Denileukin diftitox, also known as
DAB(389)IL-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.