In both the NOD mouse model, and also likely humans, B-lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of antigen presenting cells (APC) most efficiently supporting expansion of autoreactive T-cells ultimately mediating pancreatic -cell destruction. However, a clinical trial found the B- lymphocyte depleting CD20 specific rituximab antibody was only partially effective as a possible T1D intervention. While not excluding other possible contributory factors, our finding that B-lymphocytes entering the islets of NOD mice down-regulate cell surface CD20 expression may partly explain why the tested rituximab mono-therapy did not represent a robust T1D intervention. It is currently only possible to consider initiation of possible T1D interventions in humans that have already developed markers of ongoing aggressive pathogenic autoimmunity such as the presence of insulin autoantibodies (IAA). Thus, the central goal of this proposal is to identify other possible B-lymphocyte directed approaches that either independently or synergistically with anti-CD20 provide a more robust late disease stage T1D intervention strategy than those previously assessed. We have found that when initiated in NOD mice at an already IAA positive late stage of disease development transient treatment with a soluble receptor reagent blocking the B-lymphocyte survival factor BAFF efficiently inhibits T1D development. Our new aim 1 is to test the possibility supported by preliminary data that in addition to being purged of those with pathogenic APC activity whether B-lymphocytes remaining present and/or rebounding in NOD mice after transient BAFF blockade convert to a T1D protective immunoregulatory phenotype, and if so how this may mechanistically occur. Possible B-lymphocyte targeting approaches for T1D might also be aided by gaining a greater understanding of the particular autoantigen specific populations that contribute to disease and the genetic basis for their aberrant development. In this regards we have found B-lymphocytes transgenically expressing an immunoglobulin (Ig) molecule recognizing the islet autoantigen peripherin mediate a significantly accelerated rate of T1D development in NOD mice (stock designated NOD-PerIg). This NOD-PerIg stock provides a key resource to test in aim 2 the hypothesis supported by other preliminary data that a hypomorphic Ephb2 allelic variant represents a T1D susceptibility (Idd) gene in NOD mice by enabling the development of pathogenic B-lymphocytes. NOD mice made deficient in the Aicda gene that initiates B-lymphocyte affinity maturation processes are profoundly T1D resistant. Furthermore, treatment with a small molecule termed DIDS also inhibiting B-lymphocyte affinity maturation blocks progression to overt T1D when initiated in already IAA positive NOD mice.
Aim 3 will test possibilities supported by preliminary data whether B-lymphocytes remaining present in Aicda deficient or DIDs treated NOD mice inhibit T1D through activity of the immunosuppressive CD73 ecto-enzyme and/or IL-10 production, and also assess if such factors may also be relevant to disease regulation in humans.

Public Health Relevance

/RELEVANCE TO PUBLIC HEALTH 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. A B lymphocyte targeting strategy tested in a previous clinical trial was only partially 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Spain, Lisa M
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Jackson Laboratory
Bar Harbor
United States
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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
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