Ban L et al. (2008) Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci. USA 105: 13644–13649

Targeted destruction of autoreactive T cells is an optimum treatment goal for type 1 diabetes. In animal models of type 1 diabetes, administration of tumor necrosis factor (TNF) selectively kills autoreactive T cells and prevents or suppresses the disease. To assess the human therapeutic potential of this approach in vitro, Ban et al. tested whether TNF or TNF agonists selectively killed autoreactive T cells isolated from blood samples of patients with type 1 diabetes.

The researchers developed magnetic cell-separation methods to isolate high yields of purified, viable CD4 and CD8 T cells from blood samples of patients with type 1 diabetes and healthy controls. No CD4 T cells from patient or control samples were killed by TNF treatment; however, the treatment did kill a subset of CD8 T cells from the patient samples. Crucially, the subset killed was identified as the CD8 T cells responsible for the autoimmune destruction of pancreatic islets. In addition, a TNF agonist that acts through the restrictively expressed TNF receptor type 2 (which would probably have less toxicity than TNF), also specifically killed these autoimmune T cells. Importantly, CD8 T cells targeted against two common viruses in patient samples were not killed by TNF or TNF agonist treatment.

The findings raise the possibility of a highly targeted therapy for type 1 diabetes that has much higher specificity than current immunosuppressive approaches.