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Grand Rounds |

The Future of Organ and Tissue Transplantation:  Can T-Cell Costimulatory Pathway Modifiers Revolutionize the Prevention of Graft Rejection?

David M. Harlan, MD; Allan D. Kirk, MD, PhD
JAMA. 1999;282(11):1076-1082. doi:10.1001/jama.282.11.1076.
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Transplantation therapies have revolutionized care for patients with end-stage organ (kidney, liver, heart, lung, and pancreatic β-cell) failure, yet significant problems persist with treatments designed to prevent graft rejection. Antirejection therapies are not always effective, must be taken daily, and are both expensive and associated with well-known toxic effects. Recent advances have suggested that the immune system has more self-regulatory capability than previously appreciated. In this review, we discuss immune system function and new therapeutic agents that modify so-called costimulatory receptor signaling to support transplant function without generally suppressing the immune system.

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Figure 1. Antigen Recognition
Graphic Jump Location
T cells use their antigen-specific T-cell receptors (TCR) to recognize antigens (Ag). T-cell receptors recognize only antigen fragments that must be presented by major histocompatibility complex (MHC) molecules. The CD4+ T-cell subset recognizes antigens presented by MHC class II molecules, typically present only on specialized antigen-presenting cells; the CD8+ T-cell subset recognizes antigens presented by more ubiquitously expressed MHC class I molecules.
Figure 2. Two-Signal Model of T-Cell Activation
Graphic Jump Location
A, T-cell receptor–mediated antigen recognition is necessary but not sufficient to activate an antigen-specific T cell. Rather, the 2-signal model, first suggested by Lafferty and Cunningham23 and developed by others, proposes that coincident with the T-cell receptor–mediated signal 1, another costimulatory receptor–mediated signal 2 must be delivered to the T cell. B, The 2-signal model posits that a costimulatory receptor-mediated signal 2 without a T-cell receptor–mediated signal 1 has no effect on the T cell, but that a signal 1 without a signal 2 functionally inactivates the cell or results in its death. MHC indicates major histocompatibility complex; Ag, antigen; TCR, T-cell receptor.
Figure 3. Costimulatory Receptors
Graphic Jump Location
A, The CD28-B7 counter-receptor group consists of 2 B7 ligands (CD80 and CD86) and 2 T-cell receptors (CD28 and CTLA4 [CD152]). Both B7 ligands can bind to both CD28 and CD152. If a T cell receives a T-cell receptor (TCR)–mediated signal, then B7-CD28 interactions generate a costimulatory signal that promotes full T-cell activation, including CD154 expression. B7-CD152 interactions appear to inhibit T-cell activation. B, CD40-CD154 receptor pair interactions most clearly lead to effects on the antigen-presenting cell (APC), including up-regulated expression of inflammatory cytokines, adhesion molecules, and B7. The APC thus activated via its CD40 receptor serves as a more effective stimulator cell for T cells.
Figure 4. Costimulatory Receptor Blockade
Graphic Jump Location
The exact role in allograft rejection of the various costimulatory receptors (CD40, CD80, CD86, CD28, CD152, and CD154) is not completely understood. The B7-CD28 and the CD40-CD154 counter-receptor groups are interrelated and blockade of these interactions effectively prevents allograft rejection in rodents. Studies have demonstrated that either CTLA4-Ig40,41 or anti-CD15447,48 can prevent allograft rejection in rodents, and the combination appears to be especially effective.56 MHC indicates major histocompatibility complex; Ag, antigen; and TCR, T-cell receptor.
Figure 5. CD4 and CD8 T-Cell Activation and Allograft Rejection
Graphic Jump Location
Presentation of donor tissue antigens (Ag) to helper CD4 T cells by "professional" antigen-presenting cells results in CD4 T-cell activation.6164 These activated CD4 T cells then fully activate antigen-presenting cells, which are capable of stimulating CD8 T cells to become killer cells. Resting professional antigen-presenting cells can also be partially activated by lipopolysaccharide and inflammatory cytokines released during transplantation, resulting in increased expression of major histocompatibility complex (MHC) class II and B7. TCR indicates T-cell receptor.

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