Table 2.

Mechanistic Barriers to Pig-to-Human Heart Xenografting

Phenomenon	Kinetics	Mechanisms
Hyperacute rejection	Minutes to hours	Preformed antibody, complement, clot formation
Initial xenograft dysfunction	Minutes to hours	Immunological? Physiological?
Acute humoral rejection	Days	Preformed antibody rebound, elicited antibody
	Weeks	Elicited immunity, dysregulated coagulation

DXR indicates delayed xenograft rejection.

Genetic modifications to swine and mechanism-directed graft and recipient treatments have successfully prevented each of the phenomena encountered in pig-to-primate heart xenotransplantation models as described in the text. We expect that preclinical results in a life-supporting pig-to-baboon model⁴ predict safe clinical translation.

Chronic rejection will be observed in long-surviving organ xenografts if the immune response to the donor cannot be safely constrained by genetic modifications to the graft combined with immunomodulatory drug treatments. For organ xenografts, the source pig is genetically defined and known in advance, and the transplantation procedure can be timed to take advantage of recipient pretreatments designed to favor graft acceptance. Consequently, induction of cross-species tolerance—long-term graft acceptance without ongoing immunosuppressive treatment—is likely to be feasible, potentially offering advantages relative to conventional allotransplantation from deceased human donors. Patient selection criteria and clinical trial design considerations for the initial pilot studies in humans have been reviewed recently.¹⁰