Thursday, November 21, 2024
11/21/2024
DESCRIPTION (provided by applicant): 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
