While type 1 diabetes (T1D) is ultimately mediated by autoreactive T-cells, in NOD mice, and also likely in humans, B-lymphocytes play an additional key pathogenic role. Through an ability to take up pancreatic ss cell proteins by immunoglobulin (Ig) mediated capture, B-lymphocytes appear to serve as an antigen presenting cell (APC) subset that most efficiently supports expansion of diabetogenic CD4 T-cells. Results from a recent clinical trial indicated transient depletion of B-lymphocytes with the CD20 specific rituximab antibody did not provide for long-term attenuation of diabetogenic autoimmunity. We recently found treatment with a rituximab- like CD20 specific antibody fails to efficiently prevent T1D development when initiated in NOD mice already manifesting signs of established high levels of pathogenic autoimmunity similar to that currently used to identify humans at high future disease risk. This appears to result from B-lymphocytes entering the pancreatic islets of NOD mice becoming CD20 negative. Furthermore, rituximab fails to deplete the marginal zone (MZ) subset of mature B-lymphocytes that can exert potent APC activity. We have also found diabetogenic clonotypes are enriched in the peritoneal CD20 negative B1 B-lymphocyte compartment of NOD mice. These issues call into question the extent that rituximab could be used as a mono-therapeutic T1D intervention approach. Thus, the overall goal of this proposal is to identify strategies that might independently, or in conjunction with rituximab, provide an improved B-lymphocyte directed T1D intervention approach.
Aim 1 will address to what extent do diabetogenic B-lymphocytes reside in compartments refractive to anti-CD20 mediated deletion. A broader array of B-lymphocyte populations, including those in NOD islets, can potentially be deleted through use of agents inhibiting the BAFF/APRIL survival factors rather than anti-CD20. It has also been reported that in NOD mice the ability of B-lymphocytes to mediate expansion of diabetogenic T cells outpaces the capacity of other APC subtypes to support disease protective regulatory T-cell (Treg) responses. The FDA approved reagent GCSF (Neulasta) can enhance recruitment of myeloid dendritic cells with a capacity to support Treg activity. Hence, Aim 2 will evaluate whether BAFF/APRIL inhibition, rather than anti-CD20, provides a better means for B-lymphocyte directed late-stage T1D prevention in NOD mice, or if co-treatment with GCSF synergistically enhances the efficacy of either approach. Other preliminary studies indicate a currently unknown gene(s) within a T1D susceptibility locus designated Idd9/11 on Chromosome 4 contributes to disease pathogenesis in NOD mice by impairing an immunoregulatory pathway normally inhibiting autoreactive B-lymphocyte responses. We have evidence this pathway may be disrupted at other operational points by some human T1D susceptibility genes.
Aim 3 is to determine if identification of a contributory Idd9/11 region gene(s) in NOD mice may reveal an immunoregulatory pathway, also potentially regulating diabetogenic B- lymphocyte development in humans, that may be amenable to pharmacological targeting.

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 cells within the pancreas. However, it is now clear that B lymphocytes play an important role in supporting the activation of T1D-inducing T lymphocyte responses. Initial results indicate a B lymphocyte targeting strategy currently in clinical trials may be only partialy effective as a possible T1D intervention approach. Thus, the goal of the present proposal is to identify strategies that may make B lymphocyte targeting approaches a more effective means of T1D intervention than now possible.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095735-05
Application #
9238768
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Presa, Maximiliano; Racine, Jeremy J; Dwyer, Jennifer R et al. (2018) A Hypermorphic Nfkbid Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8+ T Cells in NOD Mice. J Immunol 201:1907-1917
Schloss, Jennifer; Ali, Riyasat; Racine, Jeremy J et al. (2018) HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression. J Immunol 200:3353-3363
Ratiu, Jeremy J; Racine, Jeremy J; Hasham, Muneer G et al. (2017) Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes. J Immunol 198:4255-4267
Driver, John P; Racine, Jeremy J; Ye, Cheng et al. (2017) Interferon-? Limits Diabetogenic CD8+ T-Cell Effector Responses in Type 1 Diabetes. Diabetes 66:710-721
Lin, Bixuan; Ciecko, Ashley E; MacKinney, Erin et al. (2017) Congenic mapping identifies a novel Idd9 subregion regulating type 1 diabetes in NOD mice. Immunogenetics 69:193-198
Wang, Qiming; Racine, Jeremy J; Ratiu, Jeremy J et al. (2017) Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy. J Immunol 199:3757-3770
Mahmoud, Tamer I; Wang, Jingya; Karnell, Jodi L et al. (2016) Autoimmune manifestations in aged mice arise from early-life immune dysregulation. Sci Transl Med 8:361ra137
Leeth, Caroline M; Racine, Jeremy; Chapman, Harold D et al. (2016) B-lymphocytes expressing an Ig specificity recognizing the pancreatic ß-cell autoantigen peripherin are potent contributors to type 1 diabetes development in NOD mice. Diabetes 65:1977-1987
Scheuplein, Felix; Lamont, Deanna J; Poynter, Matthew E et al. (2015) Mouse Invariant Monoclonal Antibody NKT14: A Novel Tool to Manipulate iNKT Cell Function In Vivo. PLoS One 10:e0140729
Tsaih, S-W; Presa, M; Khaja, S et al. (2015) A locus on mouse chromosome 13 inversely regulates CD1d expression and the development of invariant natural killer T-cells. Genes Immun 16:221-30

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