Oral Communications 5
12.4 - The relevance of site on immune responses after islet transplantation: bone marrow (BM) vs liver
Presenter: Elisa, Cantarelli, Milano, Italy
Authors: Elisa Cantarelli1,2, Antonio Citro1,2, Erica Dugnani1,2, Roberto Aiolfi1,2, Pietro Dilucia1,2, Giovanni Sitia1,2, Luca Guidotti1,2, Lorenzo Piemonti1,2
The relevance of site on immune responses after islet transplantation: bone marrow (BM) vs liver
Elisa Cantarelli1,2, Antonio Citro1,2, Erica Dugnani1,2, Roberto Aiolfi1,2, Pietro Dilucia1,2, Giovanni Sitia1,2, Luca Guidotti1,2, Lorenzo Piemonti1,2
1Beta Cell Biology Unit, Diabetes Research Institute-DRI , San Raffaele Scientific Institute, Milano, Italy; 2Transplantation and Infectious Diseases, Division of Immunology, San Raffaele Scientific Institute, Milano, Italy
Background: Using a syngeneic mouse model of islet transplantation (Tx) we have demonstrated that islet infusion in the BM is safe and more efficient in restoring normoglycaemia than liver.
Aim: The aim of our work is to evaluate whether immune responses after islet infusion are site-dependent (BM vs Liver).
Methods and Results: A MHC-full-mismatched mouse model (C57BL/6 islets in alloxan-induced Balb/c mice) was used to evaluate alloimmune response. The time of rejection in the absence of immunosuppression was 6±0.82 and 6±0.35 for Liver-Tx(n=8) and BM-Tx (n=9), respectively (p=0.896). The time of rejection in the presence of immunosuppression (MMF+FK-506) was 10±1.22 and 8±2.45 for Liver-Tx(n=5) and BM-Tx (n=7), respectively (p=0.3). A more stringent MHC-full-mismatched mouse model (Balb/c islets in alloxan-induced C57BL/6 mice) was used to characterize leucocytes infiltration at site of islet infusion at 0, 1, 3, 5, 7, 10, 14 days after Tx by flow cytometry analysis. CD3+ CD4+ and CD3+ CD8+ T cells were preferentially recruited at 7-10 days after Tx in the BM with islets in comparison to the controlateral sham operated. A single-antigen-mismatched mouse model (RIP-LCMV-GP+/- C57BL/6 islets in alloxan-induced C57BL/6 mice) was used to evaluate single-antigen islet specific response. To evaluate the ability of islet-specific response to reject already engrafted islets, RIP-LCMV-GP+/- C57BL/6 islets were transplanted in liver (n=12) or BM (n=8) of alloxan-induced RIP-LCMV-GP-/- C57BL/6 diabetic mice. Post transplant LCMV infection induced GP-specific immune response leading to β-cells destruction within 10-14 daysboth of islet engrafted in liver (n=10) or BM (n=5). To evaluate the ability of GP- specific memory response to reject islet, C57BL/6 diabetic micewere transplanted with RIP-LCMV-GP+/- C57BL/6 islets in liver (n=2) or BM (n=3) 30 days after LCMV infection. Islets were rejected within 5-7 days after Tx without any difference related to the site of infusion.
Conclusion: BM does not represent a disadvantageous microenvironment in comparison to liver in term of immune response, suggesting that could be used as alternative site for type 1 diabetes therapy.