Project Summary:
Type 1 diabetes (T1D) is an autoimmune disease that results in the loss of pancreatic β-cell function and lifelong dependence on exogenous insulin replacement therapy, and reduced life-expectancy and quality. T1D incidence has increased by 2-5% per year in recent decades; this has been accompanied by a reduction in the age of onset, and an increase in the number of pediatric diagnoses. In 2016, the prevalence of diagnosed T1D was 0.55%, representing 1.3 million people in the U.S. Published data from Children’s Wisconsin show that T1D incidences between 1995 to 2004 in Wisconsin parallel those elsewhere, with the largest increase seen in children over 14 years of age. Numerous therapeutic strategies aimed at modifying the disease course have now been tested in T1D; however, the responses have been of limited duration and patient response have been highly variable. There is a need for improved biomarkers of pre- or post-onset disease progression, biomarkers to identify subjects most likely to benefit from immunotherapy, and measures of therapeutic efficacy beyond the retention of β-cell function over time. As evidenced by the partial successes of immunotherapies targeting T-cells and B-cells, T1D pathogenesis involves adaptive immune responses. However, a growing body of evidence supports a role for altered innate immune responses and inflammation in T1D pathogenesis. Monocytes are innate cells that govern the initiation, development, and resolution of immune responses and have been implicated in numerous autoimmune disorders. Because the number of studies that have examined the phenotype and function of these novel monocyte subsets in T1D patients and their at-risk relatives remain limited, the project team is studying this population in unrelated healthy controls (uHC), healthy utoantibody-negative high HLA-risk siblings (HRS, DR3 and/or DR4), low HLA-risk siblings (LRS, non-DR3/non-DR4), recent onset (RO) T1D patients and long standing (LS) T1D patients (established T1D for greater than five years with little to no endogenous β-cell function). Their studies have identified heightened monocyte inflammatory/cytolytic activity associated with T1D susceptibility and progression. Specifically, monocytes of T1D patients express higher cytokine/chemokine, perforin and granzyme levels. In contrast to T1D progressors, the abundance of mono4 monocytes longitudinally decreased among non-progressors and their abundances negatively correlated with temporal increases in peripheral activated Treg cells. These novel analyses identify heightened monocyte inflammatory activity associated with T1D susceptibility and progression that is temporally counter-regulated among nonprogressors, offering insight to the age-dependent decline in T1D susceptibility.
AHW funding will help address remaining knowledge gaps in the team’s understanding of monocyte heterogeneity and function in the context of T1D progression/non-progression. This project will enable the researchers to investigate the potential regulatory/anti-inflammatory role for (Slan+) non-classical monocytes, a new subset that has not been examined in our studies so far. The knowledge gained has the potential to improve the understanding of T1D pathogenesis, to foster the development of therapeutic strategies, as well as to identify biomarkers of progression.