There is a critical need to develop antigen-specific therapies for the treatment of new onset type 1 diabetes (T1D) which will avoid the major side-effects inherent in broad-based immunosuppressive therapies. One approach is to block the activity of critical immune proteins which are required for the activation of immune T cells which are involved in destruction of insulin-producing pancreatic β cells – the pathogenic mechanism underlying T1D. Over the past few years we have worked with Compugen, Ltd. which identified a novel immunoregulatory molecule - immunoglobulin like domain containing receptor 2 (ILDR-2). We showed that short-term administration of this protein linked to an antibody molecule (ILDR2-Fc) could regulate autoimmune responses in paralyzed mice undergoing a disease model of multiple sclerosis both by directly inhibiting the brain-reactive T lymphocytes and by activating a population of regulatory T lymphocytes (Tregs) which provided long-term protection from disease progression. This mechanism of action is unique for this class of immunoregulatory proteins as the others do not lead to efficient induction of Tregs. We have preliminarily demonstrated the efficacy of ILDR2-mFc treatment to inhibit the development of T1D in NOD mice. NOD mice treated 3 times per week for 2 weeks starting at 10 weeks of age had a significantly decreased disease incidence and durable protection from development of T1D in 80% of the mice out to 30 weeks of age. In contrast, 80-90% of the mice treated with either Vehicle alone or a control protein developed T1D by 24 weeks of age. The experiments proposed in our grant application will determine the ability of ILDR2-mFc to reverse new onset diabetes in both wildtype NOD mice with spontaneous T1D and in NOD recipients of activated diabetogenic CD4+ and/or CD8+ transgenic T cells. We will test the hypothesis that ILDR2-mFc treatment induces an increase in the number of FoxP3+ BDC2.5 CD4+ and NY8.3 CD8+ T cell receptor transgenic T cells and that these Tregs are responsible for disease amelioration by regulating trafficking and effector functions of diabetogenic effector CD4 and CD8 T cells. The proposed experiments will thus further determine the mechanism of action of ILDR2-Fc on activated diabetogenic CD4+ and CD8+ T cells, and will yield necessary data required to support the clinical testing of ILDR2-Fc as a potential long-lasting treatment for human T1D and other autoimmune diseases.
|Effective start/end date||11/1/17 → 10/31/19|
- JDRF International (1-SRA-2018-556-S-B)