MHC
The MHC is a highly conserved yet polymorphic gene locus. MHC molecules are surface proteins that present intracellularly processed peptides in a helical groove to their ligand, the T-cell receptor (TCR). Cognate interaction between an MHC molecule presenting peptide on an antigen-presenting cell and a specific TCR on a T cell can result in T-cell activation if the appropriate co-stimulatory molecules are present on the antigen-presenting cell. MHC class I molecules consist of three alpha domains and a b2 microglobulin chain, which is not encoded by the MHC gene locus. MHC class II molecules consist of two alpha domains and two beta domains. Peptides that are presented on the class I molecule are usually derived from intracellular proteins, whereas class II molecules present extracellularly derived peptides. The mechanism by which these peptides are transported to the immature MHC molecule is also very different for class I and class II MHC molecules, and has been recently reviewed in this journal (Ref. 7). The MHC is the major identification molecule that triggers allograft rejection, because it determines the difference between self (syngeneic) and non-self (allogeneic). When searching for a suitable organ donor, it is the MHC antigens that are matched between donor and recipient, to give the graft as good a chance as possible of functioning. In defined situations, this potency of the MHC has been exploited to tip the balance of the immune system from immunity to tolerance. The exposure of the recipient of a graft to donor MHC antigens before transplantation to induce tolerance was first investigated in a mouse model by Billingham and colleagues in 1953, when cells from a donor strain were introduced into a recipient mouse in utero
Following this first attempt, and further studies, pre-transplantation blood transfusions (although not necessarily from graft donors) have been used in the clinic as a means of delivering MHC alloantigens before transplantation, but with limited success. However, the use of blood products also carries inherent risks, such as infections and transfusion reactions; thus, a novel therapy using a more specific approach would eliminate the risks of sensitising transplant recipients to alloantigens that are present in the blood. The delivery of donor genes to cells or tissues in a recipient would offer a highly specific therapy, one that is free from the risks associated with foreign cells and allows transplant recipients to be pre-treated with foreign genes before donor tissue becomes available.
The transfer of MHC genes is also useful in animal models to study the effects of allogeneic MHC antigens on the immune cells of a recipient without the influence of other alloantigens. Such an approach was first carried out by Madsen and colleagues (Ref. 9), when a single MHC class I gene from a donor was transfected into a recipient-type mouse cell line and administered to a recipient. Not only was unresponsiveness to a subsequent cardiac allograft achieved in this study, but it showed that the recipient did not need to be exposed to all of the mismatched donor MHC molecules. Although these experiments proved that this strategy could work, transfected recipient cells are not a practical choice in a clinical setting. The next step was made by Wong and colleagues ; bone marrow cells from recipient mice were transduced (infected with virus) ex vivo with an MHC class I gene using a retroviral gene therapy vector. This approach also resulted in long-term unresponsiveness to a fully allogeneic cardiac allograft, but rejection of a third-party graft, which had MHC class I genes that the recipient had not previously been exposed to.
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