Objective
Type 1 diabetes mellitus (T1DM) is a complex multifaceted disease. T1DM prevention is a desirable strategy given that significant beneficial effects on complications and slowing of the destruction of the pancreas by harmful immune cells is likely even if therapies only delay T1DM onset. The objective of this project is to further understand the RAGE pathway by studying children and adolescents at risk for or with recently diagnosed diabetes as well as novel cord blood derived human whole blood cells (dendritic cells) directly involved in T1DM development. The ability of RAGE inhibitory therapy to switch off unwanted immune responses and promote beneficial ones will be assessed and builds on our previous extensive preclinical data testing medicines likely to be safe for use and efficacious in humans. This will lay important foundations for future clinical studies and narrow the knowledge gap in the understanding of the disease progression, when is the best time to intervene and how long to treat for. However most importantly it will create an opportunity for these therapies to be made available to individuals with T1DM.
Background Rationale
Type 1 diabetes mellitus (T1DM) is a chronic disorder affecting younger people each year from diverse cultural backgrounds. One of the hallmarks of T1DM is activation of harmful immune cells causing an individual’s immune system to self-attack. This leads to immune cell driven destruction of the pancreas and reduced or diminished ability to produce insulin. The affected individuals are dependent on other sources of insulin. This involves life-long multiple daily injections/boluses of insulin making it challenging to manage, especially in younger children. Therapy design for prevention of T1DM is difficult due to the lack of symptoms that could identify disease manifestation at early stages. However, careful application of the lessons learned from preclinical models and more recent population based screening studies have now made this more feasible as a future approach. Recent studies in ‘at-risk’ individuals highlighted changes in a protein implicated in other chronic diseases termed RAGE (receptor for advanced glycation end products). Our team has previously shown that targeting this protein using various therapies likely safe for use in humans, significantly delays disease progression in preclinical T1DM, improves glucose management and preserves insulin release and beta cell function as well as improving immune system profiles. In Finnish populations, we have also generated robust evidence for increases in RAGE activating molecules (AGEs) and a decrease in the natural decoy RAGE inhibitor, soluble RAGE in the bloodstream of individuals considered “high risk” in large populations but we do not know if this is the case in a more heterogenous population such as seen in Australia or the USA.
Description of Project
Type 1 diabetes mellitus (T1DM) is the most common chronic childhood disease manifesting in early life and affects millions of people globally. Its prevalence is rising and the available treatment option only slows its onset via generalised suppression of the immune system (immunosuppression). During T1DM development, the insulin producing cells in the pancreas are progressively damaged by a person’s own immune system. This results in a lifelong dependency on exogenous insulin delivered via multiple daily injections or pumps for survival. Insulin is an important hormone required for energy production by cells using glucose. Although insulin injections/pumps and continuous blood glucose monitoring have revolutionized disease management, they do not constitute a cure. Life-long T1DM management is complex and is associated with a long list of severe complications including low and high blood glucose emergencies, blindness, kidney, and cardiovascular disease.
In its early stages, T1DM progresses sub-clinically in a ‘silent’ fashion with a substantial loss of insulin producing cells and their function often occurring before diagnosis. Therefore, it is extremely important to identify ‘at risk’ individuals and focus on understanding disease progression to optimise preventative strategies during these earlier stages, a major purpose of the present study. The attack against the pancreatic beta cells which make insulin is driven by white blood cells called T lymphocytes. Previous attempts to develop prevention therapies for T1DM have commonly focused on either expanding protective (regulatory) cells or eliminating harmful (effector) T cells that cause damage.
The Receptor for Advanced Glycation Endproducts (RAGE), found on beta cells and T cells is thought to be involved in many inflammatory conditions including T1DM. Although tantalising evidence shows increases in RAGE on harmful T cells from autoantibody positive youth ‘at-risk’ for type 1 diabetes, these studies are in very small numbers of people and need confirmation in larger studies such as the proposed study. We have generated robust evidence for increases in RAGE activating molecules (AGEs) and a decrease in the natural decoy RAGE inhibitor, soluble RAGE in the bloodstream of individuals considered “high risk” in large populations from Finland, who have a very high incidence of T1D. Again however, we do not know if this is the case in a more heterogenous population such as seen in Australia or the USA. This limitation will be addressed in the present study where we will examine RAGE expression on T cells in an Australian population of children and adolescents at risk of or with very recent onset of diabetes. T cells, are thought act in concert with other immune cells, particularly myeloid cells such as dendritic cells and the effects of RAGE expression on the function of these cells will also be examined.
Finally, one of the main reasons for studying RAGE is its potential as a target for therapy to prevent T1D. Indeed, in our preclinical studies, RAGE targeting therapeutics delay T1D onset, progression and improve beta-cell function which are being expanded in other projects involving industry partners. In other human clinical studies of Alzheimer’s disease and asthma, RAGE targeting therapies have reassuringly shown exceptional safety profiles with minimal side effects in early clinical studies and are not immunosuppressive. Therefore, greater understanding of this pathway in the early stages of T1D is key for these therapies to be optimised for secondary prevention of type 1 diabetes, the ultimate goal of our program of research.
Anticipated Outcome
This project will contribute the development of prevention therapies to slow or stop type 1 diabetes onset. It will address limitations and knowledge gaps in RAGE biology in humans to better understand how and when to target this pathway using our medicines developed in other projects. In the present study where we will examine RAGE expression on T cells and dendritic cells in an Australian population of children and adolescents at risk of or with very recent onset of diabetes to understand the timeline of RAGE expression. We will also test how these therapies affect interactions between specialised cells, dendritic cells and T cells.
It is predicted that these models will provide a more comprehensive overview of the efficacy of these therapies and the pathways affected in human immune cells. One of the therapies tested has already shown an excellent safety profile in humans. We are well placed in both clinical and laboratory research settings. Therefore, it is anticipated this study has potential to continue towards first in human clinical trials.
Relevance to T1D
Currently, individuals with type 1 diabetes mellitus (T1DM) have limited options to slow the loss of insulin producing pancreatic beta-cells or prevent its onset. Life-long T1DM management is complex and is associated with a long list of severe complications including low and high blood glucose emergencies, blindness, kidney, and cardiovascular disease. It also can significantly impact the mental health of affected individuals and their families. This project will fill in the knowledge gaps required for translation of novel therapies targeting RAGE for dampening pathogenic immune responses and enhancing positive ones. Specifically, this study will provide valuable information on the behaviour of human immune cells that are key players in T1DM in response to the preventative treatments proposed. The study will also analyse blood derived white blood cells from of individuals at high risk or recently diagnosed with T1DM. It will allow in-depth characterization of human immune cells and answer pertinent questions regarding the effects of RAGE targeting therapeutics. This will offer an invaluable insight and enable translation of this research into clinic where it could transform the lives by preventing or slowing T1DM onset.