A long-term cure for autoimmune type 1 diabetes requires both the prevention of further immune attack of the pancreatic islets and replacement of the destroyed islets. New research published in Science indicates that both of these tasks can be carried out by donor splenocytes.

Denise Faustman and colleagues first reported this in 2001 in the Journal of Clinical Investigation. They used donor splenocytes matched for MHC class I to restore peripheral T-cell tolerance to pancreatic islets in non-obese diabetic (NOD) mice, and were then planning to carry out islet transplants to restore islet function. However, they found that many of the mice did not require islet transplants and began to produce insulin after splenocyte infusion. Now, these authors have revisited these findings to determine the source of the new pancreatic islets.

The authors compared the ability of live versus irradiated, male donor splenocytes to restore normoglycaemia in severely diabetic female mice. A temporary implant of syngeneic islets under the kidney capsule was used to maintain normoglycaemia during the treatment. When the islet implant was removed after 40 days, none of the animals that received irradiated splenocytes remained normoglycaemic, compared with two-thirds of the mice that received live splenocytes. By contrast, when the islet graft was maintained for 120 days, almost all of the mice that received irradiated splenocytes also remained normoglycaemic. Therefore, both live and irradiated splenocytes can result in islet replacement, but irradiated splenocytes require longer.

Using fluorescence in situ hybridization (FISH) analysis to detect the Y chromosome of the male donor splenocytes, Faustman and colleagues showed that a significant proportion of the new islets in mice treated with live cells were of donor origin. Fusion between host and donor cells is not thought to have occurred as the regenerated islet cells were of normal size, and did not contained enlarged nuclei or multiple nucleoli. Also, there were rare if any islet cells with an XXY or XXXY genotype. Therefore, live splenocytes can not only re-educate peripheral T cells, but also reconstitute functional islets, and further studies attributed this property to a subset of CD45− non-lymphoid cells.

However, in NOD mice treated with irradiated splenocytes, none of the regenerating islet cells contained a Y chromosome, indicating that these cells are of host origin. Adult NOD mice must also contain endogenous precursor cells that can contribute to islet regeneration over a longer time scale, once the autoimmunity has been corrected by donor splenocytes.

This demonstration of adult precursor cells in both host and donor could have important implications for future treatments for type 1 diabetes, while avoiding the ethical and technical difficulties associated with the use of embryonic stem cells or islet transplants.