Postdoctoral Research Trainee Vanderbilt Univ. Med. Ctr., United States
Disclosure(s):
Tyler W. Jenkins, PhD: No financial relationships to disclose
Introduction/Rationale: Type 1 diabetes (T1D), results from T cell-mediated destruction of insulin-producing beta cells. Developing new immunotherapies that control islet autoimmunity without compromising protective immune responses is an important therapeutic goal. Insulin autoantibodies predict T1D in mice and humans, implicating B lymphocytes in islet attack. Anti-insulin B cells present autoantigen to T cells to promote T1D in non-obese diabetic (NOD) mice and are required for diabetes to develop. AKS-107 is an antigen-specific immunotherapy composed of a hormonally inactive insulin moiety that lacks a critical T cell epitope and which is fused to an Fc. AKS-107 specifically eliminates anti-insulin B cells and prevents diabetes in mice. However, it is unknown whether AKS-107 can deplete anti-insulin B cells in the pancreas or reduce islet inflammation.
Methods: VH125SD.NOD mice were treated either once or twice weekly with 0.4 mg/kg of AKS-107 for either 2 or 8 weeks. Pancreas, pancreatic lymph nodes, and spleen were harvested, and flow cytometry phenotyping was used to evaluate selective anti-insulin B cell depletion. NOD mice were treated twice weekly with 2 mg/kg of AKS-107 for 9 weeks after which pancreata were harvested, sectioned, and insulitis severity was blind scored.
Results: AKS-107 therapy selectively depletes anti-insulin B cells (but not other B cells) in the pancreas and pancreatic lymph nodes of VH125SD.NOD BCR transgenic mice, in which a 1-3% population of anti-insulin B cells can be readily tracked. This observed depletion is not caused by AKS-107 masking the detection of the anti-insulin B cells by biotinylated insulin. NOD mice treated with AKS-107 from 4-13 wks of age showed decreased insulitis severity relative to controls.
Conclusion: Our data highlight pancreas tissue actions of the antigen-specific immunotherapy, AKS-107 which supports its potential as a novel T1D immunotherapy.
