Fig. 15.46 Even complete matching at the MHC does not ensure graft survival. Although syngeneic grafts are not rejected (left panels), MHC‑identical grafts from donors that differ at other loci (minor H antigen loci) are rejected (right panels), albeit more slowly than MHC‑disparate grafts (center panels).
Percentage 100 of grafts surviving
Fig. 15.47 Minor H antigens are peptides derived from polymorphic cellular proteins bound to MHC class I molecules. Self proteins are routinely digested by proteasomes within the cell’s cytosol, and peptides derived from them are delivered to the endoplasmic reticulum, where they can bind to MHC class I molecules and be delivered to the cell surface. If a polymorphic protein differs between the graft donor (shown in red on the left) and the recipient (shown in blue on the right), it can give rise to an antigenic peptide (red on the donor cell) that can be recognized by the recipient’s T cells as nonself and elicit an immune response. Such antigens are the minor H antigens.
(Fig. 15.47). One set of proteins that induce minor histocompatibility responses are encoded on the male Y chromosome. Responses induced by these proteins are known collectively as H-Y. As Y chromosome-specific genes are not expressed in females, female anti-male responses occur; however, male anti-female responses do not occur, because both sexes express X-chromosome genes. One H-Y antigen has been identified in mice and humans as peptides from a protein encoded by the gene Smcy. An X-chromosome homolog of Smcy (or Kdm5d), called Smcx (or Kdm5c), does not contain these peptide sequences, which are therefore expressed uniquely in males. Most minor histocompatibility antigens are encoded by autosomal genes and their identity is largely unknown, although an increasing number have now been identified at the genetic level.
The response to minor histocompatibility antigens is in many ways analogous to the response to viral infection. However, whereas an antiviral response eliminates only infected cells, a large fraction of cells in the graft express minor histocompatibility antigens, and thus the graft is destroyed in the response against these antigens. Given the virtual certainty of mismatches in minor histocompatibility antigens between two individuals, and the potency of the reactions they incite, it is understandable that successful transplantation requires the use of powerful immunosuppressive drugs.
15-32 There are two ways of presenting alloantigens on the transplanted donor organ to the recipient’s T lymphocytes.
Before naive alloreactive T cells can develop into effector T cells that cause rejection, they must be activated by antigen-presenting cells that express both the allogeneic MHC and co-stimulatory molecules. Organ grafts carry with them antigen-presenting cells of donor origin, sometimes called passenger leukocytes, and these are an important stimulus to alloreactivity. This route for sensitization of the recipient to a graft seems to involve donor antigen-presenting cells leaving the graft and migrating to secondary lymphoid tissues of the recipient, including the spleen and lymph nodes, where they can activate those host T cells that bear the corresponding T-cell receptors. Because the lymphatic drainage of solid organ allografts is interrupted by transplantation, migration of donor antigen-presenting cells occurs via the