AbstractsBiology & Animal Science

Reversal of Overt Type 1 Diabetes in the NOD Mouse through the Use of Combination Therapy

by Matthew Parker

Institution: University of Florida
Department: Medical Sciences, Immunology and Microbiology (IDP)
Year: 2008
Keywords: aat, atg, autoimmunity, beta, combination, diabetes, gcsf, hyperglycemia, insulin, januvia, lymphocyte, neupogen, nod, rapamycin, remission, reversal, scd26, sirolimus, sitagliptin, thymoglobulin; Immunology and Microbiology (IDP)
Record ID: 1828856
Full text PDF: http://ufdc.ufl.edu/UFE0022816


The autoimmune destruction of the insulin-producing beta cells by autoreactive T lymphocytes results in a loss of blood glucose control and is known as type 1 diabetes (T1D). While exogenous insulin therapy has been available commercially since 1923, this treatment is not considered a cure as it is life-long and typically results in long-term complications including retinopathy, nephropathy, and various cardiovascular disorders. As such, there has been a desire to increase our understanding of disease pathogenesis in order to potentially prevent and/or cure overt diabetes. Many such studies have been carried out using animal models of T1D, perhaps most prolifically in the non-obese diabetic (NOD) mouse. After recent clinical trials in which prevention therapies have not proven efficacious, there has been an increasing desire for intervention therapies immediately post-onset. As such, the need to control the autoimmune response may be considered a critical component to these therapies. In these studies, anti-thymocyte globulin (ATG) was used immediately post-onset in NOD mice in order to halt the autoimmune destruction of the remaining beta cells as well as to attempt to induce a more tolerant immune phenotype. Only two doses of ATG were administered, resulting in a short-term T lymphocyte ablation. In addition, secondary compounds were added in combination with ATG in different stages of this project based upon the hypothesis that combination therapy targeting multiple pathways would prove more effective at inducing long-term disease remission than monotherapy. These studies will demonstrate that not only was ATG effective at inducing significant remission in new-onset NOD mice, but also that through combination therapy with granulocyte-colony stimulating factor (G-CSF) insulitis was diminished while beta cell area increased, as demonstrated through analysis of histology. In addition a more tolerant immune phenotype was induced as quantified through analysis of regulatory T cell populations.