Gal and Anti Gal

It has been 15 years since the first report on the isolation of anti-Gal from human serum and the demonstration that this antibody is the most prevalent antibody in humans (Galili et al. , ]. Exp. Med. 160: 1519, 1984). Subsequent interdisciplinary studies in immunology, carbohydrate biochemistry, molecular biology, and evo lution demonstrated the highly restricted specificity of anti-Gal for the carbohy drate epitope Gal al-3Galpl-4GIcNAc-R, (termed here the a-gal epitope), the unprecedented evolutionary pattern of distribution of a-gal and anti-Gal in mam mals, and explained the evolution of this antigen and antibody by analysis of the a 1 ,3galactosyltransferase gene, the gene that encodes the enzyme that synthesizes the a-gal epitope. These studies have suggested that a major selection process that occurred in the course of evolution of ancestral Old World primates resulted in the inactivation of the a1 ,3galactosyltransferase gene and the subsequent appearance of anti-Gal in these primates. Other studies in immunoparasitology have demon strated the possible physiologic significance of anti-Gal in protection against cer tain parasitic infections. Major scientific attention was focused on a-gal and anti-Gal with the real ization in the early nineties that the interaction between this antigen and antibody is the major obstacle to xenotransplantation. The success of immunosuppressive drugs, in the last two decades of the 20th century, in preventing allograft rejection, has raised hopes for cure in many patients in need of organ transplant. Because of limited supply of allografts, only 20% of patients receive the needed organ.

Texte du rabat

This is an interdisciplinary book which for the first time assembles the wide spectrum of information on the basic and clinical aspects of the natural anti-Gal antibody, the alpha-gal epitope and the enzyme producing it, alpha-1,3-galactosyltransferase. Anti-Gal is the most abundant antibody in humans, apes and Old World monkeys (monkeys of Asia and Africa). It binds specifically to the alpha-gal epitope (Galalpha1-3Galbeta1-4GlcNAc-R) on glycoproteins and glycolipids. Humans, apes and Old World monkeys lack alpha-gal epitopes. In contrast, the alpha-gal epitope is produced in large amounts on cells of nonprimate mammals prosimians and New World monkeys (monkeys of South America), by the glycosylation enzyme alpha-1,3-galactosyltransferase. This differential distribution of the alpha-gal epitope and anti-Gal in mammals is the result of an evolutionary selective process which led to the inactivation of alpha-1,3-galactosyltransferase in ancestral Old World primates. A direct outcome of this event is the present rejection of xenografts such as pig organs in humans and monkeys because of the binding of human anti-Gal to alpha-gal epitopes on pig cells. The various chapters in this book were contributed by researchers studying basic and clinically related aspects of this area. The book aims to provide comprehensive and updated information on this antigen/antibody system, which at present is the major obstacle in xenotransplantation, and on some of the genetic engineering approaches developed for overcoming this obstacle. In addition, this book describes the significance of anti-Gal and alpha-gal epitopes in some parasitic, bacterial and viral infections, as well as in the pathogenesis of autoimmune diseases such as Graves' disease. Finally, this book describes novel approaches for exploiting the natural anti-Gal antibody for increasing immunogenicity of cancer and viral vaccines in humans. This book is edited and partly written by Dr. Uri Galili who originally discovered anti-Gal and the unique evolution of &agr;-1,3-galactosyltransferase, and by Dr. Jose-Luis Avila who has been studying anti-Gal significance in Chagas' disease and in Leishmania infections. This book covers the main areas of research on &agr;-1,3galactosyltransferase, its product the &agr;-gal epitope (Gal&agr;1-3Gal&bgr;1-4GlcNAc-R) and the natural anti-Gal antibody that interacts with this epitope. The book includes chapters on: The evolution of &agr;-1,3 galactosyltransferase in mammals; the structure of the &agr;-1,3galactosyltransferase gene; the structure function relationship of the &agr; 1,3galactosyltransferase enzyme; the molecular characteristics of &agr;-gal epitopes on glycolipids and glycoproteins and methods for its detection; the natural anti-Gal antibody and its significance in xenotransplantation; attempts to prevent xenograft rejection by elimination of &agr;-1,3galactosyltransferase gene, and by modulating &agr;-gal epitope expression and anti-Gal activity; significance of anti-Gal and &agr;-gal epitopes in viral, bacterial and protozoal infections; and the possible clinical exploitation of anti-Gal for the enhancement of cancer and viral vaccine immunogenicity.

Contenu
1 Evolution of ?l,3Galactosyltransferase and of the ?-Gal Epitope.- 2 The ?1,3-Galactosyltransferase Gene.- 3 Structure Function Studies of a New World Monkey ?1,3Galactosyltransferase: Analysis of Alternative Splicing and Expression in Baculovirus System.- 4 The Natural Anti-Gal Antibody.- 5 ?-Gal Epitopes in Animal Tissue Glycoproteins and Glycolipids.- 6 The Griffonia simplicifolia I B4 Isolectin: A Probe for ?-D- Galactosyl End Groups.- 7 ?-Gal Epitopes on Viral Glycoproteins.- 8 ?-Galactosyl-Bearing Epitopes as Potent Immunogens in Chagas' Disease and Leishmaniasis.- 9 Enterotoxin A of Clostridium difficile and ?-Gal Epitopes.- 10 Anti-Gal, ?-Gal Epitopes, and Xenotransplantation.- 11 Generation of ?1,3Galactosyltransferase Deficient Mice.- 12 Anti-Xenograft Immune Responses in ?1,3-Galactosyltransferase Knock-Out Mice.- 13 Modulation of ?Gal Epitope Expression on Porcine Cells.- 14 Graves' Disease as a Model for Anti-Gal Involvement in Autoimmune Diseases.- 15 Enhancement of Autologous Tumor Vaccine Immunogenicity by Anti-Gal.