Regulatory T Cells Targeting an Islet Antigen for Treating Type 1 Diabetes
Abstract
Topic: Diabetes is one of the Topic Areas of Encouragement related to FY21 PRMRP. At present, there is no cure for the more than three million Americans affected by Type 1 Diabetes (T1D). Currently, patients will rely on insulin replacement therapy for their entire lives. Although being treated with insulin shots a few times per day or continuously through an insulin pump, patients still frequently develop life-threatening complications. When a Service Member is diagnosed with T1D, he/she is considered unfit for active duty in most fields due to the rigors of an unpredictable lifestyle and intense physical requirements. Not to mention that many people with T1D may not even make it into the military. This project proposes a cell therapy to solve the root issue of T1D. Background: T1D is an autoimmune disease in which the body’s effector lymphocytes mistakenly destroy its own islet cells. When the damaged islets cannot produce enough insulin to maintain blood sugar at normal levels, T1D subsequently occurs. HLA-DQ8 is a T1D high-risk gene, and individuals carrying this gene have a significantly elevated risk for T1D. Normally, HLA-DQ8 proteins handle foreign intruders, such as viruses, presenting them to effector lymphocytes, and thus protecting the body from viral infection. HLA-DQ8 captures a piece of insulin in an unusual position and forms the HLA-DQ8/Insulin complex. Unfortunately, the body’s effector lymphocytes regard this complex as a foreign intruder, killing these intruders, mistakenly killing islet insulin-produce cells and causing T1D. Regulatory lymphocytes are a different group of cells. They can suppress nearby effector lymphocytes directly or send messages (named cytokines) to order them stop. In T1D patients, the number and function of T1D protective regulatory lymphocytes are defective. Using an advanced CART technique successfully used in cancer treatment, normal lymphocytes can be engineered to gain the ability to recognize the target of interested. Previous mouse studies showed that immune approaches that target mouse insulin-containing complexes were able to reduce T1D, by allowing the engineered lymphocytes to travel to the pancreas, inhibiting islet inflammation, and thereby protecting mice against T1D. We have generated HLA-DQ8/Insulin complex reactive regulatory lymphocytes and plan to test the potential of these cells in reducing human T1D. Method and Design: We hypothesize that HLA-DQ8/Insulin reactive regulatory lymphocytes can inhibit islet-attacking effector lymphocytes and reduce the development of T1D. We will test this hypothesis by two objectives. Objective 1 will test whether the engineered regulatory lymphocytes can inhibit islet-reactive lymphocytes of peripheral blood of T1D patients. If the self-attacking peripheral blood lymphocytes can be suppressed, it suggests self-attacking lymphocytes at the pancreas can also be suppressed. Objective 2 will test whether the HLA-DQ8/Insulin reactive regulatory lymphocytes can reduce the development of T1D and reverse the abnormally high blood glucose in a humanized mouse model. The humanized mice develop T1D because they carry the human high-risk HLA-DQ8 gene. Evidence of HLA-DQ8/Insulin reactive regulatory lymphocytes reduce the onset of T1D in the humanized mice suggests its ability to reduce T1D in the presymptom T1D people and ability even to reverse abnormally high blood sugar levels in the new onset patients. Innovation and Impact: This project is innovative in several ways. Firstly, our proposed approach uses HLADQ8/Insulin, a stimulator for bad lymphocyte, to stimulate protective regulatory lymphocytes. Secondly, our approach only targets T1D-related inflammation but does not disturb the normal protection of our immune system. HLA-DQ8/Insulin reactive regulatory lymphocytes will be enriched at the pancreas attracted by insulin, and ultimately limiting its suppression within pancreas. Thus, our approach is safer than the general im
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210087
Entities
People
- Li Zhang
Organizations
- Indiana Biosciences Research Institute
- United States Army