In addition to long known contributions from particular MHC class II molecules, there is growing appreciation that in both humans and NOD mice some MHC class I variants also play an essential role in autoimmune type 1 diabetes (T1D) development by mediating pathogenic CD8 T-cell responses. The overall goal of this renewal application continues to be dissection in NOD based mouse models of the mechanistic basis for MHC class I restricted diabetogenic CD8 T-cell development, and use of this information to identify potentially clinically translatable means to attenuate such effectors. While the H2g7 MHC haplotype encoded Kd and Db class I molecules are essential to T1D development in NOD mice, they are common variants also characterizing many non-autoimmune prone strains. This suggested H2g7 MHC class I molecules aberrantly mediate diabetogenic CD8 T-cell responses in NOD mice through interactions with some of the many other disease susceptibility (Idd) genes characterizing this strain.
Aim 1 will test the hypothesis based on preliminary mRNA transcript profiling and congenic truncation analyses that a hyper-expression variant of the NFkB inhibitory Nfkbid gene located within the previously identified Idd7 locus is an important contributor to the failure of diabetogenic CD8 T-cells to undergo thymic negative selection in NOD mice. Similarly, epidemiological studies indicate that in humans certain common class I molecules such as HLA-A2.1 can aberrantly contribute to T1D development also likely through a genetically contextual process. Indeed, we found that when expressed in the context of the NOD genome, human HLA-A2.1 molecules mediate diabetogenic CD8 T-cell responses. HLA-A2.1 restricted diabetogenic CD8 T-cells in this NOD background stock primarily recognize two peptides each derived from the pancreatic ss cell proteins insulin (INS) and islet specific glucose-6-phosphatase catalytic subunit related protein (IGRP). Immunological tolerance can be efficiently induced to antigens bound to autologous leukocytes by the cross-linking agent ethylene carbodiimide (ECDI), and such an approach is in a clinical trial as a possible multiple sclerosis intervention. However, there are many hurdles to cell based therapies, and possible T1D intervention approaches can only be considered in humans already at a late prodromal stage of disease development. Therefore, to broaden potential clinical translation, Aim 2 will test the possibility supported by new preliminary data that treatment with synthetic microparticles bearing appropriate ECDI coupled INS and/or IGRP autoantigenic peptides can exert late disease stage T1D protective effects in NOD-HLA-A2 mice, and/or enables reversal of established disease by pancreatic islet transplantation. Finally, epidemiological evidence implicates B39 as a potentially highly potent diabetogenic HLA class I variant in humans. Thus, Aim 3 will assess whether transgenically expressed B39 molecules mediate diabetogenic CD8 T-cell responses in NOD mice, and if so, identify ss cell autoantigens displayed by this class I variant, and test their capacity to serve as broadened disease intervention reagents.

Public Health Relevance

Type 1 diabetes (T1D) is a life threatening disease that results when T lymphocytes mount an aberrant autoimmune response that destroys insulin producing ss cells within the pancreas. Thus, the overall goal of this renewal application continues to be dissection in NOD based mouse models of the genetic and mechanistic basis for development of a T-cell population that is a key mediator of T1D causative autoimmune ss cell destruction, and utilize this information to identify potentially clinically translatable mean to attenuate such effectors.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK046266-20A1
Application #
8759110
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Akolkar, Beena
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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