Graft from F1 hybrid is rejected by inbred parental strain

FIGURE 16-3 The genetics of graft rejection. In the illustration, the two different mouse colors represent inbred strains with different MHC haplotypes. Inherited MHC alleles from both parents are codominantly expressed in the skin of an A x B offspring, and therefore these mice are represented by both colors. Syngeneic grafts are not rejected (A). Allografts are always rejected (B). Grafts from an A or B parent will not be rejected by an (A x B)F1 offspring (C), but grafts from the offspring will be rejected by either parent (D). These phenomena are due to the fact that MHC gene products are responsible for graft rejection; grafts are rejected only if they express an MHC type (represented by green or orange) that is not expressed by the recipient mouse.

and see both A and B tissues as self, whereas inbred A or B animals express only one allele and see (A x B)F1 tissues as partly foreign. This is why an (A x B)F1 animal does not reject either A or B strain grafts and why both A and B strain recipients reject an (A x B)F1 graft.

The molecules responsible for almost all strong (rapid) rejection reactions are called major histocompatibility complex (MHC) molecules. George Snell and colleagues used pairs of congenic strains of inbred mice, which were bred to be genetically identical to each other except for genes needed for graft rejection, to identify the polymorphic genes that encode the molecular targets of allograft rejection. This approach led to the identification of MHC genes as the underlying genetic basis of graft rejection. Transplants of most tissues between any pair of individuals, except identical twins, will be rejected because MHC molecules, the major polymorphic targets of graft rejection, are expressed on virtually all tissues. As discussed in Chapter 6, the normal function of MHC molecules is to present peptides derived from protein antigens in a form that can be recognized by T cells. The role of MHC molecules as the antigens that cause graft rejection is a consequence of the nature of T cell antigen recognition, as we will discuss later. Recall that human MHC molecules are called human leukocyte antigens (HLA), and in the context of human transplantation, the terms MHC and HLA are used interchangeably.

Allogeneic MHC molecules of a graft may be presented for recognition by the T cells of the recipient in two fundamentally different ways, called direct and indirect (Fig. 16-4). Initial studies showed that the T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft, and this is called direct presentation of alloantigens. Subsequent studies showed that sometimes, the recipient T cells recognize graft MHC molecules only in the context of the recipient's MHC molecules, implying that the recipient's MHC molecules must be presenting allogenic graft MHC proteins to recipient T cells. This process is called indirect presentation, and it is essentially the same as the presentation of any foreign (e.g., microbial) protein antigen. Not only MHC molecules but other alloantigens in a graft that are different between the donor and recipient can also be presented to host T cells by the indirect pathway. We discuss the mechanisms of direct and indirect presentation separately.

Direct alloantigen recognition

Allogeneic APC in graft

I Alloreactive T cell

Allogeneic MHC

I Alloreactive T cell

B Indirect alloantigen presentation

Allogeneic MHC

Professional APC in recipient

Alloreactive

Allogeneic MHC

Professional APC in recipient

Alloreactive

Self MHC Uptake and processing of allogeneic MHC molecules by recipient APC

Peptide derived from allogeneic MHC molecule

T cell recognizes unprocessed allogeneic MHC molecule on graft APC

Presentation of processed peptide of allogeneic MHC molecule bound to self MHC molecule

FIGURE 16-4 Direct and indirect alloantigen recognition. A, Direct alloantigen recognition occurs when T cells bind directly to an intact allogeneic MHC molecule on a graft (donor) antigen-presenting cell (APC). B, Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up and processed by recipient APCs and peptide fragments of the allogeneic MHC molecules containing polymorphic amino acid residues are bound and presented by recipient (self) MHC molecules.

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