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.