Kidney Week

Abstract: FR-PO858

Liposomal Delivery Improves the Efficacy of Prednisolone to Reduce Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection

Session Information

• Transplantation: Basic
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

• 1801 Transplantation: Basic

Authors

• van Alem, Carla, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Carla van Alem,

• Martina, Schmidbauer, Hannover Medical School, Hannover, Germany

Schmidbauer Martina,

• Rong, Song, Hannover Medical School, Hannover, Germany

Song Rong,

• Braesen, Jan H., Hannover Medical School, Hannover, Germany

Jan H. Braesen,

• Thorenz, Anja, Hannover Medical School, Hannover, Germany

Anja Thorenz,

• Chen, Rongjun, Hannover Medical School, Hannover, Germany

Rongjun Chen,

• Ruben, Jurjen, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Jurjen Ruben,

• Winter, Elizabeth Martha, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Elizabeth Martha Winter,

• Schilperoort, Maaike, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Maaike Schilperoort,

• Kooijman, Sander, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Sander Kooijman,

• Lalai, Reshma, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Reshma Lalai,

• Metselaar, Josbert, Enceladus Pharmaceuticals, Naarden, Netherlands

Josbert Metselaar,

• Klemann, Christian, Hannover Medical School, Hannover, Germany

Christian Klemann,

• Meier, Martin, Hannover Medical School, Hannover, Germany

Martin Meier,

• van Kooten, Cees, Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Cees van Kooten,

• Gueler, Faikah, Hannover Medical School, Hannover, Germany

Faikah Gueler,

• Rotmans, Joris I., Leiden University Medical Center, Leiden, Zuid Holland, Netherlands

Joris I. Rotmans,

Background

Allograft rejection remains one of the main obstacles in kidney transplantation. Although treatment with high doses of corticosteroids is often efficacious, systemic exposure and activation of the glucocorticoid receptor (GR) results in substantial side effects. In this study we used a mouse model of acute renal allograft rejection to investigate whether liposomal encapsulation could facilitate local delivery of prednisolone to the allograft and enhance its therapeutic effect.

Methods

Male BalbC^HanZtm recipients received a kidney transplant from male C57BL/6J^HanZtm donors (n=10 per group). Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or liposomal prednisolone (LP) intravenously on day 0, 3, and 6, or no additional treatment (NA). Functional MRI was performed at day 6 (N=6) to study graft perfusion and organs were harvested at day 7 for FACS- and qPCR analysis.

Results

MRI analysis revealed better allograft perfusion upon LP treatment, as compared to NA treatment (428.3±114 vs 218.5±117 ml/min*100g, p<0.05) while P vs NA treatment showed no significant improvement. FACS analyses of allografts revealed a reduced number of CD45+ leukocytes in LP vs P or NA treatment (5,3 and 6,6 fold decrease, p<0.05), less CD3+ T cells in LP vs NA (3,7 fold decrease, p<0.05), and less F4/80+ macrophages in LP vs P and NA (4,3 and 4,2 fold decrease, p<0.05). Upon LP treatment, the expression of the GR responsive gene Fkbp5 was upregulated in the allograft, as compared to P and NA treatment (3,7 and 4,4 fold change, p<0.05).This was also observed in the spleen, but not in the heart, a non-target organ.

Conclusion

Liposomal delivery results in a higher local bioavailability of prednisolone, increased perfusion and a reduced cellular infiltrate in the transplanted kidney, compared to conventional prednisolone. Future clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.

Funding

• Commercial Support –