B-lymphocyte Targeting Therapies for Autoimmune Diabetes

PROJECT SUMMARY While the autoimmune destruction of pancreatic ß-cells causing type 1 diabetes (T1D) is ultimately a T-cell mediated process, it is clear in the NOD mouse model and also likely humans, that B-lymphocytes play an additional key pathogenic role. B-lymphocytes likely contribute to T1D by being the subset of APC most efficiently supporting pathogenic T-cell activation. This is due to the presence of B-lymphocytes expressing immunoglobulin (Ig) molecules that can efficiently capture and internalize ß-cell autoantigens. Thus, defects in mechanisms normally blocking the development or activity of autoreactive B- as well as T-lymphocytes contribute to T1D. Due to their role in supporting pathogenic T-cell responses there has been considerable interest in developing possible B-lymphocyte directed T1D interventions. Hence, the central hypothesis of this proposal is that gaining an increased understanding of the developmental and functional activity basis of T1D relevant B-lymphocytes in NOD mice could be of significance in identifying a means by which they could be effectively targeted. In this regards, current data indicate BAFF blockade may be a more effective B- lymphocyte directed T1D intervention than anti-CD20 treatment. Preliminary data now indicate a hypomorphic Ephb2 allelic variant may represent a T1D susceptibility (Idd) gene in NOD mice acting at the level of B- lymphocytes. Transgenically elevating Ephb2 expression inhibits T1D development through a B-lymphocyte dependent process. Aim 1 will address the currently unknown question if NOD B-lymphocytes with elevated Ephb2 expression have lost an ability to functionally activate diabetogenic T-cells, or alternatively have gained a capacity to functionally suppress such pathogenic effectors. We also previously found that a genetic and pharmaceutical approach inhibiting the ability of B-lymphocytes to undergo the processes of Ig somatic hypermutation (SHM) and class switch recombination (CSR) inhibits T1D development in NOD mice. Such T1D protection resulted from B-lymphocytes unable to undergo SHM and CSR converting to a regulatory phenotype (Breg) that inhibit pathogenic T-cells through increased activity of the immunosuppressive CD39/CD73 ecto-enzyme axis. More recent studies unexpectedly indicate ablation of the CD39 gene inhibits T1D development in NOD mice, and this is associated with a respective proportional increase and decrease in total B- and T-lymphocytes. Thus, Aim 2 is to determine if ablation of CD39 inhibits T1D development in NOD mice by expanding B-lymphocytes with a capacity to suppress pathogenic T-cell responses. We have also found T1D onset is accelerated in NOD mice with B-lymphocytes transgenically expressing an Ig specificity recognizing the peripherin molecule present in both pancreatic islets and neurons (NOD-PerIg mice), but this strain can also develop a potential multiple sclerosis (MS) relevant neurtitis syndrome. Aim 3 will determine the potential overlap in B-lymphocyte driven T-cell populations mediating T1D and neuritis development in NOD-PerIg mice, and assess if either of these pathologies can be attenuated by BAFF blockade.