The IL-2 Diphtheria Toxin Fusion Protein Denileukin Diftitox Modulates the Onset of Diabetes in Female Nonobese Diabetic Animals in a Time-Dependent Manner and Breaks Tolerance in Male Nonobese Diabetic Animals

Abstract

Denileukin diftitox, also known as DAB389IL-2 or Ontak, is a fusion protein toxin consisting of the full-length sequence of the IL-2 protein and as toxophore the truncated diphtheria toxin. As a consequence, it delivers the toxic agent to CD25-bearing cells, whereby CD25 represents the high-affinity α-subunit of the IL-2 receptor. Initially it was developed for the treatment of patients with cutaneous T cell lymphoma. Meanwhile, denileukin diftitox is also used as an adjuvant in other tumor therapies and neoplastic disorders. In this study, to our knowledge we report for the first time that denileukin diftitox has also dramatic effects regarding the pathology of type 1 diabetes using the NOD mouse model. Repeated injections of denileukin diftitox into female NOD mice at 12 wk of age led to a clear acceleration of disease onset, whereas injection at 7 wk of age did not. Using male NOD mice, which are much less susceptible to diabetes, we demonstrate that the injection of denileukin diftitox leads to a dramatic development of type 1 diabetes within days after injection, thereby obviously breaking pre-existing tolerance mechanisms. This is accompanied by an increased IFN-γ production of autoreactive splenic cells and a decreased presence of regulatory CD4+CD25+Foxp3+ T cells. In contrast, transfer of CD4+CD25+Foxp3+ T cells could correct the defect after denileukin diftitox treatment. Furthermore, whereas IFN-γ production was increased in the pancreata of treated animals, insulin expression was strongly reduced. These finding should be considered when denileukin diftitox is used for the treatment of patients suffering from tumors and/or autoimmune disorders.

Immunogenic and tolerogenic effects of the chimeric IL-2-diphtheria toxin cytocidal agent Ontak®on CD25+cells

“…Injection of Ontak ® into mice has been observed to deplete T regs and enhance T-cell immunity 7 . However, in the non-obese diabetic (NOD) mouse model of human type-1 diabetes, we reported that Ontak ® either promoted disease or had no effect, depending on the time point of application 8 . Several clinical studies (cited in ref.…”