The MHC-Based Suppression (MBS) Theory: Implications for Transplantation

Abstract

Abstract:Complex areas of scientific endeavor may sometimes benefit from a theoretical and/or reductionist approach to guide the direction of future experiments, perhaps best illustrated by the field of cosmology. The field of immunology in general, and transplantation immunology in particular, is certainly complex. This commentary draws attention to a theory that proposes an alternative role for MHC molecules, placing them central to the process of tolerance induction, with major implications for transplantation and all fields of immunology.Key Words: Immune tolerance, MHC-based suppression, peptide/MHC complex, peripheral tolerance, regulatory T cells, xenotransplantation. WHAT IS KNOWN ABOUT MHC MOLECULES?Originally named as human leukocyte antigens (HLA), later the term major histocompatibility (MHC) antigens came into common use. In this article, the term HLA will be used to indicate the human system, whilst the term MHC will be used only to indicate a deliberate widening to include other mammalian species, all of which have a superficially similar immune system. Many of the immunological mechanisms and concepts mentioned are arguably established facts and will not be referenced, unless the point being made is of particular importance for the concepts presented here. The term "cognate ligand " is used to mean the combination of MHC and bound peptide which binds fully to a particular T cell receptor. HLA -THE HUMAN MHCHLA molecules have been under intensive investigation for more than 25 years and a number of remarkable features have been discovered. Firstly, there are several molecular families -HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, HLA-DR, HLA-E, HLA-F, HLA-G, HLA-H -that are structurally related (Ig superfamily) membrane-bound molecules with 4 immunoglobulin-like domains, an anchoring transmembrane portion, and a groove on the exterior portion of the molecule which normally has a peptide bound to it. (Further discussion will be limited to the "classical" HLA genes and their products, whereas HLA-E, HLA-F, HLA-G, HLA-H, will not be discussed further here). HLA-A, HLA-B and HLA-C form a more closely-related sub-group, called HLA Class 1, that use a constant molecule, 2 microglobulin, as one of the four domains. HLA-DP, HLA-DQ, HLA-DR form a second structurally-related subgroup, known as MHC Class *Address correspondence to this author at the Nuffield Department of Surgery, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; Tel: 44(0)1865220145; Fax: 44(0)1865768876; E-mail: derek.gray@nds.ox.ac.uk II, that use two different double-Ig-like molecules to produce the 4-domain structure.Secondly, both MHC Class I and MHC Class II molecules exhibit genetically-coded (and therefore heritable) polymorphism that is so extensive that completely identical matching by non-related persons is rarely possible. Despite the polymorphism, all Type 1 and Type II MHC molecules are able to bind peptides derived from a wide range of proteins, holding them in the groove on the surface of the molecule, where they may be prese...