The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation

Abstract

Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

“…20,21 Despite the plethora of combinations potentially available, it is unclear which ones will be necessary and/or sufficient for successful xenotransplant. 17,[24][25][26][27][28] Our induction immunosuppression strategy used peritransplant depletion with mAbs directed at CD4 and CD8, mimicking the T cell depletion effects of a clinically available agent like antithymocyte globulin. 22,23 Beyond the humoral response and intraspecies compatibility of the coagulation and complement systems lies the T cell response to xenogeneic tissues, which is comparable, if not more formidable, than in allotransplant.…”

“…To date, most successful immunosuppression regimens in xenotransplant have used some form of T cell depletion as induction along with mAb therapy to disrupt the CD40-CD154 pathway. 17,[24][25][26][27][28] Our induction immunosuppression strategy used peritransplant depletion with mAbs directed at CD4 and CD8, mimicking the T cell depletion effects of a clinically available agent like antithymocyte globulin. An additional advantage to this particular regimen is the ability to delineate the independent contributions of either CD4 or CD8 T cells through selective depletion.…”

“…Blockade of the CD40-CD154 pathway has been a critical component of almost all immunosuppressive regimens that have ultimately led to long-term xenograft survival in preclinical models 17,[24][25][26][27][28]. To date, we have relied on anti-CD154 therapy as the cornerstone of our immunosuppression regimen.…”

Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

“…Xenotransplant may provide an effective alternative to solve the problem of organ shortage . The availability of pigs with multiple genetic modifications and the introduction of novel immunosuppressive agents have resulted in greatly increased pig organ graft survival in nonhuman primates (NHPs) . However, there remain problems, such as inflammation, that contribute to graft failure and immune‐related complications …”

Xenotransplantation

“…The resurgence of xenotransplantation is now obvious [9,10,106], with prolonged survival of cellular and solid organ xenografts (Figure 2) associated with the administration of newer costimulation blockade agents [107,108] and access to genetically-engineered pigs. Our increasing knowledge of the pig genome [109] will almost certainly lead to further genetic manipulations.…”