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Blocking of proinflammatory cytokine, interleukin-6 (IL-6) is effective in decreasing resistance to allogenic tolerance. In this study, we investigated whether anti-IL-6 receptor producing nonviral minicircle (MC)-DNA, is competent to inhibit alloresponse-induced IL-6 in highly immunogenic murine skin allograft model. We designed MC-DNA producing IL-6R antibody and verified in vitro system. One day before skin allograft modeling, systemic MC-DNA exposed via hydrodynamic delivery of MC-DNA in vivo (50 ug of DNA, tail vein, single injection). Using GFP tagging MC-DNA, we confirmed its organ distribution. At day 5, we measured the amount of IL-6 and IL-6R antibody in serum. As functional examinations, we evaluated survival rate, morphological changes of graft, immune cell infiltration, and population of T helper 17 cells (Th17, FACS marker: CD4+/RoRγt) and regulatory T cells (Treg, FACS marker: CD4+ Foxp3+). We compared its alloimmunity and graft survival efficiency with the cyclosporine A (CsA)-treated group (50 mg/kg, daily administration via oral gavage). Hydrodynamic delivery of MC-DNA was mainly localized in hepatocytes. Serum IL-6 and IL-6R antibody detected in anti-IL-6R MC-DNA treated mice. At day 8.5, untreated mice completely rejected the graft confirming by daily observation of loss of skin graft and erosion. However, mice received either anti-IL-6R MC-DNA or CsA presented prolonged acceptance of graft until day 15 or 15.6, respectively. Results from morphological changes and immune cell infiltration in the graft were also consistent with survival rate. FACS results showed that anti-IL-6R MC-DNA treatment markedly suppressed Th17 population compared with the untreated mice. However, there was no effect on Treg population. On the other hand, administration of CsA showed the increased Th17 and decreased Treg population compared with untreated group. We found that single injection of nonviral minicircle DNA targeting IL-6R is effective in both acute allograft acceptance and allogenic tolerance. This suggests that simple and effective gene therapy method using antibody producing minicircle DNA may represent a powerful tool for the transplantation.

Tacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new onset of diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase (DPP) IV inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury. Methods: Rats were treated with TAC (1.5 mg/kg, subcutaneously) and DPP IV inhibitor MK-0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined with the serum active glucagon like peptide (GLP)-1 level after glucose loading. Protective effect of MK-0626 was evaluated by measuring markers for oxidative stress, oxidative resistance, and apoptosis. To reveal whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of GLP-1 receptor (GLP-1R) and effect of GLP-1 analogue exendin-4 on cell viability and oxidative stress in isolated islets. Results: MK-0626 treatment attenuated TAC-induced pancreatic islet dysfunctions and islet morphology. TAC treatment showed defective in active GLP-1 secretion; however, MK-0626 recovered these effects. TAC treatment increased the level of 8-hydroxy-2’deoxyguanosine (8-OHdG), number of apoptotic cell death, active caspase-3 and decreased the level of manganese superoxide dismutase and heme oxygenase-1, and MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R and direct exendin-4 treatment in isolated islet reduced TAC-induced cell death and 8-OHdG expression. Conclusions: DPP IV inhibitor MK-0626 is an effective anti-diabetic agent with antioxidative and antiapoptotic properties by enhanced GLP-1 signaling in TAC-induced diabetics. These beneficial effects of DPP IV inhibitor could be helpful to a delay in the new onset of diabetes in transplant recipients.

We extend the entanglement bootstrap program to (3+1)-dimensions. We study knotted excitations of (3+1)-dimensional liquid topological orders and exotic fusion processes of loops. As in previous work in (2+1)-dimensions [Ann. Phys. 418, 168164(2020), Phys. Rev. B 103, 115150 (2021)], we define a variety of superselection sectors and fusion spaces from two axioms on the ground state entanglement entropy. In particular, we identify fusion spaces associated with knots. We generalize the information convex set to a new class of regions called immersed regions, promoting various theorems to this new context. Examples from solvable models are provided; for instance, a concrete calculation of knot multiplicity shows that the knot complement of a trefoil knot can store quantum information. We define spiral maps that allow us to understand consistency relations for torus knots as well as spiral fusions of fluxes.