CHAPTER 40: Transplant Immunology

INTRODUCTION

The major barrier to successful transplantation is the recipient’s immune response directed against the donor kidney. The transplanted kidney is recognized as foreign by the body’s immune system. This foreignness is mediated primarily by proteins encoded by the genes located in the major histocompatibility complex (MHC) region. The focus of this chapter is to outline the major immune processes of allograft recognition and response and the methods used to define the patient’s immune profile.

RECOGNITION OF ALLOGRAFTS

Major Histocompatibility Antigens

• MHC is a gene cluster in jawed vertebrate deoxyribonucleic acid (DNA) that codes for cell surface proteins essential for the immune system.

• MHC is so called because it was identified during the study of tissue compatibility in transplantation.

• The main purpose of MHC is to differentiate between self and nonself—to facilitate the immune system to fight infections.

• The MHC system is the major mechanism by which the recipient immune system recognizes the allografts.

• In humans, the MHC is located on chromosome 6 and encodes highly polymorphic cell surface glycoproteins known as human leukocyte antigens (HLAs).

• The first HLA was discovered in 1958 by Jean Dausset (Nobel Prize 1980). Called antigen MAC in honor of three volunteers for the experiment, the first discovered HLA was later renamed HLA-A2.¹

• These polymorphic glycoproteins present peptides to T lymphocytes.

• A genetic locus is a specific position on a chromosome where a gene is located. For any gene, an allele is one of two or more versions of that gene. Humans are diploid organisms because they have two alleles at each genetic locus—one allele inherited from each parent. Alleles are due to variations in the DNA sequence at a genetic locus. Some genes have only one allele, but most have two or more. Such variations in DNA sequence are called polymorphisms. A gene is polymorphic if its locus in a population has more than one allele and each allele is present at >1% in the population.

• MHC genes are the most polymorphic of all genes. With the exception of identical twins, no two individuals in a mixed population have the exact same set of MHC genes.

• The variability in DNA sequence (that makes MHC genes polymorphic) is in the region of the MHC that binds to the peptide.

• The evolution of the MHC polymorphism ensures that at least some individuals in a population will be able to respond to a new or mutated pathogen.

• Polymorphisms, however, make the HLA a major obstacle for successful transplantation.

• The entire HLA is closely linked and is inherited en bloc as a haplotype.

• HLA gene products—membrane-bound glycoproteins—are of two major classes: HLA class I and class II.

Human Leukocyte Antigens Class I

• HLA class I gene products are expressed on the surface of all nucleated cells.

• HLA class I molecules present peptides from intracellular proteins to cytotoxic CD8+ ...