Q CAO1, C WANG1, T CHEN1, Q LI1, V LEE1, G ZHENG1, S ALEXANDER2, Y WANG1, D HARRIS1
1Centre for Transplant and Renal Research, Westmead Institute for Medical Research, , Westmead, Australia, 2Centre for Kidney Research, Children’s Hospital at Westmead, Westmead, Australia
Aim and Background: Regulatory macrophages (Mreg) are highly versatile effector cells which have become a valuable source of cell therapy for clinical transplantation. In this study, we examined the potential of using Mreg induced from peritoneal mononuclear phagocytes to promote transplanted islet survival and function in diabetic mice.
Methods: Peritoneal macrophages separated from a murine peritoneal dialysis model were polarized to Mreg by incubating with M-CSF and IFN-γ. Mreg were given at day 1, 3 and 7 after islet transplantation in STZ-induced diabetic mice. Islet function (blood glucose and IP-GTT) and T cell responses were measured to assess the effect of Mreg.
Results: In vivo, Mreg significantly improved diabetic control and islet survival after islet transplantation in diabetic mice. Blood glucose was normal for 30 days post transplantation following Mreg treatment. The number of insulin positive cells in islet allograft of transplanted mice treated with Mreg was significantly higher than that in transplanted mice without Mreg. The numbers of CD4+ and CD8+ T cells in islet allografts were significantly reduced in transplanted mice by treatment with Mreg. The percentages of CD4+ and CD8+ T cells in the blood and spleen of transplanted mice were significantly lower with Mreg treatment. In vitro, Mreg suppressed CD4+ and CD8+ T cell proliferation, and reduced CD25 and CD69 expression by both CD4+ and CD8+ T cells. Mreg also promoted CD4+ and CD8+ T cell apoptosis.
Conclusion: This study demonstrates that peritoneal regulatory macrophages prolong allograft survival in islet transplantation, probably through suppression of CD4+ and CD8+ T cell activation and proliferation.
Dr. Qi Cao works as a senior research fellow in Centre for Transplant and Renal Research, Westmead Institute for Medical Research at University of Sydney. His recent focus has been on the role of renal mononuclear phagocytes in chronic kidney diseases (CKD) and their therapeutic potential for CKD.