Related Experiment Video
Updated: Dec 23, 2025
A Rat Orthotopic Renal Transplantation Model for Renal Allograft Rejection
Published on: February 2, 2022
Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney
Jean Kwun1, Brian Ezekian1, Miriam Manook1
1Duke Transplant Center, Department of Surgery, Duke University, Durham, NC.
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.
Insights
A new drug targeting calcium channels showed immunosuppressive effects in kidney transplant models but was less effective than tacrolimus in preventing rejection. Further research is needed to optimize its use in transplantation.
Area of Science:
- Immunology
- Transplantation Medicine
- Pharmacology
Background:
- Calcineurin inhibitors control organ transplant rejection but cause nephrotoxicity.
- A novel drug inhibits store-operated calcium release-activated calcium channel (CRACM1) in lymphocytes.
Purpose of the Study:
- To evaluate a CRACM1 inhibitor (PRCL-02) for transplant rejection control without nephrotoxicity.
- To assess PRCL-02's efficacy in a rhesus monkey kidney transplantation model.
Main Methods:
- Kidney transplantation in rhesus monkeys.
- Treatment groups: tacrolimus alone, PRCL-02 alone, or tacrolimus converted to PRCL-02.
- PRCL-02 administered orally via gastrostomy tube.
Main Results:
- PRCL-02 demonstrated in vitro T-cell suppression comparable to tacrolimus.
- Tacrolimus monotherapy prevented rejection; PRCL-02 monotherapy showed minimal graft survival benefit.
- Conversion from tacrolimus to PRCL-02 prolonged survival but not as effectively as tacrolimus.
Conclusions:
- PRCL-02 exhibits in vivo immunosuppressive activity in primate kidney transplants.
- PRCL-02 was inferior to tacrolimus in suppressing immune-mediated transplant rejection.
- Inconsistent drug exposure may have impacted PRCL-02 efficacy.
Related Concept Videos
01:28Kidney Transplant I: Introduction
01:26Kidney Transplant II: Surgical Procedure