Long term elimination of epitope-specific diabetogenic CD8+ T cells using toxin coupled tetramers in NOD mice (50.37)

Abstract

Abstract Type 1 diabetes (T1D) is an autoimmune disease in which CD8+ T cells with help from CD4+ T cells and B cells kill the insulin-producing islet cells in the pancreas. Although islet transplants have been successful in treating T1D, the transplants may not persist because of the ongoing autoimmunity. Patients can be treated with immunosuppressants, however these drugs have serious side effects. Selective elimination of diabetogenic T cells should specifically eliminate islet autoimmunity. We previously showed MHC class I tetramers coupled to the toxin saporin could selectively kill transgenic virus specific T cells. We have now used saporin coupled NRP-V7 tetramers to target diabetogenic T cells in vitro and in vivo in non-obese diabetes-prone (NOD) mice. NRP-V7 is a high affinity mimotope that is recognized by the 8.3 T cell clone, a known diabetogenic T cell. Treatment with saporin coupled NRP-V7 tetramers acutely depleted NRP-V7+ CD8+ T cells expressing Vβ 13-3 and elimination appeared to be long term since very few NRP-V7+ T cells were detectable in the islets of toxic-NRP-V7 tetramer treated NOD mice up to 45 weeks later. Treatment with toxic NRP-V7 tetramers resulted in a delay of T1D with a mean onset of 24 weeks compared to 16 weeks for treatment with PBS. Toxic tetramers could potentially be used to treat T1D as well as other T cell mediated autoimmune disease. Supported by JDRF 5-2006-13 and 1-2008-24.