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2013 - CTS 2013 Congress

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Oral Communications 1

5.3 - Localized immune modulation with fingolimod for allogeneic islet transplantation into a biohybrid device

Presenter: Carmen, Fotino, Miami, United States
Authors: R. Damaris Molano1,2,3,4,5, Carmen Fotino1,2,3,4,5, Ann-Christina Brady1,2,3,4,5, Nicola Bocca1,2,3,4,5, Simona Marzorati1,2,3,4,5, Elsie Zahr-Akrawi1,2,3,4,5, Luca Inverardi1,2,3,4,5, Camillo Ricordi1,2,3,4,5, Peter Buchwald1,2,3,4,5, Antonello Pileggi 1,2,3,4,5

Localized immune modulation with fingolimod for allogeneic islet transplantation into a biohybrid device

R. Damaris Molano1,2,3,4,5, Carmen Fotino1,2,3,4,5, Ann-Christina Brady1,2,3,4,5, Nicola Bocca1,2,3,4,5, Simona Marzorati1,2,3,4,5, Elsie Zahr-Akrawi1,2,3,4,5, Luca Inverardi1,2,3,4,5, Camillo Ricordi1,2,3,4,5, Peter Buchwald1,2,3,4,5, Antonello Pileggi 1,2,3,4,5

1Diabetes Research Institute, University of Miami, Miami, FL, United States; 2Medicine, University of Miami Miller School of Medicine, Miami, FL, United States; 3Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, FL, United States; 4Surgery, Microbiology and Immunology, Biomedical Engineering, University of Miami, Miami, FL USA, FL, United States; 5Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, United States

Replacement of beta-cell function via intrahepatic islet transplantation restores metabolic control in patients with type 1 diabetes.  The need for systemic immunosuppression and its associated untoward side effects currently limit the indication of islet transplantation to the most severe cases of instable diabetes.  Tissue engineering is opening new opportunities for the development of more efficient biological treatments for diabetes.  We have previously reported that transplantation of syngeneic islets corrects diabetes into prevascularized, subcutaneous biohybrid devices (BHD). To overcome the need for chronic systemic immunosuppression, we sought to evaluate the effects of localized immuno-suppression (LIS) on allogeneic islet allograft survival into BHD.

Allogeneic Wistar Furth (RT1u) rat islets were implanted into a pre-vascularized BHD with infusion port in chemically-diabetic Lewis rats (RT1l) on day 0. Induction with IP anti-lymphocyte serum (ALS days -3) was followed by daily oral administration of mycophenolic acid (MPA 20 mg/kg/day) for 3 weeks alone or combined with chronic fingolimod (15 ug/kg/day) delivered directly to the BHD’s lumen for the duration of the follow-up starting on day 0. Control animals received no treatment.
 
Control animals (n=5) rejected islet allografts with a median of 9 (7-11) days. The induction protocol (ALS+MPA) led to graft survivals of 29 (19-40) days (n=5, p=0.002 vs. control). The combinatorial treatment based on induction protocol plus chronic local fingolimod (n=9) significantly prolonged allograft survival to 36 (26->67) days and long-term function in two animals (22%; >42 and >67 days, respectively)(p<0.0001 vs. controls).  Notably, LIS reduced donor-specific antigens responses of lymphocytes but did not alter third party responses in mixed lymphocyte reactions and in antiCD3/CD28 stimulation assay.  Also, cellular composition (CD4, CD8, B cells, Macrophages) and activation markers of the lymph nodes draining the devices, but not in distal nodes, were altered in animals receiving LIS.
 
Our study demonstrates that prolonged islet allograft survival can be achieved after transplantation into a BHD by the means of local immunosuppression using doses that are ~100 times lower than needed systemically. Our approach may represent an appealing therapeutic strategy to avoid the toxicity of systemic immunosuppression for beta-cell replacement therapies in insulin-requiring diabetes.

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