| Autor: |
Nylander, Karen, Harnaha, Jo, Gillis, Kimberly, Brown, Larry, Trucco, Massimo, Giannoukakis, Nick |
| Předmět: |
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| Zdroj: |
Diabetes; Jun2007 Supplement 1, Vol. 56, pA81-A81, 1/4p |
| Abstrakt: |
Type 1 diabetes mellitus is a disorder of glucose homeostasis caused by a chronic autoimmune inflammation of the pancreatic islets of Langerhans. The inflammation compels migratory antigen presenting cells, dendritic cells most prominently, to acquire beta cell-resident antigens derived from apoptotic and/or necrotic beta cells. The migratory dendritic cells then undergo an intrinsic "maturation" program which renders them capable of activating T-cells (including autoreactive, beta cell-specific T-cells) as they accumulate inside the draining pancreatic lymph nodes. We have previously shown that administration of dendritic cells with low-level expression of CD40, CD80 and CD86 costimulatory molecules into the genetically-diabetic non-obese diabetic (NOD) mouse can considerably delay and prevent the onset of disease and can reverse new-onset disease. Considerable logistics to generate these dendritic cell embodiments, necessitate a means to stabilise immaturity directly in vivo. Microparticle cartiers can direct DC to the administration site and once phagocytosed, the contents can shape the DC unctional phenotype. We have adapted PROMAXX(TM) microspheres to formulate antisense oligonucleotides previously shown to render autologous dendritic cells diabetes-suppressive. This formulation, when injected subcutaneously prevented type 1 diabetes in the non-obese diabetic (NOD) mouse strain and most importantly, exhibited a capacity to reverse new-onset clinical hyperglycemia, suggesting reversal of new onset disease. Mechanistically, we demonstrate that the formulation augments CD25+ Foxp3+ T regulatory cells which confer suppressive activity in vitro to NOD-derived pancreatic beta cell antigen without compromising global immune response to alloantigen and nominal antigen. Furthermore, T-cells from diabetes-free recipients of the microspheres are capable of suppressing adoptive transfer of disease by diabetogenic splenocytes into secondary immunodeficient recipients. We believe that these data form the foundation upon which a bona fide type 1 diabetes negative vaccine can be developed that is logistically-simple to produce and rapidly scalable to population levels. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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