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Published on: August 12, 2017
The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman
Steven Perrin1, Marianne Magill2
1Eledon Pharmaceuticals, Irvine, CA, United States.
Abstract:
The prevention of allograft transplant rejection by inhibition of the CD40/CD40L costimulatory pathway has been described in several species. We searched pubmed for studies reporting the prevention of kidney transplant rejection in nonhuman primates utilizing either anti CD40 or anti CD40L (CD154) treatment. Inclusion of data required treatment with anti CD40 or anti CD154 as monotherapy treatment arms, full text available, studies conducted in nonhuman primate species, the transplant was renal transplantation, sufficient duration of treatment to assess long term rejection, and the reporting of individual graft survival or survival duration. Eleven publications were included in the study. Rejection free survival was calculated using the Kaplan-Meier (KM) life test methods to estimate the survival functions. The 95% CI for the medians was also calculated. A log-rank test was used to test the equality of the survival curves between control and treatment arms (CD40 and CD154). The hazard ratio for CD154 compared to CD40 and 95% CI was calculated using a Cox proportional-hazards model including treatment as the covariate to assess the magnitude of the treatment effect. Both anti CD40 and anti CD154 treatments prevented acute and long term graft rejection. The median (95% CI) rejection free survival was 131 days (84,169 days) in the anti CD40 treated animals and 352 days (173,710 days) in the anti CD154 treated animals. Median survival in the untreated animals was 6 days. The inhibition of transplant rejection was more durable in the anti CD154 group compared to the anti CD40 group after cessation of treatment. The median (95% CI) rejection free survival after cessation of treatment was 60 days (21,80 days) in the anti CD40 treated animals and 230 days (84,552 days) in the anti CD154 treated animals.
Insights
Inhibiting the CD40/CD40L pathway prevents kidney transplant rejection in nonhuman primates. Anti-CD154 treatment offered more durable rejection-free survival than anti-CD40, significantly improving graft survival post-treatment.
Area of Science:
- Immunology
- Transplantation Biology
- Preclinical Research
Background:
- Allograft transplant rejection is a major clinical challenge.
- The CD40/CD40L costimulatory pathway is a key target for preventing immune-mediated rejection.
- Nonhuman primate models are crucial for evaluating transplant therapies.
Approach:
- Systematic review and meta-analysis of published studies on anti-CD40 or anti-CD154 (CD40L) monotherapy in nonhuman primate kidney transplant models.
- Kaplan-Meier analysis for rejection-free survival and log-rank tests for statistical comparison.
- Cox proportional-hazards model to determine the hazard ratio between anti-CD154 and anti-CD40 treatments.
Key Points:
- Both anti-CD40 and anti-CD154 treatments effectively prevented acute and long-term kidney allograft rejection in nonhuman primates.
- Anti-CD154 treatment resulted in significantly longer median rejection-free survival (352 days) compared to anti-CD40 (131 days).
- The protective effect of anti-CD154 was more durable after treatment cessation, with a median rejection-free survival of 230 days versus 60 days for anti-CD40.
Conclusions:
- Targeting the CD40/CD40L pathway is a viable strategy for preventing kidney transplant rejection.
- Anti-CD154 demonstrates superior efficacy and durability in preventing allograft rejection compared to anti-CD40 in nonhuman primate models.
- These findings support further investigation of anti-CD154 as a therapeutic agent for preventing human kidney transplant rejection.
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