The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

TLDR

Acute vascular rejection remains the main barrier to long‑term xenotransplant success, and its cause is thought to involve the recipient’s humoral immune response to the donor. The study aimed to determine whether antibodies contribute to acute vascular rejection in a pig‑to‑baboon heterotopic cardiac transplant model. The authors used transgenic pigs expressing human decay‑accelerating factor and CD59 and transplanted their hearts into baboons, with or without antibody depletion via anti‑immunoglobulin columns. In pig‑to‑baboon cardiac transplants, hearts from transgenic pigs expressing human decay‑accelerating factor and CD59 underwent acute vascular rejection within five days, whereas antibody‑depleted baboons showed no rejection in five of six cases, with biopsies revealing minimal IgM/IgG and normal complement activity, indicating that antibodies are a key driver of rejection and that humoral‑targeted therapies could prevent or treat this complication.

Abstract

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens.