title: Combination of an Antigen-Specific Therapy and an Immunomodulatory Treatment to Simultaneous Block Recurrent Autoimmunity and Alloreactivity in Non-Obese Diabetic Mice.
abstract: Restoration of endogenous insulin production by islet transplantation is considered a curative option for patients with type 1 diabetes. However, recurrent autoimmunity and alloreactivity cause graft rejection hindering successful transplantation. Here we tested whether transplant tolerance to allogeneic islets could be achieved in non-obese diabetic (NOD) mice by simultaneously tackling autoimmunity via antigen-specific immunization, and alloreactivity via granulocyte colony stimulating factor (G-CSF) and rapamycin (RAPA) treatment. Immunization with insB9-23 peptide alone or in combination with two islet peptides (IGRP206-214 and GAD524-543) in incomplete Freund's adjuvant (IFA) were tested for promoting syngeneic pancreatic islet engraftment in spontaneously diabetic NOD mice. Treatment with G-CSF/RAPA alone or in combination with insB9-23/IFA was examined for promoting allogeneic islet engraftment in the same mouse model. InsB9-23/IFA immunization significantly prolonged syngeneic pancreatic islet survival in NOD mice by a mechanism that necessitated the presence of CD4+CD25+ T regulatory (Treg) cells, while combination of three islet epitopes was less efficacious in controlling recurrent autoimmunity. G-CSF/RAPA treatment was unable to reverse T1D or control recurrent autoimmunity but significantly prolonged islet allograft survival in NOD mice. Blockade of interleukin-10 (IL-10) during G-CSF/RAPA treatment resulted in allograft rejection suggesting that IL-10-producing cells were fundamental to achieve transplant tolerance. G-CSF/RAPA treatment combined with insB9-23/IFA did not further increase the survival of allogeneic islets. Thus, insB9-23/IFA immunization controls recurrent autoimmunity and G-CSF/RAPA treatment limits alloreactivity, however their combination does not further promote allogeneic pancreatic islet engraftment in NOD mice.
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Georgia
authors.initials: G
authors.lastname: Fousteri
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Jofra
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Di Fonte
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D007114:Immunization; D056747:Immunomodulation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D016381:Islets of Langerhans Transplantation; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D020123:Sirolimus / Q000627:therapeutic use*
chemical_list: D007166:Immunosuppressive Agents; D016179:Granulocyte Colony-Stimulating Factor; D020123:Sirolimus