Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused, in part, by a T cell mediated destruction of the insulin producing beta cells in the islets of Langerhans. Studies in animal models and limited human clinical studies demonstrate that modulation of T cell responses can alter the natural history of diabetes. However none of the currently available immune suppressive treatments induce a permanent remission. The absence of markers of the autoimmune process has limited the ability to evaluate the efficacy of potential immune modulatory drugs. The studies in this Project complement a Phase I/II trial of hOKT3gamma1 (Ala-Ala) for treatment of new onset will not cause the cytokine release syndrome or development of neutralizing antibodies preclude use of OKT3 in otherwise healthy patients with T1DM. Studies in the NOD mouse have shown that non-FcR binding anti-CD3 mAb can reverse diabetes. These studies in mice suggest that the reagent can selectively inhibit previously activated cells that produce Th1 cytokines thought to be involved in the disease.
The aims of the Phase I/II trial are: 1) Test the safety, tolerability, and immune effects of hOKT3gamma1 (Ala-Ala), and obtain data concerning possible biologic effects on the natural history of beta-cell destruction in T1DM. The hypothesis to be tested in this Project is that non-FcR binding mAb will inhibit islet antigen reactive Th1 cells and alter the natural history of T1DM. As part of these studies we plan to apply novel techniques available in the Autoimmunity Center, to identify and study autoreactive T cells in TG1DM. Because CD3, the target of the mAb, is expressed on all T cells, our approach will involve sequential studies first characterizing the effects of the mAb on bulk populations of peripheral cells, then defining its effect on islet antigen specific cells, and finally narrowing the focus to clonal populations of islet antigen reactive T cells. We will also study the effects of the mAb treatment on B/T cell interactions and regulation of autoantibody isotypes. At each step, we will correlate our cellular immunology findings with changes in metabolic function. These studies are highly dependent and interactive with the Cores of the Center. A key component of these studies will be to define the responses to islet antigens at the clonal level in different individuals following or in the absence of mAb treatment. By adopting this approach, we will also identify new peripheral markers of the cellular autoimmune process that will enable physicians and scientists to follow the course of the """"""""silent"""""""" autoimmune destruction of the insulin-producing beta cells, and to improve application of this or other novel immunotherapeutics to the treatment of autoimmune diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI046132-02
Application #
6354585
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2000-09-01
Project End
2001-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$200,166
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Winchester, Robert; Wiesendanger, Margrit; Zhang, Hui-Zhu et al. (2012) Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell ?-chain clonotypes in progressive lupus nephritis. Arthritis Rheum 64:1589-600
Ablamunits, Vitaly; Henegariu, Octavian; Preston-Hurlburt, Paula et al. (2011) NKG2A is a marker for acquisition of regulatory function by human CD8+ T cells activated with anti-CD3 antibody. Eur J Immunol 41:1832-42
Jiang, Hong; Canfield, Steve M; Gallagher, Mary P et al. (2010) HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. J Clin Invest 120:3641-50
Wu, Yilun; Zheng, Zongyu; Jiang, Yihua et al. (2009) The specificity of T cell regulation that enables self-nonself discrimination in the periphery. Proc Natl Acad Sci U S A 106:534-9
Jiang, Hong; Chess, Leonard (2009) How the immune system achieves self-nonself discrimination during adaptive immunity. Adv Immunol 102:95-133
Jiang, Hong; Chess, Leonard (2008) Qa-1/HLA-E-restricted regulatory CD8+ T cells and self-nonself discrimination: an essay on peripheral T-cell regulation. Hum Immunol 69:721-7
Chen, Weiling; Zhang, Linging; Liang, Bitao et al. (2007) Perceiving the avidity of T cell activation can be translated into peripheral T cell regulation. Proc Natl Acad Sci U S A 104:20472-7
Wu, Henry D; Maurer, Mathew S; Friedman, Richard A et al. (2007) The lymphocytic infiltration in calcific aortic stenosis predominantly consists of clonally expanded T cells. J Immunol 178:5329-39
Ben-Horin, Shomron; Green, Peter H R; Bank, Ilan et al. (2006) Characterizing the circulating, gliadin-specific CD4+ memory T cells in patients with celiac disease: linkage between memory function, gut homing and Th1 polarization. J Leukoc Biol 79:676-85
Tsai, E B; Sherry, N A; Palmer, J P et al. (2006) The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 49:261-70

Showing the most recent 10 out of 32 publications