Candidate: The investigator is a veterinary oncologist at NCSU-CVM, with a PhD in immunology. His immediate goals are to continue a recently-begun project examining the use of cytotoxic class I tetramers to eliminate pathogenic CD8+ T cells in type 1 diabetes (T1D). His long-term goals are to direct an externally-funded, basic research laboratory investigating the regulation of T cell immunity, which will hopefully lead to the development of innovative therapeutic strategies for autoimmunity and cancer. For several years the candidate has worked collaboratively in the laboratory of his sponsor, Dr. Jeffrey Frelinger, Kenan Professor of Immunology at UNC-CH. Under the proposed 4-year award, the candidate will transition his research project from UNC-CH into a laboratory that he will establish in a new facility at NCSU. To assist in this transition, and to provide guidance on research, scholarly productivity, and career development, the candidate will have two co-sponsors: Dr. Hauck (NCSU), an oncologist and former mentor;and Dr. Tisch (UNC-CH), an expert on T1D and a co-investigator on the candidate's current project. Planned and informal meetings with mentors, as well as other specialized training, will assist in the candidate's growth as an independent scientist. Environment: The sponsor has an impressive track record of scientific productivity, funding, and training^ clinician-scientists. The laboratory and core facility resources at both institutions are well-suited to completing the proposed work, and the intellectual climate is excellent. The candidate's department is committed to his career development as a scientist and supports the time requirements necessary for research. Research project: Studies in the NOD model of T1D implicate CD8+ T cells in diabetogenesis, and a dominant islet-infiltrating clonotype that recognizes IGRP206-214 has been identified. Our preliminary data show that these T cells can be selectively deleted in vivo by a cytotoxic high-avidity cognate tetramer;however, this tolerogenic strategy may ultimately fail if pathogenic T cells re-expand to fill the clonotype """"""""space"""""""" created by deletion. We propose to evaluate strategies for preferentially expanding non-pathogenic T cells within this vacancy, and if successful, investigate the effects of this dual strategy on the functional composition of islet T cell populations. Relevance: This research will help to determine the role of killer T cells in juvenile diabetes, and potentially characterize a new strategy for treating this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK082264-03
Application #
7813865
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Hyde, James F
Project Start
2008-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$123,674
Indirect Cost
Name
North Carolina State University Raleigh
Department
Other Clinical Sciences
Type
Schools of Veterinary Medicine
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Bennett, A L; Williams, L E; Ferguson, M W et al. (2017) Canine acute leukaemia: 50 cases (1989-2014). Vet Comp Oncol 15:1101-1114
Kidd, J A; Ross, P; Buntzman, A S et al. (2015) Development of an ELISA to detect circulating anti-asparaginase antibodies in dogs with lymphoid neoplasia treated with Escherichia coli l-asparaginase. Vet Comp Oncol 13:77-88
Hess, Sabrina M; Young, Ellen F; Miller, Keith R et al. (2013) Deletion of naïve T cells recognizing the minor histocompatibility antigen HY with toxin-coupled peptide-MHC class I tetramers inhibits cognate CTL responses and alters immunodominance. Transpl Immunol 29:138-45
Holmes, Jennifer C; Holmer, Savannah G; Ross, Peter et al. (2013) Polymorphisms and tissue expression of the feline leukocyte antigen class I loci FLAI-E, FLAI-H, and FLAI-K. Immunogenetics 65:675-89
Gojanovich, Gregory S; Ross, Peter; Holmer, Savannah G et al. (2013) Characterization and allelic variation of the transporters associated with antigen processing (TAP) genes in the domestic dog (Canis lupus familiaris). Dev Comp Immunol 41:578-86
Ross, Peter; Holmes, Jennifer C; Gojanovich, Gregory S et al. (2012) A cell-based MHC stabilization assay for the detection of peptide binding to the canine classical class I molecule, DLA-88. Vet Immunol Immunopathol 150:206-12
Ross, P; Buntzman, A S; Vincent, B G et al. (2012) Allelic diversity at the DLA-88 locus in Golden Retriever and Boxer breeds is limited. Tissue Antigens 80:175-83
Vincent, Benjamin G; Young, Ellen F; Buntzman, Adam S et al. (2010) Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice. J Immunol 184:4196-204