Review of the safety and efficacy of immunosuppression in the pig-to-nonhuman primate islet xenotransplantation model
Wayne Hawthorne1,2,5, Adwin Thomas2, Evelyn Salvaris3, Nicole Byrne2, Mark Nottle6, Peter J Cowan3,4.
1Department of Surgery, Westmead Hospital, Westmead, Australia; 2Centre for Transplant and Renal Research, Westmead Institute of Medical Research, Sydney, Australia; 3Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia; 4Department of Medicine, University of Melbourne, Melbourne, Australia; 5School of Medical Science, University of Sydney, Sydney, Australia; 6Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia
Background: With the recent progress of xenotransplantation moving to the clinic there is renewed enthusiasm in the field of xenotransplantation, but the need for strong immunosuppressive and anti-inflammatory agents remains. The effects and safety of these agents need to be reviewed in detail to allow progress to the clinic. This project aimed to evaluate the short-term (100 days) effects of immunosuppression on haematological and immunological parameters following neonatal porcine islet cell cluster (NICC) xenotransplantation in a diabetic non-human primate model.
Methods: Four baboons received 5 doses of anti-CD2 at 5mg/kg from day -3 to day 21 along with fortnightly anti-CD154 administration at 20-30mg/kg and belatacept administration at20mg/kg. This was followed by daily maintenance immunosuppression of tacrolimus at 5mg/kg or sirolimus at 2mg/kg. Prior to immunosuppression administration, blood was collected to establish baseline haematological and immunological parameters. Full haematological parameters were assayed and immunological parameters including B cells, T cells, monocytes, and granulocytes were assessed by flow cytometry.
Results: The immunosuppressive therapy was highly effective in suppressing total white cell counts in all recipients. By day 100, B and T cells were depleted by 50-60% compared to baseline. In the 14-day gap between treatment with anti-CD154+belatacept, the immune cells (particularly B and T cells) recovered but were suppressed at each subsequent time point as compared to previous levels. There was a gradual reversal of the CD4:CD8 ratio, with a reduction of CD4+ cells and an increase in CD8+ cells over the 100 days. Tregs, a key component of achieving tolerance, gradually increased from day 30-60. Other hematological parameters such as mean corpuscular hemoglobin concentration (MCHC) and red cell count (RCC) remained unaffected by immunosuppression.
Conclusion: This novel combination of immunosuppressive agents is effective and safe in baboons receiving neonatal porcine islet cell cluster xenotransplantation.
