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Prolonging discordant xenograft survival with anticomplement reagents K76COOH and FUT175
S Miyagawa1, R Shirakura, G Matsumiya
1First Department of Surgery, Osaka University Medical School, Japan.
Insights
Complement inhibition prolongs xenograft survival. Blocking complement factor B and C3 with reagents like FUT175 is effective in preventing rapid rejection of transplanted organs, crucial for discordant xenotransplantation research.
Area of Science:
- Immunology
- Transplantation Biology
- Complement System
Background:
- The alternative complement pathway is a key driver of hyperacute rejection in discordant xenotransplantation.
- Guinea pig hearts transplanted into rats are rejected within 30 minutes due to this pathway.
- Natural antibodies do not play a significant role in this rejection process.
Purpose of the Study:
- To evaluate the efficacy of anti-complement reagents in prolonging discordant xenograft survival.
- To investigate the specific roles of complement factors B and D in xenograft rejection.
- To determine the impact of inhibiting the alternative complement pathway on xenograft survival time.
Main Methods:
- Utilized a rat heterotopic guinea pig heart transplantation model.
- Administered anti-complement reagents K76COOH (K76) and FUT175 (FUT) in vivo.
- Assessed complement pathway activity (ACH50), complement factor levels (B, D, C3), and xenograft survival time.
Main Results:
- FUT175 significantly inhibited complement factors B and C3, abrogating alternative pathway activity (ACH50) for over 6 hours.
- FUT175 administration prolonged xenograft beating time approximately threefold.
- K76COOH showed only slight suppression of factors B and D and a decrease in C3, with no significant effect on graft survival.
- Combined K76 and FUT treatment yielded the longest graft survival, but this was negated by antigraft antibodies.
Conclusions:
- Direct inhibition of complement factor B is critical for suppressing the alternative pathway and achieving xenograft survival.
- Anti-complement reagents targeting factors B and C3 are promising for managing xenograft rejection mediated by the alternative complement pathway.
- Further strategies are needed to overcome antibody-mediated rejection in conjunction with complement inhibition.
Abstract:
The guinea pig heart, when transplanted into the rat heterotopically, is rejected within 30 min via activation of the alternative complement pathway. Natural antibody does not contribute to rejection. This xenotransplantation model was used to assess the effect of anti-complement reagents on discordant xenograft survival. In vivo administration of K76COOH (K76) to rats induced only slight suppression of factors B and D and a marked decrease of C3, leading to the depression of ACH50 (reflecting the potency of the alternative pathway). On the other hand, FUT175 (FUT) reduced C3 activity by about 80% and inhibited factor B activity nearly 100% < 1 hr after the administration, but inhibited factor D activity only marginally. FUT abrogated ACH50 for > 6 hr. Of note, the xenograft beating time was prolonged approximately 3 times by FUT but not by K76, suggesting that direct inhibition of plasma serine protease factor B results in the complete suppression of ACH50 and graft survival. The administration of both K76 and FUT resulted in the longest graft survival, but the effects of these reagents were abolished by additional antigraft antibody. Anticomplement reagents that block factor B and C3 are therefore effective for prolongation of discordant xenograft survival when the graft rejection is associated with the complement alternative pathway.