When a recipient that has previously rejected a graft is regrafted with skin from the same donor, the second graft is rejected more rapidly (6–8 days) in an accelerated rejection (see Fig. 15.45). Skin from a third-party donor grafted onto the same recipient at the same time does not show this faster response but follows a first-set rejection course. The rapid course of second-set rejection can also be transferred to new recipients by T cells from the initial recipient, showing that second-set rejection is caused by a memory-type response (see Chapter 11) from clonally expanded and primed T cells specific for the donor skin.
Immune responses are the major barrier to effective tissue transplantation, destroying grafted tissue by an adaptive immune response to its foreign proteins. These responses can be mediated by either CD8 or CD4 T cells, or both. Antibodies can also contribute to second-set rejection of tissue grafts.
15-30 Transplant rejection is caused primarily by the strong immune response to nonself MHC molecules.
Antigens that differ between members of the same species are known as alloantigens, and an immune response against such antigens is known as an alloreactive response. When donor and recipient differ at the MHC, an alloreactive immune response is directed at the nonself allogeneic MHC molecule or molecules on the graft. In most tissues these are predominantly MHC class I antigens. Once a recipient has rejected a graft of a particular MHC type, any further graft bearing the same nonself MHC will be rapidly rejected in a second response. The frequency of T cells specific for any nonself MHC molecule is relatively high, making differences at MHC loci the most potent trigger of initial graft rejections (see Section 6-13); indeed, the MHC was originally so named because of its central role in graft rejection.
Once it became clear that recognition of nonself MHC molecules was a major determinant of graft rejection, a considerable amount of effort was put into MHC matching of recipient and donor. Today, with advances in immunosuppression, MHC matching has become largely irrelevant for most allografts, although it remains important for bone marrow transplantation, for reasons that are discussed in Section 15-36. Even a perfect match at the MHC locus, known as the HLA locus in humans, does not prevent rejection reactions. Grafts between HLA-identical siblings will invariably incite a rejection reaction, albeit more slowly than an unmatched graft, unless donor and recipient are identical twins. This reaction is the result of differences between antigens from non-MHC proteins that also vary between individuals.
Thus, unless donor and recipient are identical twins, all graft recipients must be given immunosuppressive drugs chronically to prevent rejection. Indeed, the current success of clinical transplantation of solid organs is more the result of advances in immunosuppressive therapy (see Chapter 16) than of improved tissue matching. The limited supply of cadaveric organs, coupled with the urgency of identifying a recipient once a donor organ becomes available, means that accurate matching of tissue types is achieved only rarely, with the notable exception of matched-sibling donation of kidneys.
15-31 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules.
When donor and recipient are identical at the MHC but differ at other genetic loci, graft rejection is not as rapid, but left unchecked it will still destroy the graft (Fig. 15.46). This is the reason that grafts between HLA-identical siblings would be rejected without immunosuppressive treatment. MHC class I and II molecules bind and present a large selection of peptides derived from self proteins made in the cell, and if these proteins are polymorphic, then different peptides will be produced from them in different members of a species. Such proteins can also be recognized as minor histocompatibility antigens