C3: Treatment of type 1 diabetes with porcine islet cells: transplantation of multi-transgenic islets expressing immunomodulatory molecules

The aim of the project is to cure type 1 diabetes by transplantation (Tx) of transgenic porcine beta cells. In previous studies we provide the proof-of-principle that overexpression of the immunomodulatory molecule LEA29Y in porcine islets prevents T cell-meditated xenorejection in humanized NOD-scid-IL2 receptor gammanull (NSG) mice. Since protection from rejection was not observed in animals carrying a fully matured immune system, it is planned to knockout major porcine xenoantigens, to overexpress multiple transgenes targeting T cells, B cells and innate immune cells and to study their effects in several mouse models with and without addition of low-dose immunosuppressive drugs. When rejection of transplanted beta cells is inhibited, efficiency of the method will be confirmed by Tx in non-human primates to provide the preclinical studies for the transfer of this novel approach to the clinic.

C3 Bild 1 klein              C3 Bild 3 klein                  C3 Bild 4 klein

Immunhistologische Färbung von            Immunhistologie einer transplantierten            Hemmung der Abstoßungsreak-
isolierten neonatalen porcinen                INSLEA29Y transgenen Langerhans´schen         tion durch Expression von
Inselzellclustern: Färbung mit                   Insel. Insulin (rot), Glukagon (braun)                  LEA29Y in porzinen Inselzellen.
Cytokeratin-Antikörper (rot)                                                                                                        LEA29Ytg Inseln sind nach
und Insulin (Grün)                                                                                                                         Transplantation in diabetische
                                                                                                                                                          NSG Mäuse, die ein humanes
                                                                                                                                                          Immunsystem tragen, über 6
                                                                                                                                                          Monate vor der Abstoßung
                                                                                                                                                          geschützt ohne zusätzliche Gabe
                                                                                                                                                          von Immunsuppressiva. Färbung
                                                                                                                                                          mit Insulinantikörper (rot) und
                                                                                                                                                          Antikörper gegen CD45 auf
                                                                                                                                                          humanen Leukozyten (braun)