The Fast pathway has a primary function in regulating T cell homeostasis through elimination of chronically activated T cells. Engagement of Fas by its ligand (FasL) transduces caspase signaling cascade that leads to nuclear fragmentation, cytoplasmic condensation and cell death. Therefore, when it was found that spontaneous mutations of either Fas (lpr) or its ligand (gld) prevents rather than aggravates organ-specific autoimmune diseases including type 1 diabetes (T1D) and multiple sclerosis in animal models, it was thought that the Fas-transduced signals are responsible for destruction of insulin producing-beta cells. Subsequent studies found that the role of the Fas pathway in the death of beta cells is dispensable thereby indicating the existence of critical but yet to be discovered roles for the Fas pathway in the diabetogenic process. Revealing these mechanisms, however, has been difficult due to the massive CD4:CD8: double negative (DN) T cells that accumulate in NOD mice bearing homozygous gld or lpr mutations. The lymphoproliferative syndrome has also dampened interest in the therapeutic potentials of targeting the Fas pathway as it was believed that the two phenomena are inseparable. We propose that the Fas pathway can become a valuable therapeutic target if the problem of lymphoproliferation is eliminated and the underlying mechanism is understood. This is because the Fas pathway is not required for host defense and its inactivation does not cause immunosupression. Our preliminary data strongly support this hypothesis as we found that mice bearing heterozygote gld mutation (NOD-gld/+ mice) are protected from diabetes without developing lymphoproliferation indicating that partial blockade of FasL is sufficient to inhibit the diabetogenic process. Consistent with this notion, antibody blockade of FasL in young prediabetic NOD-wt mice resulted in long-lasting protection from diabetes without causing lymphoproliferation or immunosuppression. The long term goal of this proposal is to assess the therapeutic potentials of targeting the Fas pathway and to understand the underlying mechanism.
In Aim 1, we will use FasL- neutralizing to inhibit diabetes development during late stages of insulitis and to reverse hyperglycemia in new-onset cases. In addition, we will determine whether FasL blockade promotes islet transplantation.
In Aim 2, we will use the NOD-gld/+ mouse to test the hypothesis that IL-10 producing B cells play a major role in mediating the protective effect and to characterize the function of a novel of population of B cells that express low surface level of CD40 costimulatory molecule and accumulate selectively in pancreata of NOD-gld/+ but not in NOD-wt littermates.
In Aim 3, we will identify the cell types in which FasL expression is responsible for the promoting disease development. Successful completion of these studies will assess the therapeutic value of targeting FasL and provide novel insights into mechanisms underlying gld-mediated protection.
The Fas pathway can be an attractive therapeutic target because it is not essential for normal immune responses and its blockade is not expected to cause immune suppression. Genetic or pharmacological blockade of Fas ligand prevents autoimmune diabetes in animal models of type 1 diabetes (T1D) - a chronic autoimmune disease that affects children at young age. There is currently no proven cure for T1D. Identifying the mechanisms by which blockade of the Fas pathway prevents autoimmune diabetes in animal models could prove useful in developing new therapeutic strategies for T1D.
| Xiao, Zuoxiang; Mohamood, Abdiaziz S; Uddin, Sophia et al. (2011) Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development. Am J Pathol 179:725-32 |
