Immunological Considerations of Transplantation

IMMUNOLOGICAL CONSIDERATIONS OF TRANSPLANTATION

The human major histocompatibility com-plex (MHC) comprises a set of genes on the short arm of chromosome 6. These genes are highly polymorphic and are codominantly expressed, each individual having inher-ited one set of MHC genes from each par-ent. MHC molecules present foreign anti-gens, as well as self-peptides, to T cells for recognition and response. In general, class I MHC molecules present peptides to CD8⁺ T cells, while class II MHC molecules present peptides to CD4⁺ T cells. In the context of transplantation, this process can determine acceptance or rejection of the donor graft.

Class I and II M HC loci carry the great-est significance for transplantation com-pared with other loci within the complex. While their polymorphisms are inherently critical to the species’ ability to resist various pathogens, these polymorphisms also pose one of the major obstacles to transplantation tolerance. Every individual expresses three different pairs of class I molecules (designated as HLA-A, HLA-B, and HLA-C) and three different pairs of class II molecules (designated as HLA-DP, HLA-DQ, and HLA-DR). In addition, the MHC contains other genes that encode complement pro-teins, cytokines, and other proteins involved in antigen processing. Class I MHC molecules are expressed on all nucleated cells, whereas class II MHC molecules are expressed on antigen-presenting cells like macrophages, dendritic cells, B lymphocytes, endothelial cells, and thymic epithelial cells. Expression of MHC gene products is greatly enhanced by cytokines, especially interferon, which stimulates transcription of MHC genes.

Matching the class I and class II MHC genes between the graft and recipient has varying degrees of influence on graft–host interactions and tolerance, differing some-what with the inherent immunogenicity or tolerogenicity of the organ being trans-planted. In kidney transplantation, renal allograft survival directly correlates with the degree of similarity between graft and recipient MHC antigens. Complete HLA matching in liver transplantation is less criti-cal for long-term graft acceptance. Clinically, the HLA-A, HLA-B, and HLA-DR loci are the most relevant for predicting outcome, although the importance of other loci and allelic subtypes is increasingly recognized. Minor histocompatibility antigens are self-peptides derived from nucleotide polymor-phisms that differ between HLA identical siblings yet require HLA identity for presen-tation. These cannot be routinely typed in the laboratory but can greatly influence graft– host interactions in transplantation, especially hematopoietic stem cell transplants.