Tolerance in Heart Transplantation: The Cost of Achieving the Holy Grail of Transplant

Tolerance is the Holy Grail of transplant for several reasons. First, harmful lifelong immunosuppression and related complications can be avoided. Second, the ultimate goal of “one transplant for life” can be achieved by improving the health of transplant recipients and the longevity of transplanted organs.1 However, tolerance is not yet a regular daily practice, and the induction of a successful tolerance may bring up important challenges and complications. Most importantly, it is known that different organs behave differently to the same tolerogenic protocols. Although abdominal organ transplants, such as kidney and liver allografts, are considered to be “tolerance-prone” organs due to their relatively weaker immunogenicity, thoracic organ transplants (ie, heart and lung allografts) are considered as “tolerance-resistant” organs due to their higher immunogenicity.2 In 2008, the Boston group reported that they stopped all maintenance immunosuppression therapy 9 to 14 mo after renal transplantation with the use of a nonmyeloablative preparative regimen, which included thymic irradiation and bone marrow transplant.3 Although the study was limited to 4 patients, renal function remained stable for 2 to 5 y without immunosuppression, and T cells from those 4 patients obtained after withdrawal of immunosuppressive therapy showed donor-specific unresponsiveness.3 In 2014, the same Boston group reported 10 tolerogenic renal transplant recipients with long-term outcomes.4 In an effort to use clinically applicable costimulation-based immunosuppressive regimen and delayed bone marrow transplant as a transient mixed hematopoietic chimerism protocol, Hotta et al5 showed long-term renal allograft tolerance in nonhuman primates. Other groups showed kidney allografts-induced tolerance of heart allografts through mixed hematopoietic chimerism when transplanted simultaneously in mice, swine, and nonhuman primates, which has been considered as “kidney-induced heart allograft tolerance.”6 However, there was no successful report of tolerance of heart allografts when they were transplanted as heart transplants alone. In this issue of Transplantation, Chaban et al7 reported their experience in “heart” (alone) allograft tolerance in nonhuman primates using enhanced costimulation blockade regimen with anti-CD154 monoclonal antibody (mAb), anti-CD2 mAb, and anti-CD28 mAb. They transplanted 8 macaques with heterotopic hearts from major histocompatibility complex-mismatched donors. The regimen included intensive costimulation blockade-based immunosuppression as well as other powerful treatments, such as total body irradiation, thymic irradiation, and donor bone marrow transplantation. The authors concluded that intensive costimulation pathway blockade with anti-CD154 mAb, CD2 mAb, and anti-CD28 mAb promoted lymphocyte chimerism at the cost of high incidence of posttransplantation lymphoproliferative disease and opportunistic infections. Unfortunately, these serious complications prevented the assessment of the immunosuppressive regimen’s long-term effectiveness to promote alloimmune tolerance.7 The study by Chaban et al has exciting new findings as well as certain limitations.7 First, the study used novel humanized anti-CD154 mAb that contains the hu5c8 Fab region and an engineered Fc region, which downregulates FcγR2 binding to reduce platelet activation, therefore anti-CD154 pathway-related prothrombotic events. Second, the study targeted the CD2 pathway on mature T cells, inhibiting T-cell proliferation and memory T cells, and the CD28 pathway reducing acute cellular rejection through the inhibition of different costimulation pathways, such as CD28/B7 and CD28-dependent CD154 blockade. In contrast, the study was limited because of (1) its small sample size, (2) high incidence of complications not enabling long-term follow-up, (3) variation in the quantity of viable bone marrow cells for each transplant, and (4) other immunological diversity, such as level of immunosuppression and amount of blood transfusion with cross-reactive antidonor antibodies. Despite all challenges and negative results, the preclinical tolerance induction study by Chaban et al in heart allotransplant alone in nonhuman primates showed us again that the Holy Grail of transplant is not easy to achieve, and more research needs to be done to reach the goal of “one transplant for life.” Currently, the cost of achieving tolerance in heart allotransplant alone is too high that recipients pay the price with life-threatening complications, such as posttransplantation lymphoproliferative disease, lethal infections, or irreversible rejections. Therefore, it is crucial to understand and acknowledge that clinical heart transplantation is currently not ready to handle such a risk. However, with continued rigorous research into new tolerogenic protocols,8 the ultimate goal of having tolerance in heart allografts could be a clinical reality. We, therefore, acknowledge the importance of work by Chaban et al, which paves an important stone to the long but important road of tolerance.