Type I diabetes mellitus is an autoimmune disease whose etiopathogenesis lies in the selective destruction of the insulin-producing beta cells of the islets of Langerhans in the pancreas. The current insulin replacement therapy strategies are not fully effective at recapitulating tight glucose control and consequently, many patients eventually succumb to debilitating and life-threatening complications such as kidney failure and heart disease. While transplantation of intact islets of Langerhans offers the potential to restore physiologic glycemic control, the requirement for life-long immunosuppressive interventions carries with it significant risks of rendering the islet transplants dysfunctional. Moreover, these strategies can lead to an array of other problems including kidney failure and a risk of malignancy. In contrast, preventing autoimmunity altogether will prevent beta cell destruction, thereby obviating the need for life-long insulin therapy or transplantation concomitant with chronic immunosuppressive therapy. Most of the preventive strategies in experimental animals to date have focused on the induction of tolerance to either soluble islet antigens or putative autoantigens like insulin and glutamic acid decarboxylase. Intrathymic injection of islet lysates or putative autoantigens has resulted in either the prevention of diabetes or prolongation of time to onset in diabetic rodent models. Intrathymic injection, however, is not practical in humans, and the candidate autoantigen approach is risky in that the identity of the causative diabetogenic autoantigens remains unknown. This application focuses on developing proof-of-principle studies of an alternative means of achieving tolerance to autoantigens by manipulating a subtype of the diabetic host's immune cells in order to educate the host immune system to ignore beta cell antigens before the onset of disease. The subtype of immune cells that this application aims to manipulate into a cell vaccine are dendritic cells, considered to be the body's natural adjuvant. These cells normally initiate potent immune responses against foreign tissue. Dendritic cells however, have also been manipulated to tolerise the host immune system to foreign antigens, including allogeneic, and it is possible that similar manipulation may promote tolerance to autoantigens in diabetes. By blocking co-stimulatory pathways in which dendritic cells figure prominently, it has been possible to achieve long-term acceptance of both allogeneic and xenogeneic transplants. The central hypothesis that this application will test is whether administration of a prediabetic animal host's dendritic cells, rendered unable to provide adequate costimulatory signals by ex vivo gene transfer technology and presenting islet antigens, can prevent or prolong the time to onset of diabetes when reintroduced into the host. Oligonucleotide decoys for NF-kappaB, a transcriptional regulator of dendritic cell activation, as well as antisense oligonucleotides against the transcripts encoding the costimulation molecules CD80 and CD86 will be used to engineer the host's dendritic cells into a cell vaccine for autoimmune diabetes.
| Phillips, Brett; Nylander, Karen; Harnaha, Jo et al. (2008) A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes. Diabetes 57:1544-55 |
| Machen, Jennifer; Harnaha, Jo; Lakomy, Robert et al. (2004) Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells. J Immunol 173:4331-41 |
