Molecular definition of the transplantation antigens.

In the first half of the 20th century, the major histocompatibility complex (MHC) of the laboratory mouse, the H-2 complex, was defined by a combination of serology and genetics. In the second half of the 20th century, its human counterpart, the human leukocyte antigen (HLA) complex was similarly defined and shown to mediate rejection of allogeneic kidney grafts. The clinical relevance of the transplantation antigens created the field of transplant immunology, which aimed to reduce graft rejection by HLA matching of transplant donors and recipients, and to use immunosuppressive drugs to prevent and treat rejection. Because tissue transplantation is not a natural phenomenon, the relevance of the MHC for immunology and immune defense against microbial pathogens was frequently questioned. In the 1970s, the general observation that cytotoxic T-cell responses to viral infection required recognition of both a viral antigen and a transplantation antigen argued for the immunological importance of the MHC. Proving this point was not achieved until close to the end of the 20th century. This required detailed biochemical and structural analysis of the transplantation antigens, the viral antigens, and the T-cell receptors that recognized them. This century of research culminated in 1996 with the three-dimensional crystallographic structure of the complex of these three components. In this complex is MAC, the very first HLA antigen to be detected and now more formally known as HLA-A*02:01.

Fifty years in the vineyard of transplantation: looking back.

The past 5 decades have documented remarkable advances in basic knowledge and clinical expertise in transplantation. The first 12 years of this half century of my participation in the enterprise were consumed with the isolation, chemical characterization, and application of histocompatibility antigens purified from mouse, guinea pig, and human tissues, demonstrating that their specificity was based on unique amino acid sequences in protein structures. Initial unsuccessful attempts to use native molecules to induce tolerance in rat renal or heart transplantation models were followed by limited success when they were administered with a brief perioperative course of cyclosporine (CsA). Production of allochimeric constructs of class I major histocompatibility complex molecules bearing donor-type amino acid substitutions into the host-type C-terminal portion of the α1 helix yielded tolerogens whose activity was not dependent on conditioning with CsA or total lymphoid irradiation (TLI). The allochimeric molecules serve as altered peptide ligands that induce an aberrant T-cell signal 1 response producing transplantation tolerance. The potent activity of CsA in this experimental model was extended to clinical settings. Pharmacologic tools were employed to explore intra- and interindividual variations in drug exposure leading to the development of a better drug formulation. However, the intrinsic nephrotoxicity of CsA necessitated marked 80% reductions in de novo drug exposure as were achieved by exploiting the synergistic pharmacodynamic and pharmacokinetic interactions of CsA with sirolimus. The final decade in this 50-year experience includes editorship of this journal with marked changes in its direction. These experiences have afforded insights into future avenues for preclinical exploration and therapeutic drug development.

The somatic generation of immune recognition. 1971.

Antibody specificity is determined by structural v-genes that code for the amino acid sequences of the variable regions of antibody polypeptide chains. The present hypothesis proposes that the germ-cells of an animal carry a set of v-genes determining the combining sites of antibodies directed against a complete set of certain class of histocompatibility antigens of the species to which this animal belongs. The evolutionary development of this set of v-genes in phylogeny is traced back to the requirements for cell to cell recognition in all metazoa. The hypothesis leads to a distinction between two populations of antigen-sensitive cells. One population consists of cells forming antibodies against foreign antigens; these lymphocytes have arisen as mutants in clones descending from lymphocytic stem cells which expressed v-genes belonging to the subset (subset S) coding for antibody against histocompatibility antigens that the individual happens to possess. The other population consists of allograft rejecting lymphocytes that express v-genes of the remaining subset (subset A) coding for antibody against histocompatibility antigens of the species that the individual does not possess. The primary lymphoid organs are viewed as mutant-breeding organs. In these organs (e.g. in the thymus), the proliferation of lymphocytes expressing the v-genes of subset S and the subsequent suppression of the cells of these "forbidden" clones, leads to the selection of mutants cells expressing v-genes that have been modified by spontaneous random somatic mutation. This process generates self-tolerance as well as a diverse population of antigen-sensitive cells that reflects antibody diversity. The proliferation in the primary lymphoid organs of lymphocytes expressing v-genes of subset A generates the antigen-sensitive cell population that is responsible for allo-aggression. The theory explains how a functional immune system can develop through a selection pressure exerted by self-antigens, starting during a period in early ontogeny that precedes clonal selection by foreign antigens. The hypothesis provides explanations for the variability of the N-terminal regions of antibody polypeptide chains, for the dominant genetic control of specific immune responsiveness by histocompatibility alleles, for the relative preponderance of antigen-sensitive cells directed against allogeneic histocompatibility antigens, for antibody-idiotypes, for allelic exclusion, for the precommitment of any given antigen-sensitive lymphocyte to form antibodies of only one molecular species and for the cellular dynamics in the primary lymphoid tissues.

Human histocompatibility proteins.

Transplantation antigens (later called histocompatibility proteins) were named by Peter Gorer in the 1930s. After 4 decades of immunological work emphasizing their importance in immunobiology, structural work on these proteins began about 1970. During the first decade, HLA proteins were isolated and then separated into two groups. Biochemical studies established the close structural relationships of these groups (now called class I and class II MHC proteins). These structures both contained four domains, although the domains were linked differently. Two of these domains were immunoglobulin-like. They were the first proteins (aside from immunoglobulins) identified as members of the immunoglobulin superfamily of proteins. The crystallization of these proteins in the second decade led to elucidation of the structures of class I and class II MHC proteins, which has changed the way we think about immunology. These molecules each present peptides (8-9mers in the case of class I and 13-14mers in the case of class II) to initiate the immune response.

Protein-bound carbohydrates on cell-surface as targets of recognition: an odyssey in understanding them.

Multidisciplinary approaches by a number of investigators have established that cell-surface carbohydrates are integral components of recognition systems regulating survival, migration, adhesion, growth and differentiation of various cells. Our own experience and contributions to this exciting field are described. We discovered Endo D as the first endoglycosidase acting on glycoproteins, found complementary specificity of two endoglycosidases (Endo D and Endo H), and applied these enzymes for glycoprotein research. Endo-beta-galactosidase C, which hydrolyzes Galalpha1-3Galbeta1-4GlcNAc xenoantigenic determinant, was later found and molecularly cloned. We also found highly branched poly-N-acetyllactosamines in early embryonic cells, and demonstrated developmentally regulated carbohydrate changes during early mammalian development. The binding site for Dolichos biflorus agglutinin was introduced as a new differentiation marker. Basigin and embigin, two related members of the immunoglobulin superfamily, a sialomucin MGC-24 and other glycoproteins were discovered as carriers of developmentally regulated carbohydrate markers. We proposed enhancement of integrin action as a function of sugar chains with Lewis X epitope, and observed a relationship between the expression of carbohydrate markers and invasive properties of human carcinoma. Midkine, a heparin-binding growth factor, was discovered more recently and its interaction with heparin and oversulfated chondroitin sulfate was elucidated. N-Acetylglucosamine-6-sulfotransferase was cloned and used to reconstitute L-selectin ligands. Gene knockout was applied to reveal in vivo function of basigin, syndecan-4 and chondroitin 6-sulfate. Throughout my research on all these subjects, I have been fortunate in obtaining unexpected observations and enjoying fruitful collaborations.

Past, present, and future aspects of histocompatibility.

We have stressed problems attendant on studies of the MHC, ignoring non-HLA factors and their role in allograft immunity. Many other topics could have been chosen for discussion is any such overview; our selection reflects our own interests. We felt assured, however, that excellent coverage by our many colleagues of the diverse and varied aspects of histocompatibility not approached in this summary has allowed us this freedom.