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Expression of Fas but not Fas ligand on fetal pig beta cells
Lijun Bai1, Kathrin Maedler, Marc Donath
1Diabetes Transplant Unit, Prince of Wales Hospital, The University of New South Wales, Sydney, NSW, Australia.
Background:
The aim of this study was to determine whether fetal pig insulin-producing cells, a potential source of transplantable tissue for the treatment of type 1 diabetes, are affected by the Fas-FasL interaction, one of the cytotoxic pathways involved in T-cell-mediated autoimmune destruction of pancreatic beta cells.
Methods:
Expression of Fas/FasL on fetal pig beta cells was assessed by immunohistochemistry, flow cytometry, Western blot, and RT-PCR. Apoptosis of fetal pig beta cells induced by soluble FasL (sFasL) or anti-Fas antibody (APO-1) was detected by flow cytometry using PI. Expression of FLIP on fetal pig pancreatic tissue was detected by immunofluorescent staining and Western blot.
Results:
Fas was expressed on fetal pig pancreatic cells, both beta and non-beta cells, and the level of expression could be upregulated by exposure to human interleukin-1beta (IL1beta) 2000 pg/ml for 24 h. In contrast, FasL was not detected on fetal pig pancreatic cells but could be induced on both beta and non-beta cells when the cells were treated with IL1beta. Fas persisted on fetal pig beta cells transplanted as islet-like cell clusters into severe combined immunodeficient mice, with expression of this antigen at all times examined, 1 day, 2, 3 and 4 weeks. FasL was absent. Despite the presence of Fas on fetal pig beta cells, addition of sFasL or anti-Fas antibody failed to induce apoptosis of the fetal pig beta cells. In contrast, pig lymphocytes, which express Fas, were destroyed by addition of both sFasL and APO-1. A possible reason for this is the expression on the fetal pig pancreatic cells of FLIP, an inhibitor of Fas-induced apoptosis.
Conclusions:
Fetal pig beta cells are resistant to Fas-FasL destruction. Our data imply that fetal pig beta cells transplanted into humans with type 1 diabetes may not be destroyed by activated T cells through the Fas-FasL-mediated pathway.
Insights
Fetal pig beta cells, a potential treatment for type 1 diabetes, resist Fas-FasL destruction. This suggests transplanted cells may evade T-cell-mediated autoimmune attack, offering hope for diabetes therapy.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Type 1 diabetes involves autoimmune destruction of pancreatic beta cells.
- Fetal pig beta cells are explored as a potential transplantable tissue source.
- The Fas-FasL pathway is implicated in T-cell-mediated beta cell destruction.
Purpose of the Study:
- To investigate if fetal pig beta cells are affected by the Fas-FasL interaction.
- To assess the susceptibility of fetal pig beta cells to Fas-mediated apoptosis.
Main Methods:
- Immunohistochemistry, flow cytometry, Western blot, and RT-PCR were used to detect Fas and FasL expression.
- Apoptosis was induced using soluble FasL (sFasL) or anti-Fas antibody (APO-1).
- FLIP expression, an apoptosis inhibitor, was also examined.
Main Results:
- Fetal pig beta cells express Fas, which can be upregulated by IL1beta.
- FasL was not detected on untreated cells but could be induced by IL1beta.
- Despite Fas expression, fetal pig beta cells were resistant to sFasL- or anti-Fas antibody-induced apoptosis, unlike pig lymphocytes.
Conclusions:
- Fetal pig beta cells are resistant to Fas-FasL-mediated apoptosis.
- Transplanted fetal pig beta cells may be protected from T-cell-mediated destruction in type 1 diabetes patients.
