Thursday September 23, 2021 - 15:00 to 16:15
Adwin Thomas, Australia has been granted the IXA Congress Scientific Awards
Efficacy and safety of relevant immunosuppression in non-human primate neonatal islet cell cluster xenotransplantation
Adwin Thomas1, Evelyn Salvaris2, Yi Vee Chew1, Nicole Byrne1, Peter J. Cowan2,3, Wayne J. Hawthorne1,4.
1Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, Westmead, Australia; 2Immunology Research Centre, St Vincent's Hospital, Fitzroy, Australia; 3Department of Medicine, University of Melbourne, Melbourne, Australia; 4University of Sydney, Sydney, Australia
Background: Progress in xenotransplantation has been made through genetic engineering of the donor pig, but the need for strong immunosuppressive and anti-inflammatory agents still remains. In order to make advances and significant changes to our immunosuppression we need to improve our understanding of its effects on haematological and immunological parameters to allow progress to the clinic.
Aim: To evaluate the short-term (100 days) effects of immunosuppression on haematological and immunological parameters following neonatal porcine islet cell cluster xenotransplantation in a diabetic non-human primate model.
Methods: Four baboons received 5doses of anti-CD2 at 5mg/kg from day -3 to day 21 along with fortnightly anti-CD154 admisnatration at 20-30mg/kg and belatacept administration at20mg/kg. This was followed bydaily maintenance immunosuppression of tacrolimus at 5mg/kg or sirolimus at2mg/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: Across all xenotransplanted recipients, the immunosuppressive therapy was effective in suppressing total white cell count including all key immune cells (B cells, T cells, monocytes and granulocytes. 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 compared to previous levels. Looking at the CD4:CD8 ratio within CD3 lymphocytes, there was an inverse relationship over 100 days with a gradual reduction of CD4+ cells and a gradual increase in CD8+ cells. Tregs, a key component of achieving tolerance, gradually increased from day 30-60 to reach 5-10% of the total CD4 cell population, compared to 2-3% at baseline; this level was maintained up to 100 days. Other hematological parameters such as mean corpuscular hemoglobin concentration (MCHC) and red cell count (RCC) remained unaffected by immunosuppression.
Discussion/Conclusion: The current immunosuppressive protocol is effective and safe in baboons receiving neonatal porcine islet cell cluster xenotransplantation.