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.

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.

MCS-18, a novel natural plant product prevents autoimmune diabetes.

There is still a vital need for new therapies in order to prevent or treat type I diabetes. In this respect, we report that MCS-18 a novel natural product isolated from the plant Helleborus purpurascens (i.e. Christmas rose) is able to increase diabetes free survival using the NOD-mouse model, which is accompanied with a diminished IFN-γ secretion of splenocytes. In the animal group which has been treated with MCS-18 during week 8 and week 12 of age 70% of the animals showed a diabetes free survival at week 30, whereas in contrast in the untreated animals less than 10% were free of diabetes. MCS-18 treatment significantly reduced islet T-cell infiltrates as well as the rate of T-cell proliferation. Periinsular infiltrates in the MCS-18 treated animals showed a significantly enhanced number of Foxp3(+) CD25(+) T cells, indicating the increased presence of regulatory T cells. These studies show that MCS-18 exerts an efficient immunosuppressive activity with remarkable potential for the therapy of diseases characterized by pathological over-activation of the immune system.

Herpes simplex virus type I (HSV-1) replicates in mature dendritic cells but can only be transferred in a cell-cell contact-dependent manner.

HSV-1 is a very successful representative of the α-herpesvirus family, and ∼ 90% of the population is seropositive for this particular virus. Although the pathogen usually causes the well-known mild lesions on the lips, also, severe infections of the eye or the brain can be observed in rare cases. It is well known, that this virus can efficiently infect the most potent APCs, i.e., the DCs, in their immature and mature state. Although the infection of the iDC has been shown to be productive, infection of mMDDCs is believed to be abortive in the early phase of the viral replication cycle. In line with these findings, no virus particles can be detected in the supernatant of HSV-1-infected mMDDC. In this study, however, we show for the first time that this pathogen completes its replication cycle in mMDDCs. We detected the presence of viral gene transcripts of all three phases of the replication cycle, as well as of late viral proteins, and even the generation of small amounts of progeny virus. Although we could confirm the findings that these particles are not released into the supernatant, surprisingly, the newly generated viral particles can be passed on to Vero cells, as well as to primary keratinocytes in a cell-cell contact-dependent manner. Finally, we provide evidence that the viral gE is involved in the transfer of infectious virus from mMDDCs to other permissive cells.