Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell-mediated destruction of the insulin-producing ? cells in the pancreatic islets. Several T1D-associated class I MHCs have been identified, including HLA-A*0201, expressed by many T1D patients; ? cell epitopes restricted to this MHC have been identified as well. We hypothesize that these ? cell epitopes may be utilized as part of immunomodulatory therapies to prevent the onset of T1D. This may be done by utilizing the dendritic cell (DC) endocytic receptorDEC-205. In the absence of adjuvant, epitopes delivered via DEC-205 are presented to T cells in a tolerogenic manner, resulting in T cell tolerance towards those epitopes. Our laboratory has shown that when murine ? cell epitopes linked to anti-murine DEC-205 are delivered to DCs in vivo, T cells specific for those epitopes are deleted in non-obese diabetic (NOD) mice. We will further these studies in humanized mouse models. Importantly, while only a subset of murine DCs expresses DEC-205, it is present on all human myeloid DCs; our model replicates the human case via expression of human DEC-205 on all murine myeloid DCs. We hypothesize that, as with anti-murine DEC-205 treatments, the delivery of murine ? cell epitopes via antibodies against human DEC-205 will also induce T cell tolerance. Previous studies have also shown that simultaneous delivery of several HLA-A*0201-restricted ? cell epitopes, chemically linked to splenocytes, to HLA-A*0201-transgenic NOD mice prevented the onset of diabetes. To develop more clinically relevant reagents, we will simultaneously deliver these epitopes to NOD mice transgenic for both human DEC-205 and HLA-A*0201; we expect the induction of T cell tolerance towards these epitopes and prevention of T1D. This has the potential to aid the many T1D patients who express HLA-A*0201. However, HLA-A*0201 is not expressed by all T1Dpatients. To develop treatments for these patients, other T1D-associated class I MHCs should be considered, including the early onset-associated HLA-B*3906. While HLA-B*3906 is itself a rare allele, we have shown it to be a member of the HLA-B27 super type, whose members are expressed by 28% of the population. Studying HLA-B*3906 has the potential to have a large impact as peptides presented by one super type member are often capable of being presented by another. Our preliminary studies suggest that expression of HLA-B*3906in NOD mice results in the acceleration of T1D. To further examine the effect of HLA-B*3906 on T1D, we will also determine the effect of HLA-B*3906 on T1D incidence in NOD mice lacking murine class I MHC. A similar model has been used to identify HLA-A*0201-restricted ? cell epitopes, a method we will apply to HLA-B*3906.To do so, we will map potential epitopes from both human and murine ? cell antigens. These epitopes could then be used in future immunomodulatory therapies.
Type 1 diabetes is caused by T cells specific for ? cell epitopes presented by the insulin-producing ? cells; these epitopes are presented on type 1 diabetes-associated class I MHC molecules. Some of these epitopes have already been identified, and we will use them to develop type 1 diabetes treatments by linking them to anti-DEC-205 antibodies, to be delivered to dendritic cells which can then induce T cell tolerance towards those epitopes and therefore towards ? cells. This aforementioned work will be done using humanized mouse models to allow for easier translation of treatments to clinical use and, in that same vein, we will also work with mice transgenic for HLA-B*3906, an MHC molecule recently found to be associated with type 1 diabetes, to identify new ? cell peptides that can be used in future treatments.
| 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 |
| Racine, Jeremy J; Stewart, Isabel; Ratiu, Jeremy et al. (2018) Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes 67:923-935 |
| Sidney, John; Schloss, Jennifer; Moore, Carrie et al. (2016) Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06. Immunogenetics 68:231-6 |
| Babad, Jeffrey; Ali, Riyasat; Schloss, Jennifer et al. (2016) An HLA-Transgenic Mouse Model of Type 1 Diabetes That Incorporates the Reduced but Not Abolished Thymic Insulin Expression Seen in Patients. J Diabetes Res 2016:7959060 |
