Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. In the NOD mouse model of the disease, CD8+ T cells are required pathogenic effectors that have begun to show promise as therapeutic targets. CD8+ T cells specific for beta cell antigens are also present in the peripheral blood of T1D patients. We are working to harness the potent tolerogenic properties of dendritic cells (DC) to develop an immunotherapeutic intervention for T1D that targets CD8+ T cells. We have found that antigen targeting to steady-state DC via the DC endocytic receptor DEC-205 can lead to T cell tolerance even in the context of ongoing autoimmunity in NOD mice with known tolerance defects. Transition of this strategy to the human disease will require a better understanding of its therapeutic efficacy and the factors that determine its outcome. Antigen delivery reagents appropriate for human use, and preclinical models suitable for their testing, will also need to be developed and evaluated, and the identification of antigenic targets relevant to large numbers of patients will also be required. These needs will all be met upon completion of the Specific Aims proposed in this renewal application.
In Aim 1, using both murine and human T cells, we will test the hypothesis that T cell receptor (TCR) affinity and/or prior antigen experience influence the outcome of exposure to an antigen delivered to steady-state DC via anti-DEC-205, an outcome that can range from T cell deletion, non-responsiveness, or development of a regulatory phenotype. These studies will be conducted using sets of TCRs having defined and variable affinities.
In Aim 2, we will test the hypothesis that simultaneous delivery of multiple critical CD8+ T cell epitopes to DC via anti-DEC-205 will lead to improvement of disease course in NOD mice and in NOD.m?2m-/-.HHD(HLA-A2).hDEC-205 mice to be developed here.
In Aim 3, we will examine the HLA-restricted CD8+ T cell response to the important beta cell antigens IGRP and insulin using islet-infiltrating cells from NOD mice transgenic for one of four HLA molecules that we will additionally engineer here to express human IGRP or insulin. As each HLA molecule to be examined is representative of a unique HLA supertype, and a peptide identified using one supertype member will often also bind other members of that supertype, our strategy to identify epitopes using our panel of HLA- transgenic mice expressing human beta cell antigens should result in monitoring and therapeutic reagents relevant to large numbers of patients and at-risk individuals. Our proposed studies will have important implications for the development of antigen-specific therapeutics for T1D and will provide information that will help to guide the future development of immunomodulatory therapies for this disease.
Our work will lay a foundation for the development of antigen-specific therapies for type 1 diabetes, which is a growing health problem that is associated with significant morbidity and mortality. The proposed work seeks to induce immunological tolerance in response to presentation of beta cell antigens by steady-state dendritic cells and to identify therapeutic and immune monitoring targets that will provide broad population coverage.
|Lamont, Deanna; Mukherjee, Gayatri; Kumar, P Rajesh et al. (2014) Compensatory mechanisms allow undersized anchor-deficient class I MHC ligands to mediate pathogenic autoreactive T cell responses. J Immunol 193:2135-46|
|Mukherjee, Gayatri; Geliebter, Ari; Babad, Jeffrey et al. (2013) DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8? T cells independently of PD-1 and PD-L1. Int Immunol 25:651-60|
|Antal, Zoltan; Baker, Jason C; Smith, Carla et al. (2012) Beyond HLA-A*0201: new HLA-transgenic nonobese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+ T cell epitopes. J Immunol 188:5766-75|
|Samanta, Dibyendu; Mukherjee, Gayatri; Ramagopal, Udupi A et al. (2011) Structural and functional characterization of a single-chain peptide-MHC molecule that modulates both naive and activated CD8+ T cells. Proc Natl Acad Sci U S A 108:13682-7|
|Brims, Daniel R; Qian, Jie; Jarchum, Irene et al. (2010) Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect. Int Immunol 22:191-203|
|Chaparro, Rodolfo José; Dilorenzo, Teresa P (2010) An update on the use of NOD mice to study autoimmune (Type 1) diabetes. Expert Rev Clin Immunol 6:939-55|
|Jarchum, Irene; Takaki, Toshiyuki; DiLorenzo, Teresa P (2008) Efficient culture of CD8(+) T cells from the islets of NOD mice and their use for the study of autoreactive specificities. J Immunol Methods 339:66-73|
|Antal, Zoltan; Jarchum, Irene; DiLorenzo, Teresa P (2008) HLA class I supertypes in type 1 diabetic children in an urban children's hospital. Ann N Y Acad Sci 1150:86-9|
|Chaparro, Rodolfo Jose; Burton, Amanda R; Serreze, David V et al. (2008) Rapid identification of MHC class I-restricted antigens relevant to autoimmune diabetes using retrogenic T cells. J Immunol Methods 335:106-15|
|Mukhopadhaya, Arunika; Hanafusa, Tadashi; Jarchum, Irene et al. (2008) Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. Proc Natl Acad Sci U S A 105:6374-9|
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