Past, present, and future prospects for inducing donor-specific transplantation tolerance for composite tissue allotransplantation

Abstract

Composite tissue allotransplantation (CTA) is among the most immunologically complex and newest transplant fields. Although the field has made considerable advances, there are still concerns that these procedures are performed to enhance quality-of-life issues and are not lifesaving procedures that restore physiologic function. Two challenges limit the widespread application of CTA; the first is chronic rejection, the most prevailing cause of organ allograft failure after transplantation; the second barrier is the numerous health complications associated with lifelong immunosuppressive therapy. Several tolerance-inducing strategies, including costimulatory blockade, T-cell depletion, mixed chimerism, and gene targeting of transplanted organs, have the potential to induce lifelong tolerance to organ allografts without chronic immunosuppression. Effective clinical tolerance protocols that improve CTA acceptance and offer an alternative to the requirement for chronic immunosuppressive therapy could be a major advance in the field. Tolerance would allow allotransplantation to provide a currently unmet need for reconstruction of large tissue defects. This article reviews the history of CTA, current challenges and complications, and offers future directions for CTA research in strategies to induce tolerance.

Keywords: Composite tissue allotransplantation (CTA); immunosuppression; induction immunosuppression; maintenance immunosuppression; tolerance.

Figure 1

Master of Los Balbases (ca. 1495): The Miracle of Cosmas and Damian.

Figure 2

Matt Scott, the world's first successful hand transplant recipient, being evaluated.

Figure 3

(A) Depiction of the anatomy of laryngeal allograft. (B) Dr. Marshall Strome with the world's first laryngeal transplant recipient.

Figure 4

Association of CD4⁺ helper T cells with APCs requires the interaction of multiple T-cell membrane proteins with their respective receptors on the target APC. (Adapted from: Abbas AK and Lichtman AH. Cellular and Molecular Immunology. 5th ed. Amsterdam: Elsevier; 2005:114, Fig. 6–8.)

Figure 5

Mixed hematopoietic chimerism for induction of donor-specific tolerance.

Figure 6

Chimeras accept CTA.