The long-term objective of this proposal is to design a novel immunomodulatory therapy for tolerance induction for treatment of autoimmune (type 1) diabetes.
The specific aim of the proposal is to test a transforming growth factor-beta 1 (TGF-beta1) based methodology for inducing islet antigen-specific regulatory T cells that are capable of transferring self-tolerance in the mouse model of human type 1 diabetes. The potential findings from this research proposal would have significant implications in treatment of patients with type 1 diabetes. The candidate will perform the proposed studies using the non-obese diabetic (NOD) mouse model of human type 1 diabetes. The step-wise approach for pursuing these goals will be: (1) to induce TGF-beta1 dependent islet antigen-specific regulatory T cells from a polyclonal naive T cell population, using dendritic cells for selecting antigen specificities;(2) to test the therapeutic efficacy of the TGF-beta 1-induced regulatory T cells in reverting established diabetes in the NOD mouse;and (3) to determine the potential endogenous source(s) of TGF-beta1, particularly among dendritic cell subsets which are newly recognized to play an important role in tolerance induction. Current treatment for human type 1 diabetes requires life-long insulin therapy or long-term immunosuppression for transplantation, both of which have significant risks and unwanted side-effects. Successful completion of the proposed project will help us design immunomodulatory therapies that specifically target the autoimmune process for treatment of this devastating disease. In addition to having intrinsic research importance, the proposed research contains the necessary components of serving as a suitable vehicle for learning the methodology, theories, and conceptualizations necessary for transition of the candidate to an independent investigator. Together with the conducive environment at Northwestern University Feinberg School of Medicine, the dedication and commitment of the candidate's sponsor and co-sponsors to the candidate's career development, and the candidate's accomplished research background, this proposed research and training would provide the central force for bringing these elements together and ultimately contribute to fulfillment of the candidate's career goal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK070029-04
Application #
7679479
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2006-09-20
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$127,221
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Lerret, N M; Houlihan, J L; Kheradmand, T et al. (2012) Donor-specific CD8+ Foxp3+ T cells protect skin allografts and facilitate induction of conventional CD4+ Foxp3+ regulatory T cells. Am J Transplant 12:2335-47
Chen, G; Kheradmand, T; Bryant, J et al. (2012) Intragraft CD11b(+) IDO(+) cells mediate cardiac allograft tolerance by ECDI-fixed donor splenocyte infusions. Am J Transplant 12:2920-9
Kheradmand, Taba; Wang, Shusen; Gibly, Romie F et al. (2011) Permanent protection of PLG scaffold transplanted allogeneic islet grafts in diabetic mice treated with ECDI-fixed donor splenocyte infusions. Biomaterials 32:4517-24
Yu, Yuming; Zitzner, Jennifer R; Houlihan, Josetta et al. (2011) Common gamma chain cytokines promote rapid in vitro expansion of allo-specific human CD8+ suppressor T cells. PLoS One 6:e28948
Pothoven, K L; Kheradmand, T; Yang, Q et al. (2010) Rapamycin-conditioned donor dendritic cells differentiate CD4CD25Foxp3 T cells in vitro with TGF-beta1 for islet transplantation. Am J Transplant 10:1774-84
Luo, Xunrong; Herold, Kevan C; Miller, Stephen D (2010) Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity 32:488-99
Xia, Guliang; Shah, Malathi; Luo, Xunrong (2009) Prevention of allograft rejection by amplification of Foxp3(+)CD4(+)CD25(+) regulatory T cells. Transl Res 153:60-70
Luo, Xunrong; Pothoven, Kathryn L; McCarthy, Derrick et al. (2008) ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms. Proc Natl Acad Sci U S A 105:14527-32
Luo, Xunrong; Tarbell, Kristin V; Yang, Hua et al. (2007) Dendritic cells with TGF-beta1 differentiate naive CD4+CD25- T cells into islet-protective Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:2821-6