An early step in a long ascent

Molecular Pathology of Type 1 Diabetes Mellitusedited by M.G. von Herrath, Karger, 2001. CHF 288.00/EUR 205.50/US$250.50 (X + 360 pages) ISBN 3-8055-7240-9This book presupposes a sound general understanding of immunology. As a general pediatric endocrinologist with no particular background in immunology, I nevertheless found Molecular Pathology of Type I Diabetes Mellitus of interest as a reference volume, although it was often difficult to follow. For the clinical investigator, clinical or basic immunologist, or molecular biologist involved in the pathogenesis of type 1 diabetes mellitus (T1DM), the volume should serve as an up-to-date review of the complex and confounding field of the molecular basis of T1DM.Although general immunology is reviewed piecemeal throughout the volume, an introductory chapter reviewing the general principles of immunology would have strengthened the utility of this book for the non-immunologist considerably. In particular, because much of the volume considers experimental models of diabetes, a review of rodent immunology, its relationship to human immunology, its terminology, and a glossary of terms to be used later in the book would have been invaluable. Without this, much of the terminology and many of the abbreviations in the book were difficult to follow for the uninitiated.In striving to bring together the wealth of research into the pathogenesis of T1DM, the chapters volley back and forth between the genetics and immunology of human T1DM and that of experimental models of T1DM. For the clinician, the chapters on the genetics of human T1DM, the role of the intestinal mucosa in determining the impact of environment on the condition, and the review of autoantibodies in human diabetes are particularly worthwhile. In these chapters, the interaction between genetics and environment is reviewed in the context of the theories of antigen mimicry, HLA predispositions, and thymic versus peripheral selection and regulation of T-cell recognition of self-antigens. Of necessity, most of the other chapters describe experimental models of diabetes such as the non-obese diabetic mouse and the BB rat. Within these chapters, the reader's enthusiasm for enticing and provocative findings in experimental animals is often muffled by the admonition that what applies to rodent physiology and disease might not apply to human disease, with ample examples of where this has proved to be the case.There are several main themes that weave through the chapters of this book: the intriguing idea that early hygiene might determine susceptibility of a population to T1DM; the potential importance of the potency of self-antigen signal in determining thymic deletion or selection of a T-cell precursor; the importance of peripheral regulation of T cells that recognize self-antigens but have escaped deletion in the thymus; and the role of cytokines in driving immune responses and pancreatic β-cell or T-cell apoptosis.The final chapter considers the holy grail of T1DM – immunotherapy and prevention – by reviewing some of the successes in decreasing the frequency or severity of diabetes in experimental models of T1DM (e.g. pretreatment with antigens and anti-CD3 antibodies). Clinical studies are underway in humans to test these same strategies for preventing T1DM. The book was published before release of the initial results of the Diabetes Prevention Trial 1 (DPT1) – the disappointing finding that subcutaneous and periodic intravenous insulin therapy to prediabetic, ‘at risk’, first-degree relatives of patients with T1DM does not prevent the development of the disease [1xInfo-congress. Insulin therapy for preventing type 1 diabetes in high-risk relatives: negative results of the Diabetes Prevention Trial – Type 1. Schhen, A.J. and Philips, J.C. Revue Medical de Liege. 2001; 56: 536–538PubMedSee all References[1]. Perhaps immunotherapy with oral insulin, as is also being tested in a second arm of the DPT1, or humanized anti-CD3 antibody therapy will prove more promising. Reality, however, is probably reflected best in the concluding words of Ridgway and Fathman in one of the chapters:'We are likely decades away from a convincing integrated view of the pathological genetic and cellular response cascade that results in autoimmune diabetes.' Without this understanding of pathogenesis, hope for successful prevention and immunotherapy of human T1DM remains slim.