Viral IL-10-Mediated Immune Regulation in Pancreatic Islet Transplantation

Abstract

Protection of transplanted pancreatic islet grafts in recipients with autoimmune diabetes depends on the suppression of autoimmune recurrence and allogeneic rejection. The aim of this study was to investigate the efficiency of viral IL-10 gene delivery in the prevention of autoimmune recurrence following islet transplantation. We evaluated the effectiveness of a systemically delivered adeno-associated viral vector (AAV vIL-10) carrying viral IL-10 in protecting islet engraftment. We observed significant prolongation of graft survival after treatment with AAV vIL-10 when using islets from donors lacking autoimmunity. We found that the mechanism of vIL-10-mediated protection was associated with suppression of T cell activation and that donor immune cells that were simultaneously transferred with the islet grafts could induce autoimmune recurrence. AAV vIL-10 gene transfer suppressed previously activated T cells and protected grafted islets from autoimmune-mediated destruction. We conclude that vIL-10 can regulate autoimmune activity and that transfer of its gene may have potential for therapeutic islet transplantation.

Autoantigens Plus Interleukin-10 Suppress Diabetes Autoimmunity

“…The effectiveness of this VV immunostimulated autoantigen/IL-10 multicomponent immunosuppression strategy for arresting or reversing the progression of diabetes symptoms of insulitis and hyperglycemia remains to be determined. However, if the proposed immunological suppression strategy is found to be less effective in human trials, this strategy may be coupled with transplanted pancreatic islet engraftment 87,88 and mesenchymal stem cell therapies 87,89 as additional promising cellular alternatives for diabetes prevention or cure, Thus, it is conceivable that VV-delivered immunomodulated autoantigens and IL-10 could be combined to arrest diabetes progression coupled with pancreatic islet grafts or stromal stem cells to repopulate the pancreas with ''beta-like'' cells to provide an effective and durable interventional therapy for restoration of euglycemia and immunological homeostasis in the large patient population suffering from T1DM.…”

“…Furthermore, increased levels of diabetes immunosuppression following co-delivery of CTB::GAD and IL-10 suggest that cognate naive Th0 lymphocytes that recognize CTB and bind to dendritic cells may develop into immunosuppressive Th2 cells or Tr1 regulatory T cells, which may help to suppress cytotoxic T-cell expansion and activation leading to down-regulation of the immune response. 87 …”

Gene Therapy to Improve Pancreatic Islet Transplantation for Type 1 Diabetes Mellitus

“…Table 2 Pathway Transgene Vector Comment CTLA4Ig Adenovirus Expression of CTLA4Ig in islets can prolong islet graft survival [93][94][95][96] Lentivirus Islets transduced with CTLA4Ig prolong graft survival in a rat to mouse transplantation model [74] Interleukin-10 Adeno-associated virus IL-4 transduced islets resulted in impaired metabolic function in recipient mice and normoglycaemia in only 1/7 mice [102]. Viral IL-10 introduced systemically sustained suppression of autoimmune responses and prolonged islet allograft survival [101] Interleukin-4 Adeno-associated virus AAV-8 mediated IL-4 gene transfer to islets prevented the onset of diabetes in NOD mice [103] Immunomodulation CTLA4Ig/CD40Ig Adenovirus Results in simultaneous blockade of co-stimulation pathways [97] Bcl-2 Adenovirus Over expression of Bcl-2 in islet cells failed to prevent cytokine induced toxicity [110] and reduce inflammation in porcine islets [112] Lentivirus Bcl-2 transduction of an pancreatic β-cell line provided protection against apoptosis induced by various stimuli including hypoxia and pro-inflammatory cytokines and corrected hyperglycaemia for several months when transplanted under the kidney capsule of diabetic C3H mice [111] Herpes Simplex Virus-1 Cytokine-mediated beta-cell apoptosis was blocked by transduction with an Bcl-2 expressing HSV-1 vector [63] Bcl-XL Adenovirus Bcl-XL transduction of a rat insulinoma cell line blocked cytokine induced apoptosis [114] Anti-Apoptotic XIAP Adenovirus Adenoviral-XIAP transduced βTC-Tet cells and human islets are highly resistant to hypoxia and cytokine induced apoptosis in vitro and βTC-Tet cells transplanted into SCID mice successfully reverse diabetes in 3 days compared to 21 for control cells [121][122][123] VEGF Adenovirus Rat islet grafts with elevated VEGF production exhibited significantly increased microvasculature, insulin content and reversed hyperglycaemia in diabetic mice [136] Angiogenic HGF Adenovirus Co-expression of hHGF and hIL-1Ra led to significant decrease in caspase-3 induced in human islets by cytokine challenge in vitro. Transduction of human islets improved the outcome of islet transplantation [137].…”

“…In fact, under some circumstances, expression of IL-10 within the pancreatic islet has been associated with early and rapid development of diabetes in autoimmune-prone NOD mouse [100]. However, when viral IL-10 was introduced systemically using AAV in NOD mice, there was sustained suppression of autoimmune responses and prolongation of islet allograft survival was observed [101].…”

How not to be seen: immune-evasion strategies in gene therapy

“…48 Remarkably, IL-10 is also able to prevent autoimmune diabetes in NOD mice since a single administration of an AAV vector carrying the vIL-10 gene postponed the onset of diabetes in young (3 weeks old) and prediabetic (6 weeks old) NOD mice. 49 Moreover, the same approach protects transplanted islets from autoimmune destruction in a murine model. 50 Conditioning the recipient A small population (1-2%) of CD4 + T cells controls immune homeostasis.…”