Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney Transplantation.

Published

Journal Article

BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.

Full Text

Duke Authors

Cited Authors

  • Kwun, J; Ezekian, B; Manook, M; Park, J; Yoon, J; Freischlag, K; Song, M; Farris, AB; Sloan-Lancaster, J; Fortier, C; Rao, PE; Knechtle, SJ

Published Date

  • May 2020

Published In

Volume / Issue

  • 104 / 5

Start / End Page

  • 970 - 980

PubMed ID

  • 32317615

Pubmed Central ID

  • 32317615

Electronic International Standard Serial Number (EISSN)

  • 1534-6080

Digital Object Identifier (DOI)

  • 10.1097/TP.0000000000003078

Language

  • eng

Conference Location

  • United States