The major goal of this revised competing renewal is the development of antigen-specific preventative therapies of type 1 diabetes that can be translated to man. Our studies to date have been aimed at a mechanistic understanding of the pathogenic processes in the NODmouse model focused on a family of class 8 protein tyrosine phosphatases that are major targets of humoral autoimmunity in humans. We have identified conserved antigenic peptide sequences that are common targets of both human and mouse CD4+ T cell clones, and conformational epitopes recognized by diabetes autoantibodies that have been conserved through over 300 million years of evolution. We have implemented new technologies for the in vitro evaluation of T cell cytokine responses (ELISPOT), and methodologies for rapidly screening pathogenic T cell receptors using retrogenic mice to further evaluate the pathogenic importance of these antigens. The grant also supported the initial characterization of humoral and cell-mediated immune responses to human Zn transporter 8, a major new ss-cell specific human diabetes autoantigen;the first to be discovered in over a decade. The current proposal while building upon these preliminary data embodies a shift in emphasis by using the NOD mouse as a pre-clinical model for the development of mechanistically-based new therapies for prevention of type 1 diabetes in humans.
Specific Aim 1 : Characterization of spontaneously-arising autoreactive T cells recognizing ZnT8 in NOD mice. Our approach here is largely empirical aimed at identifying multiple candidate antigen-specific TCRs and evaluating their disease potential by retrogenesis in a NOD mouse model. The fundamental objective is to identify 5-10 peptides from ZnT8 that are key to the pathogenesis of disease and which may have therapeutic potential. We will also test the diabetogenesis of the phogrin TCRs identified in the previous funding period.
Specific aim 2 : Pre-clinical studies of ZnT8-directed interventions in NOD mice This aim explores the practical development of ZnT8-and phogrin-based therapies, while at the same time giving heed to the mechanisms by which such suppression might occur in early and late stages of the disease. Experimentally this involves analysis of the incidence and rate of progression of T1D in NOD mice lacking ZnT8, and development of peptide and DNA based vaccination strategies based on dominant ZnT8 or phogrin T cell epitope peptides, or encoding cDNA. We anticipate that our results will confirm that both autoantigens can be effective therapeutic targets in NOD mice, both early and late during diabetogenesis, and will provide important new insight into the design of drugs and protocols that can ultimately be translated to humans.
Type 1A insulin dependent diabetes mellitus is one of the most frequent chronic diseases of children and young adults, and carries a high risk of devastating complications in later life. It is an autoimmune disease characterized by the selective destruction of the insulin-producing pancreatic ss-cells by autoreactive T-cells. a mechanistic understanding of the pathogenic processes in the NODmouse model focused on a family of class 8 protein tyrosine phosphatases that are major targets of humoral autoimmunity in humans
|Kozhakhmetova, A; Wyatt, R C; Caygill, C et al. (2018) A quarter of patients with type 1 diabetes have co-existing non-islet autoimmunity: the findings of a UK population-based family study. Clin Exp Immunol 192:251-258|
|Culina, Slobodan; Lalanne, Ana Ines; Afonso, Georgia et al. (2018) Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol 3:|
|Lahner, Edith; Brigatti, Cristina; Marzinotto, Ilaria et al. (2017) Luminescent Immunoprecipitation System (LIPS) for Detection of Autoantibodies Against ATP4A and ATP4B Subunits of Gastric Proton Pump H+,K+-ATPase in Atrophic Body Gastritis Patients. Clin Transl Gastroenterol 8:e215|
|Vendrame, F; Hopfner, Y-Y; Diamantopoulos, S et al. (2016) Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas-Kidney Transplants. Am J Transplant 16:235-45|
|Burke 3rd, George W; Chen, Linda J; Ciancio, Gaetano et al. (2016) Biomarkers in pancreas transplant. Curr Opin Organ Transplant 21:412-8|
|Burke 3rd, George W; Vendrame, Francesco; Virdi, Sahil K et al. (2015) Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity. Curr Diab Rep 15:121|
|Demeester, Simke; Keymeulen, Bart; Kaufman, Leonard et al. (2015) Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual ?-cell function in recent-onset type 1 diabetes. Diabetes Care 38:644-51|
|Wang, Bin; Hawa, Mohammed I; Rijsdijk, Frühling V et al. (2015) Heritability of thyroid peroxidase autoantibody levels in type 1 diabetes: evidence from discordant twin pairs. Diabetologia 58:2079-86|
|Asanghanwa, Milca; Gorus, Frans K; Weets, Ilse et al. (2014) Clinical and biological characteristics of diabetic patients under age 40 in Cameroon: relation to autoantibody status and comparison with Belgian patients. Diabetes Res Clin Pract 103:97-105|
|Davidson, Howard W; Wenzlau, Janet M; O'Brien, Richard M (2014) Zinc transporter 8 (ZnT8) and ? cell function. Trends Endocrinol Metab 25:415-24|
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