Multiple Immune Pathways to Type 1 Diabetes Mellitus: Lessons Learned from Human Clinical Trials and Animal Models of Disease Clinical Trials, Lessons Learned

Abstract

Type 1 diabetes mellitus results from progressive autoimmune attack of the endocrine pancreas. Immune cells infiltrate the pancreatic islets and focus their attack on beta cells causing loss of insulin production. Progressive insulin loss leads to lifelong insulin replacement therapy and comorbidities. The ultimate clinical goal in type 1 diabetes is to restore and preserve beta cell function thus alleviating the need for exogenous insulin replacement. A secondary goal is to prevent complications that result from chronic inflammation including cardiovascular disease, kidney disease, neuropathy, and retinopathy. These goals are neither exclusive nor interdependent. The best clinical approach will target immune cells, although beta cell replacement in addition to immune targets might lead to a cure. At present, clinical trials have involved antigen specific therapies to attempt tolerance induction through depletion of pathogenic effector cells and/or generation of regulatory T cells; infusion of autologous Tregs to control the pathogenic inflammation; monoclonal antibodies that target total T cells, total B cells, or inflammatory cytokines; small molecule drugs; and targeting T cell co-stimulation. Moreover, newly developed pluripotent beta cell clusters with immune privilege achieved through CRISPR technology appear to restore insulin secretion and avoid immune surveillance. These approaches have not yet achieved the clinical goal of halting or reversing loss of C-peptide, a marker for beta cell function, or sustained long-term reduction of daily blood glucose and insulin requirements. Some therapies like Teplizumab (humanized anti-CD3 monoclonal antibody) have slowed loss of C-peptide and it appears that several study subjects have had long-term positive responses. The totality of clinical trials points to heterogeneity within those individuals labelled as “type 1 diabetes” making a single target approach unlikely to be successful. This review considers recent and current immune modulatory drugs in T1DM clinical trials. While none have yet been fully successful, valuable information about how to better approach this serious disease is emerging. The information from clinical trials further points to the possibility that rather than being a single disease, ‘type 1 diabetes’ may better be described as a family of diseases where different cellular mechanisms reach the same clinical outcome, loss of insulin production.