| Popis: |
Work described in the chapter has examined the ability of both non-depleting anti-CD4 (YTS 177) and sIL-1R to improve islet survival in syngeneic islet transplants in NOD mice. I have clearly shown that a short course of non-depleting anti-CD4 can induce long-term graft survival in diabetic NOD mice after syngeneic islet transplants. Periopertative insulin therapy plainly improves syngeneic graft survival, possibly by reducing the high blood sugars, which are toxic to beta cells. A combination of sIL-1RII and non-depleting anti-CD4 further improves graft survival. This suggests that tolerance induction with non-depleting anti CD4, combined with therapies to reduce proinflammatory cytokines is an effective mechanism to prevent autoimmune destruction of islet grafts. Their role in induction of allograft tolerance is yet to be studied, but I believe that these therapies will contribute to the success of human islet allografts. The source of islets for reversal of diabetes in clinical transplantation is currently from cadaveric donors. This source will not be sufficient as a general treatment for diabetes. Other potential sources of islets include islet-stem-cells from both the pancreatic ducts and haemopoietic stem cells (HSCs). The following work was done to try and create a system of identifying islet stem cells in the adult pancreas and to grow them in culture. The homeodomain-box protein, PDX-1 is a potential marker of islet stem cells. To identify cells that express PDX-1, a construct of PDX-1 linked to a green fluorescent protein (GFP) gene was used. The strategy was to use an adeno-associated viral vector system to insert the PDX-1-GFP into a cell line that constitutively expressed insulin. Since HSCs may also provide a good source of islet stem cells, their ability to migrate to the pancreas was investigated. |
