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Effect of continuous complement inhibition using soluble complement receptor type 1 on survival of pig-to-primate
S K Pruitt1, R R Bollinger, B H Collins
1Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Insights
Sustained complement inhibition with soluble complement receptor type 1 (sCR1) delays hyperacute rejection in xenografts. However, this leads to cellular infiltration and accelerated acute rejection, posing a barrier to long-term xenograft survival.
Area of Science:
- Transplantation immunology
- Xenotransplantation research
- Complement system biology
Background:
- Hyperacute rejection (HAR) is a major hurdle in xenotransplantation.
- Soluble complement receptor type 1 (sCR1) can delay HAR but complement activity eventually returns.
- The impact of sustained complement inhibition on xenograft rejection is not fully understood.
Purpose of the Study:
- To investigate the effect of continuous sCR1 infusion on porcine-to-primate cardiac xenograft survival.
- To analyze the histological changes in xenografts under sustained complement inhibition.
Main Methods:
- Two cynomolgus monkeys received porcine cardiac xenografts.
- Continuous infusion of sCR1 was administered to the recipients.
- Serial biopsies of the xenografts were performed for histological analysis.
Main Results:
- Xenograft survival was extended to 5 and 7 days with continuous sCR1 infusion.
- Biopsies revealed increasing infiltration by neutrophils and macrophages.
- Histological findings included edema, hemorrhage, and myocyte necrosis.
Conclusions:
- Sustained complement inhibition delays but does not prevent xenograft rejection.
- Inhibition of complement-mediated HAR may unmask or promote cellular rejection pathways.
- Accelerated acute rejection by cellular infiltrates presents a significant challenge for long-term xenograft survival.
Abstract:
A single bolus of soluble complement (C) receptor type 1 (sCR1, TP-10) has been shown to delay hyperacute rejection (HAR) of porcine cardiac xenografts (Xgs) by primate recipients. In these recipients, C activity slowly returned and C deposition was noted in the Xgs at rejection. To evaluate the effect of sustained C inhibition using sCR1 on HAR, two additional cynomolgus monkeys received porcine cardiac Xgs and a continuous infusion of sCR1. In the first recipient, Xgs survival was 5 days (120+ hr), whereas in the second, Xg survival was 7 days (168+ hr). Serial biopsies of the Xgs were remarkable for an increasing cellular infiltrate composed predominantly of neutrophils and macrophages, and the development of edema, hemorrhage, and myocyte necrosis. These findings suggest that once C-mediated HAR has been inhibited, infiltration of the Xg by these cells may lead to accelerated acute rejection, which is an additional barrier to successful longer term Xg survival.