PI: Dr. David Galas
Location: Pacific Northwest Diabetes Research Institute (PNDRI)
Type 1 diabetes is an autoimmune disease, in which B cells and T cells collaborate in the destruction of pancreatic, insulin-producing cells. The onset of the disease is preceded by the presence of autoantibodies directed against proteins produced by islet cells, such as insulin and glutamic acid decarboxylase.
Proposed collaborative projects with the Institute for Protein Design (IPD) will develop and test peptides/self-assembling nanoparticles for eliminating B-cell and T-cell axes of the type 1 diabetes autoimmune response. Not only do these projects have the potential to develop solutions for preventing the development of type 1 diabetes, but can potentially provide proof-of-concept for the treatment of other autoimmune diseases.
The successful candidate will have the opportunity to be co-mentored by Dr Fred Ramsdell (PNDRI) and Dr David Baker (UW IPD).
PROJECT 1: Inhibition of T-cell Activation
– Affinity maturation of antibody-producing memory B cells is initiated by T-cell recognition of antigens displayed on major histocompatibility complex class II (MHCII) proteins on the surface of mature antigen-presenting cells.
– The presence of DQ8-HLA allele is highly correlated with onset of childhood diabetes.
– The DQ8-HLA receptor has been showon to bind insulin antigens with high affinity and specificity. This binding process, DQ8-HLA receptor to insulin, serves as an alert to T cells to activate.
PNDRI will collaborate with IPD to design a peptide antigen that will have even higher affinity and specificity to the DQ8 HLA receptor than insulin does. We will test the effect of blocking the DQ8 HLA receptor from binding with insulin antigens and preventing T cells from attacking the pancreatic insulin-producing cells in animal models of type 1 diabetes.
PROJECT 2: Design of Insulin-tolerizing Vaccines
– B cells produce autoantibodies that ultimately “tag” the target cells and trigger the immune cell mediated destruction of pancreatic beta cells.
– The IPD has made recent advances in designing protein-based self-assembling nanoparticles constructed of two different proteins that mimic the shape and size of natural viruses and may serve as potential tolerogens by co-presenting immunoactive molecules in a non-activating form.
We will collaborate with IPD to design and test in vivo two-component nanoparticles designed to inhibit B-cell responses through the presentation of insulin, or related antigens and a B-cell suppressor agent.