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Meta-Analysis
. 2022 Apr 7:13:861471.
doi: 10.3389/fimmu.2022.861471. eCollection 2022.

The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis

Steven Perrin  1 , Marianne Magill  2
Affiliations
Meta-Analysis

The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis

Steven Perrin et al. Front Immunol. .

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.

Keywords: CD154; CD40; CD40L; renal transplant; tolerance; transplant rejection.

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Conflict of interest statement

SP declares that he is employed by Eledon Pharmaceuticals. Eledon is developing an anti CD40L antibody for renal and islet cell transplant. MM is an independent paid statistical consultant to Eledon Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
PRISMA Flow Chart of Literature Search.
Figure 2
Figure 2
Kaplan Meier Survival Plot and Risk Table for Treatments versus Placebo. Kaplan-Meier estimates of the probability of rejection free survival by treatment group. Median survival untreated (6 days), CD40 (131 days), and CD154 (352 days) groups (P = 0.0001; log-rank test).
Figure 3
Figure 3
Meta Analysis: Inverse Variance Weighting Random Effects Model. Published studies of anti CD40 and anti CD154 antibodies in nonhuman primates. Forest plot displaying random effects meta-analysis results of the association compared to nontreated animals. The Black circle is the mean values for treatment effect across all studies. Light Grey circles are anti CD40. Dark Grey circles are anti CD154.
Figure 4
Figure 4
Kaplan Meier Survival Plot and Risk Table for Treatment Durability. Kaplan-Meier estimates of the probability of rejection free survival by treatment group after discontinuation of treatment. Median survival CD40 (38 days), and CD154 (198 days) groups (P = 0.0003 log-rank test).
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References

    1. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-Term Renal Allograft Survival in the United States: A Critical Reappraisal. Am J Transplant (2011) 11(3):450–62. doi: 10.1111/j.1600-6143.2010.03283.x - DOI - PubMed
    1. Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM. B7, A New Member of the Ig Superfamily With Unique Expression on Activated and Neoplastic B Cells. J Immunol (1989) 143(8):2714–22. - PubMed
    1. Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, et al. . B70 Antigen Is a Second Ligand for CTLA-4 and CD28. Nature (1993) 366:76–9. doi: 10.1038/366076a0 - DOI - PubMed
    1. Aruffo A, Seed B. Molecular Cloning of a CD28 cDNA by a High-Efficiency COS Cell Expression System. Proc Natl Acad Sci (1987) 84(23):8573–7. doi: 10.1073/pnas.84.23.8573 - DOI - PMC - PubMed
    1. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. . A New Member of the Immunoglobulin Superfamily–CTLA-4. Nature (1987) 328(6127):267–70. doi: 10.1038/328267a0 - DOI - PubMed