Objective
The objective of this study is to uncover molecular events that are involved in the initiation of type 1 diabetes and in the recruitment of immune cells that kill insulin-secreting beta cells, and to test novel treatment approaches that target these events. Specifically, the objective focuses on the state of cellular senescence in a minority of beta cells, and their role in recruitment of the immune system. The objectives of the study are to uncover the prevalence of beta cells that are in a senescent state of the disease, understand how they recruit immune cells through the interferon pathway, and understand why this response is triggered in the cells. Based on these findings, the objective is to target these processes therapeutically, either through drugs that target the senescent beta cells themselves, or drugs that block the immune-attracting responses.
Background Rationale
The rationale for this proposal is based on the convergence of several important concepts, some of which are quite recent. It is known that in type 1 diabetes, pancreatic beta cells attract the immune system, and the interferon system has been implicated in this process. Yet it is still unclear how this process is initiated, and why these beta cells are immunogenic. In parallel, studies of other cell types have recently revealed that cells that enter senescence activate the same immune-attracting system and are vulnerable to immune killing. This raises the possibility that senescence of beta cells, and the consequent immune-attracting activity, can lead to T1D. Indeed, there is already information indicating that beta cells in a state of senescence are prevalent in T1D. Our rationale in this study is therefore to connect these important dots and establish whether indeed senescent beta cells appear in T1D, and recruit immune cell attack through this mechanism. We present and test specific hypotheses as to why this occurs, as well as how this process may be blocked.
Description of Project
Type 1 diabetes is caused by destruction of insulin-producing beta cells in the pancreas by immune cell attack. However, the events that precede this destruction and initiate it are still poorly understood. In this proposal we explore a novel hypothesis for the processes contributing to the initiation of the disease, and to immune cell killing upon its development. It is known that cells in the body that suffer from stress or damage often enter a state of permanent cell cycle arrest called senescence, in which they remain viable, but their functions are reprogrammed. Recent studies have shown that senescent cells are able to attract and activate the immune system. More specifically, such senescent cells, through a system called the Interferon pathway, appear to display on their surface higher levels of the antigens that attract immune cells for attack. Recent work by us and by others has shown that some beta cells in the pancreas enter this state of senescence, and that it is particularly prevalent in the beta cells of type 1 diabetes patients. In the current study we propose that in early stages of diabetes, events in a subset of beta cells trigger the activation of senescence, and of the interferon pathway in them. This results in increased activation of the immune-attracting signals in these senescent beta cells, which then become more prone to killing. Thus, the presence of beta cells in a senescent state could represent a pivotal factor in recruiting immune attack against insulin-producing cells. In the study, we will characterize the exact molecular changes in senescent beta cells that are responsible for this increased attraction of immune cells. We will compare pancreata from non-diabetic subjects to subjects that are in a pre-diabetic state, and to diabetic patients, to test whether there is a change in the numbers and characteristics of the beta cells that are senescent. We will also study which events in beta cells may trigger the entry into senescence; we propose that internal changes that mimic a viral infection are a potential cause. Most importantly, we will explore novel ways to leverage this information for better therapy. We will test the potential benefit of elimination of senescent cells through “senolytic” drugs that target them, and of specific drugs that could block the signals activating the immune system against the beta cells in senescence. This study presents a novel concept for understanding the events leading to type 1 diabetes and immune cell attack, and tests the potential of novel treatment approaches targeting a specific sub-population of cells that may be particularly important for disease onset and progression.
Anticipated Outcome
Understanding the triggers for entry into senescence and the activation of the interferon response in them will provide a new conceptual understanding of the course of T1D development and its causes. Whereas much study has focused on potential infectious agents as activators of the immune response in T1D, here we propose a process that is connected to cell-intrinsic events occurring in beta cells. Most importantly, elucidation of the processes proposed in this proposal will raise immediate specific potential therapeutic approaches, which to date have not been studied in depth. The outcome of this study will therefore be highly impactful on the conceptual level, as well as the applicative level of T1D prevention and treatment.
Relevance to T1D
This study goes directly to the roots of T1D and the triggers that initiate and promote it. Beta cell senescence appears to occur in the pancreas of aging adults, yet there is now documentation that it is more prevalent in the pancreas of T1D patients, which are typically young and therefore are not expected to harbor cells in this state. This striking discovery highlights the potential contribution of pro-inflammatory senescence, and in particular a heightened interferon response, specifically to T1D. Since it has become clear that senescent cells are able to attract immune cells and promote their killing activity, their presence in T1D pancreata is a strong indicator of a potential central role in the disease.