Abstract
Aims/hypothesisGenetically engineered human beta cell lines provide a novel source of human beta cells to study metabolism, pharmacology and beta cell replacement therapy. Since the immune system is essentially involved in beta cell destruction in type 1 diabetes and after beta cell transplantation, we investigated the interaction of human beta cell lines with the immune system to resolve their potential for immune intervention protocol studies.MethodsHuman pancreatic beta cell lines (EndoC-βH1 and ECi50) generated by targeted oncogenesis in fetal pancreas were assessed for viability after innate and adaptive immune challenges. Beta cell lines were pre-conditioned with T helper type 1 (Th1) cytokines or high glucose to mimic inflammatory and hyperglycaemia-stressed conditions. Beta cells were then co-cultured with auto- and alloreactive cytotoxic T cells (CTL), natural killer (NK) cells, supernatant fraction from activated autoreactive Th1 cells, or alloantibodies in the presence of complement or effector cells.ResultsLow HLA expression protected human beta cell lines from adaptive immune destruction, but it was associated with direct killing by activated NK cells. Autoreactive Th1 cell inflammation, rather than glucose stress, induced increased beta cell apoptosis and upregulation of HLA, increasing beta cell vulnerability to killing by auto- and alloreactive CTL and alloreactive antibodies.Conclusions/interpretationWe demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3779-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Beta cell replacement by pancreas or islet transplantation is currently the only curative treatment for established type 1 diabetes
Conclusions/interpretation We demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction
We investigated immune responses to human beta cell lines that may be relevant for diabetes pathogenesis and beta cell transplantation, demonstrating the relevance of these beta cell lines for preclinical studies on immune intervention strategies (Table 1)
Summary
Beta cell replacement by pancreas or islet transplantation is currently the only curative treatment for established type 1 diabetes. Insulin independence using current islet transplantation protocols is often temporary despite aggressive immune suppression. Both innate and adaptive immune responses threaten transplanted beta cells and need to be controlled by immune suppression [1,2,3]. Knowledge of interactions of human beta cells with the immune system has been largely derived from studies on isolated islets from pancreas donors. Access to such preparations for scientific purposes is limited; variations between islet preparations and their composition, including a range of other cell types, hinder beta cell-specific studies. Beta cell lines may help to identify immune responses relevant to human type 1 diabetes and beta cell transplantation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
