Pre‐transplant antibody screening and anti‐CD154 costimulation blockade promote long‐term xenograft survival in a pig‐to‐primate kidney transplant model

Abstract

Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.

A Bridge to Somewhere

“…(3) The addition of belatacept costimulation blockade: In a pig-to-primate kidney xenotransplantation model, low anti-pig antibody titer recipients receiving belatacept demonstrated increased survival (21 days versus 6 days) when compared with primate recipients of a similar regimen without the use of belatacept. 5 Furthermore, anti-CD154 monoclonal antibody costimulation blockade extended survival to >133 days. The use of costimulation blockade has also been investigated in a pig-to-baboon heterotopic heart xenotransplantation model, where a belatacept based regimen provided the longest survival (99 and 130 days) along with the absence of thrombocytopenia.…”

Bringing Home The Bacon: Update on The State of Kidney Xenotransplantation

“…Maximum pig kidney graft survival has increased from minutes to months, and occasionally to >1 year (Fig. 1) [19, 20, 22, 23]. These encouraging results have led to consideration of initial clinical trials.…”

New life for pig-to-human transplants

“…"Now we can make a new pig from scratch in 150 days. " His group recently used CRISPR to knock out two pig genes simultaneously 7 . The researchers are now beginning to transplant CRISPR-modified pig organs into macaques, one of which has survived for more than three months.…”