Of relevance to autoimmune diabetes is the documented role of these transactivators in lymphocyte activation and beta cell apoptosis. Moreover, nuclear LY2109761 import of Nrf2, a critical responder to oxidant stress, is also attenuated by SN50 peptide. An important aspect of our nuclear import inhibitor is its ability to reach the pancreas and cells comprising pancreatic lymph nodes, as well as other lymphoid and non-lymphoid organs. We have previously elucidated the mechanism of intracellular delivery of this peptide and documented an endocytosis-independent process of crossing the plasma membrane mediated by the membrane-translocating motif, which is based on the signal sequence hydrophobic region derived from Kaposi FGF. The amphipatic helix-based Epoxomicin structure of SSHR facilitates its insertion directly into plasma membrane and the tilted transmembrane orientation permits the translocation of the nuclear import inhibitor through the phospholipid bilayer of the plasma membrane directly to the interior of the cell without perturbing membrane integrity. This mechanism explains the efficient delivery of SSHR-guided cargo across the plasma membrane of multiple cell types involved in autoimmune inflammation. Overall, our study presents a new avenue for altering the course of diabetes progression as there has been limited success in obviating the need for parenteral insulin-replacement therapy of T1D to date. Recent advances in immunosuppressive/antiinflammatory therapy using monoclonal antibodies that target T cells, B cells and cytokine receptors have produced encouraging results. These efforts have focused on targeting extracellular receptors on T and B cells without discerning islet-destructive autoreactive T and B cells from primary innate immunity cells. 
The latter encompass monocytes, macrophages, and dendritic cells that contribute not only to islet inflammation and apoptosis but also to the loss of peripheral tolerance to beta cells antigens. Consistent with their role in autoimmune inflammation, they are being also controlled by nuclear import inhibition. Hence, a broad repertoire of SRTFs-regulated genes that encode mediators of islet inflammation and beta cells apoptosis is attenuated. Contributing to the short-circuiting of this proinflammatory signaling cascade, nuclear import inhibition reversed resistance of autoreactive T cells to Activation-Induced Cell Death. Indeed, as islet-reactive lymphocytes are likely to be maximally stimulated during disease progression, cSN50 enhanced their deletion as compared to those lymphocytes without islet-reactive specificities. Thus, cSN50 treatment seems to restore peripheral T and B cell tolerance, which critically depends on the appropriate regulation of lymphocyte AICD. In addition to enhancing autoreactive lymphocyte elimination, the nuclear import inhibitor may also modulate the cytokine milieu established by immune cells in their target organs. We found that cSN50 inhibits pro-inflammatory cytokine expression in ex vivo analyzed NOD splenocytes while preserving and even modestly enhancing the anti-inflammatory cytokine IL-10. We have previously observed a similar enhancement of IL-10 in other models of acute inflammation that were ameliorated by nuclear import targeting. Moreover, we have also found an increase in IL5 in the plasma of treated mice during the first day of cSN50 therapy. We did not find increased levels of IL-4 or IL-13 and thus it is unclear whether this increased IL-5 is indicative of a shift towards a Th2 phenotype.