Blocking CoStimulatory Signals Can Induce Anergy

As described in Chapter 10, TH-cell activation requires a co-stimulatory signal in addition to the signal mediated by the T-cell receptor. The interaction between the B7 molecule on the membrane of antigen-presenting cells and the CD28 or CTLA-4 molecule on T cells provides one such signal (see Figure 10-13). Lacking a co-stimulatory signal, antigen-activated T cells become anergic (see Figure 10-15). CD28 is expressed on both resting and activated T cells and binds B7 with a moderate affinity; CTLA-4 is expressed at much lower levels and only on activated T cells but binds B7 with a 20-fold higher affinity. A second pair of co-stimulatory molecules required for T-cell activation are CD40, which is present on the APC, and CD40 ligand (CD40L or CD 154), which is present on the T cell.

D. J. Lenschow, J. A. Bluestone, and colleagues demonstrated that blocking the B7-mediated co-stimulatory signal with CTLA-4 after transplantation would cause the host's

T cells directed against the grafted tissue to become anergic, thus enabling it to survive. In their experiment, human pancreatic islets were transplanted into mice injected with CTLA-4Ig, a soluble fusion protein consisting of the extracellular domains of CTLA4 and the constant region of the IgG1 heavy chain (see Figure 10-14). Including the IgG1 heavy-chain constant region increases the half-life of the soluble fusion protein. The xenogeneic graft exhibited long-term survival in treated mice but was quickly rejected in untreated controls. The fact that the soluble form of the CTLA-4 receptor was able to block the rejection of the human tissue transplant in the recipient mice is evidence that blocking co-stimulatory signals in vivo is a viable strategy (Figure 21-9).

These exciting results were extended to transplantation of kidneys mismatched for class I and class II antigens in monkeys by Allan Kirk, David Harlan, and their colleagues. The recipients were treated for about 4 weeks after transplantation with either CTLA4-Ig or a monoclonal antibody directed against CD40L, or both in combination. Untreated control animals rejected the mismatched kidneys within 5-8 days; those treated with a single agent retained their grafts for 20-98 days. However, the animals given both reagents showed no evidence of rejection at 150 days after transplantation. This suppression of allograft rejection did not lead to a state of general immunosuppression; peripheral T-cell counts remained normal and other immune functions were present, including mixed lymphocyte reactivity between donor and recipients. Human clinical trials of the procedures developed for monkeys are planned; if successful, they could revolutionize clinical transplantation procedures. The ability to block

Mixed Lymphocyte Reaction Procedure

CD28

T cell

CD28

T cell

T cells that recognize graft antigens become activated

Graft rejected

Cells Recognize Graft
T cells that recognize graft antigens lack co-stimulation and become anergic

Graft survives

FIGURE 21-9

Blocking co-stimulatory signals at the time of transplantation can cause anergy instead of activation of the T cells reactive against the graft. T-cell activation requires both the interaction of the TCR with its ligand and the reaction of co-stimulatory receptors with their ligands (a). In (b), contact between one of the co-stimulatory re ceptors, CD28 on the T cell, and its ligand, B7 on the APC, is blocked by reaction of B7 with the soluble ligand CTLA-4Ig. The CTLA4 is coupled to an Ig H chain, which slows its clearance from the circulation. This process specifically suppresses graft rejection without inhibiting the immune response to other antigens.

allograft rejection without general immunosuppression and without the deleterious side effects of suppressive drugs would enable recipients to lead normal lives.

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Essentials of Human Physiology

Essentials of Human Physiology

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  • Mattalic
    Can anergic t cells be activated by tissue graft?
    8 years ago

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