The overall goal of this proposal is to develop a non-invasive method to detect the infiltration of CD8+ T-cells responsible for beta-cell destruction in pancreatic islets in Type 1 Diabetes (IDDM) by MR imaging. In vivo imaging of immune cells infiltration in real time would have significant impact in managing clinical IDDM, pancreas and/or islet cell transplantation and the understanding of the pathogenesis of IDDM. Unfortunately, such non-invasive techniques are currently not available. Based on our prior experience in cell labeling with crosslinked, superparamagnetic, monocrystalline iron oxide nanoparticles, we synthesized a novel MR imaging probe with high affinity ligands to T cell autoantigenic markers that allowed for high-efficiency intracellular magnetic labeling of the cells with subsequent detection by MRI. This probe specifically binds to highly diabetogenic TCR on CD8+ T cells from NOD transgenic mice, but does not recognize CD8+ T cells from healthy NOD mice. Furthermore, in our initial imaging experiments in vivo we were able to see gradual accumulation of labeled CD8+ T cells in mouse pancreas after adoptive transfer. In the current proposal we are going to conduct imaging experiments using this probe to answer highly relevant biological questions regarding the mechanisms that drive the recruitment, activation and differentiation of autoreactive CD8+ T cells. Specifically, we propose to image in vivo tracking of CD8+ T cell recruitment to the islets and beta-cell mass loss depending on the avidity of recruited killer cells. The proposed studies are a logical extension of the feasibility experiments, and if successful, a transition of this research would be tested in clinical trials. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064850-04
Application #
7089120
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Laughlin, Maren R
Project Start
2003-08-05
Project End
2007-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$259,334
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Medarova, Zdravka; Rashkovetsky, Leonid; Pantazopoulos, Pamela et al. (2009) Multiparametric monitoring of tumor response to chemotherapy by noninvasive imaging. Cancer Res 69:1182-9
Medarova, Zdravka; Vallabhajosyula, Prashanth; Tena, Aseda et al. (2009) In vivo imaging of autologous islet grafts in the liver and under the kidney capsule in non-human primates. Transplantation 87:1659-66
Moore, Anna (2009) Advances in beta-cell imaging. Eur J Radiol 70:254-7
Medarova, Zdravka; Kumar, Mohanraja; Ng, Shu-Wing et al. (2008) Multifunctional magnetic nanocarriers for image-tagged SiRNA delivery to intact pancreatic islets. Transplantation 86:1170-7
Medarova, Zdravka; Tsai, Sue; Evgenov, Natalia et al. (2008) In vivo imaging of a diabetogenic CD8+ T cell response during type 1 diabetes progression. Magn Reson Med 59:712-20
Hillman, Elizabeth M C; Moore, Anna (2007) All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast. Nat Photonics 1:526-530
Moore, Anna; Grimm, Jan; Han, Bingye et al. (2004) Tracking the recruitment of diabetogenic CD8+ T-cells to the pancreas in real time. Diabetes 53:1459-66