume was created to present the information currently on hand in this subject to the scientific public. The guest editor, Professor Lars Olding, has a long and distinguished history of contributions in this field, having been one of the main propo nents of the argument that lymphocytes from the fetus play an active role in this process by suppressing lymphocytes from the mother from proliferating and thereby acting as killer cells. His work has defined the phenomenon and identified suppressor molecules (factors) involved in the process. In a different but related chapter, Margareta Unander extends such observations to the clinical study of women with repeated "habitual" mIS carriages.
Our understanding of the function of natural killer (NK) cells has dramatically changed in recent years. The discovery of NK receptors specific for MHC class I molecules, and the study of the role of co-stimulatory and adhesion molecules have led to an understanding of how NK cells recognize tumor and virally infected cells that have lost expression of MHC class I molecules or have altered distribution of normal cell surface molecules. Such recognition events lead to intracellular signals which can be either stimulatory or inhibitory. This book provides an insight into how NK cells develop, how they learn to distinguish altered cells from normal cells, and into their biological role in controlling infections and tumors.
Chronic hepatitis C is a major worldwide health problem affecting more than 170 million people. Chronic infections lead to cirrhosis and liver failure or hepatocellular cancer in many instances. This volume includes comprehensive reviews that cover much of the vast literature that has appeared since the identification of the hepatitis C virus RNA genome. It will be an invaluable collection for anyone wanting an up-to-date picture of HCV transmission, molecular virology, immune response, cellular/molecular pathogenesis, and possible avenues for developing effective new therapeutics and vaccines.
The essence of combinatorial chemistry or techniques involving "molecular diversity" is to generate enormous populations of molecules and to exploit appropriate screening techniques to isolate active components contained in these libraries. This idea has been the focus of research both in academia and in the pharmaceutical or biotechnology industry. Its developments go hand in hand with an exploding number of potential drug targets emerging from genomics and proteomics research. When the editors of Current Topics in Microbiology and Immunology encouraged us to assemble the present volume on Combinatorial Chemistry in Biology, we immediately felt that this might prove quite beneficial for the audience of this series. The field of combinatorial chemistry extends over a broad range of disciplines, from synthetic organic chemistry to biochemistry, from material sciences to cell biology. Each of these fields may have its own view on this topic, something which is reflected in a growing number of monographs and "special editions" of jour nals devoted to this issue or aspects thereof. The title of the present volume of Springer-Verlag's series suggests that it also has its own special focus. And, generally speaking, this is not wrong: we would even claim the special focus of this volume is on the immunologically relevant aspects of combinatorial chemistry.
M. B. KASTAN Cancer is a disease resulting from alterations of cellular genes which cause phe notypic changes in somatic cells. Usually, when we think about genetic diseases, we think about inheriting one or two abnormal genes from our parents and these gene abnormalities confer the disease phenotype. In contrast, in the majority of cancers, no such inherited gene abnormalities can be identified (which does not mean that they do not exist) and there is no obvious family history suggesting an inherited disease. The vast majority of genes which are altered in the cancer cells are not transmitted through the germ line, but rather become abnormal in somatic cells sometime during the lifetime of the individual. Thus, the critical question which arises is "how do these genetic changes occur in somatic cells?". Epidemiologic data suggest that exposure to environmental carcinogens con tributes to the genesis of at least 80% of all human cancers (DOLL and PETO 1981). Thus, it is natural to suspect that the genetic changes in somatic cells which con tribute to the transformed phenotype arise from DNA damage caused by such exposures. Therefore, understanding how cells respond to DNA-damaging agents is likely to be an important component of our understanding of the genesis of human tumors.
Human gene therapy holds great promise for the cure of many genetic diseases. In order to achieve such a cure there are two requirements. First, the affected gene must be cloned, its se quence determined and its regulation adequately characterized. Second, a suitable vector for the delivery of a good copy of the affected gene must be available. For a vector to be of use several attributes are highly desirable: these include ability to carry the intact gene (although this may be either the genomic or the cDNA form) in a stable form, ability to introduce the gene into the desired cell type, ability to express the introduced gene in an appropriately regulated manner for an extended period of time, and a lack of toxicity for the recipient. Also of concern is the frequency of cell transformation and, in some cases, the ability to introduce the gene into nondividing stem cells. Sev eral animal viruses have been tested as potential vectors, but none has proven to have all the desired properties described above. For example, retroviruses are difficult to propagate in sufficient titers, do not integrate into nondividing cells, and are of concern because of their oncogenic properties in some hosts and because they integrate at many sites in the genome and, thus, are potentially insertional mutagens. Additionally, genes introduced by retroviral vectors are frequently expressed for relatively short periods of time. A second virus used as a vector in model systems has been adenovirus (Ad).