The transplantation of tissue from one individual to another most often results in an adverse immune reaction between the host and the transplanted tissue, leading to graft rejection. The inclusion of lymphoid effector cells in a tissue graft can lead to graft-versus-host disease as well. These phenomena stem primarily from discordant expression of MHC cell surface molecules encoded by polymorphic class I and class II loci of the major histocompatibility complex (MHC). Graft acceptance or rejection is most strongly associated with identity or difference at class I loci, followed by class II and so-called minor histocompatibility antigens, as described below. The clinical evaluation of donor-host compatibility involves "tissue typing" individuals to determine the alleles present at the HLA-A, -B, and -DR loci. In practice, perfect matches at these loci are rare (requiring identity at as many as six independent loci, because gene products from maternal and paternal chromosomes are co-dominantly expressed); the majority of transplants rely mainly on the use of immunosuppressive agents postoperatively to increase graft survival. Host individuals are additionally screened for the presence of serum antibodies to MHC molecules, arising from prior exposure to non-self MHC through a blood transfusion or pregnancy.
Allograft rejection involves a variety of phenomena; the discussion here is confined to mismatched donor-host class I alleles (whose gene products have often been referred to as "classical transplantation antigens") as the basis for tissue incompatibility. MHC class I molecules present peptide antigens to the clonally expressed T-cell receptors (TCRs) of cytotoxic T lymphocytes (CTLs). The composition of the peptides presented by a given class I molecule is influenced by allomorph-specific peptide binding preferences, which in turn are a function of polymorphic amino acid residues found in the peptide-binding region of the class I molecule. Under typical circumstances, CTLs are rendered tolerant to the self class I/self peptide complexes expressed in an individual. The presence of an allograft introduces a new cohort of class I/peptide complexes into the host system, and the array of peptides displayed on the cells of the graft will reflect the binding preferences of the donor’s class I allomorphs. Among these allo-MHC/peptide complexes are potentially numerous epitopes to which the host individual is not tolerant, thereby marking cells of the transplanted tissue for destruction by circulating CTL.
The cellular immune response to non-self class I/peptide complexes is termed "alloreactivity." The molecular basis for TCR recognition of allo-MHC molecules has long been an area of intensive study and debate in immunology. The preceding paragraph implies a scheme in which allorecognition is a peptide-specific phenomenon and fundamentally similar to the recognition of self class I+foreign peptide. In this view, conserved regions of the majority of class I molecules are themselves likely to provide similar molecular surfaces for contact with the TCR, regardless of the class I allomorph being considered. Specific interactions thus occur between variable regions of the TCR and the class I-bound peptide. There is now considerable evidence to support this model of allorecognition (1). However, allotypic residues on the surface of a class I molecule may also provide critical determinants for allorecognition by some TCR (2), and it is possible that both modes of recognition are utilized in the polyclonal T-cell response to an allograft.
The peptide-based nature of allorecognition also accounts for the involvement of "minor histocompatibility antigens" in graft rejection. Even when genetically nonidentical donor and host are HLA matched, they also manifest differences stemming from the expression of variants of several other polymorphic proteins. A well-known example is the H-Y antigen, encoded on the Y-Chromosome of males, which presents a barrier to successful male-to-female transplantation. This protein is expressed in nearly all tissues and differs in amino acid sequence from its X-chromosome homologue (present in both males and females) (3). Consequently, some H-Y antigen-derived peptides that are presented by MHC class I molecules (3, 4) will constitute novel epitopes in a female host receiving tissue from a male donor, provoking a cellular immune response. The total number of human minor histocompatibility loci and the identity of the proteins they encode remain as yet undetermined.
