Similar Antigenic Profiles Foster Allograft Acceptance

Tissues that are antigenically similar are said to be histocom-patible; such tissues do not induce an immunologic response that leads to tissue rejection. Tissues that display significant antigenic differences are histoincompatible and induce an immune response that leads to tissue rejection. The various antigens that determine histocompatibility are encoded by more than 40 different loci, but the loci responsible for the most vigorous allograft-rejection reactions are located within the major histocompatibility complex (MHC). The organization of the MHC—called the H-2 complex in mice and the HLA complex in humans—was described in Chapter 7 (see Figure 7-1). Because the MHC loci are closely linked, they are usually inherited as a complete set, called a haplo-type, from each parent.

VISUALIZING CONCEPTS

VISUALIZING CONCEPTS

(a) Autograft acceptance

Grafted epidermis

Days 3-7: Revascularization

(b) First-set rejection

Grafted epidermis

(c) Second-set rejection

Grafted epidermis

(a) Autograft acceptance

Grafted epidermis

(b) First-set rejection

Grafted epidermis

(c) Second-set rejection

Grafted epidermis

Autograft Acceptance

Days 3-7: Revascularization

Days 3-4: Cellular infiltration

Days 3-7: Revascularization

Days 3-7: Revascularization

Days 3-4: Cellular infiltration

Days 7-10: Healing

Neutrophils

Days 12-14: Resolution

Days 7-10: Cellular infiltration

Days 5-6: Thrombosis and necrosis

Days 7-10: Cellular infiltration

Days 5-6: Thrombosis and necrosis

Blood clots

Days 10-14: Thrombosis and necrosis

Days 12-14: Resolution

Days 10-14: Thrombosis and necrosis

Allograft Acceptance And Rejection
Necrotic tissue

FIGURE 21-1

Schematic diagrams of the process of graft acceptance and rejection. (a) Acceptance of an autograft is completed within 12-14 days. (b) First-set rejection of an allograft begins 7-10 days after grafting, with full rejection occurring by

10-14 days. (c) Second-set rejection of an allograft begins within 3-4 days, with full rejection by 5-6 days. The cellular infiltrate that invades an allograft (b, c) contains lymphocytes, phagocytes, and other inflammatory cells.

Within an inbred strain of mice, all animals are homozygous at each MHC locus. When mice from two different inbred strains, with haplotypes b and k, for example, are mated, all the F1 progeny inherit one haplotype from each parent (see Figure 7-2a). These F1 offspring have the MHC type b/k and can accept grafts from either parent. Neither of the parental strains, however, can accept grafts from the F1 offspring because each parent lacks one of the F1 haplotypes. MHC inheritance in outbred populations is more complex, because the high degree of polymorphism exhibited at each MHC locus

First skin graft, strain A

First skin graft, strain A

Naive strain = B mouse

Naive strain = B mouse

First-set rejection

14 days

Necrosis

Second skin graft, strain A

Second-set rejection

First-set rejection

Time

Necrosis

6 days

Second-set rejection

Necrosis

Spleenic T cells

Spleenic T cells

First skin graft, strain A

Naive strain = B mouse

First skin graft, strain A

6 days

Second-set rejection

Necrosis

Second-set rejection

Necrosis

Naive strain = B mouse

FIGURE 21-2

Experimental demonstration that T cells can transfer allograft rejection. When T cells derived from an allograft-primed mouse are transferred to an unprimed syngeneic mouse, the recipi ent mounts a second-set rejection to an initial allograft from the original allogeneic strain.

gives a high probability of heterozygosity at most loci. In mat-ings between members of an outbred species, there is only a 25% chance that any two offspring will inherit identical MHC haplotypes (see Figure 7-2c), unless the parents share one or more haplotypes. Therefore, for purposes of organ or bone-marrow grafts, it can be assumed that there is a 25% chance of identity within the MHC between siblings. With parent-to-child grafts, the donor and recipient will always have one hap-lotype in common but are nearly always mismatched for the haplotype inherited from the other parent.

Anti-CD8

Control

I Anti-CD4

Anti-CD4 and Anti-CD8

15 30

Time after grafting, days

FIGURE 21-3

The role of CD4+ and CD8+ T cells in allograft rejection is demonstrated by the curves showing survival times of skin grafts between mice mismatched at the MHC. Animals in which the CD8+ T cells were removed by treatment with an anti-CD8 monoclonal antibody (red) showed little difference from untreated control mice (black). Treatment with monoclonal anti-CD4 (blue) improved graft survival significantly, and treatment with both anti-CD4 and anti-CD8 antibody prolonged graft survival most dramatically (green). [Adaptec! from S. P. Cobbold et al, 1986, Nature 323:165.]

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