Davies, Joanna D., PhD
Immune homeostasis and mechanisms of disease progression in children with newly diagnosed type I diabetes
General Research Subject: Type 1 Diabetes
Focus: Immunology, Pediatrics, Pediatrics\Type 1
Type of Grant: Clinical Translational Research
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Patients who are newly diagnosed with type I diabetes (TID) are required to take a large dose of insulin to reduce the blood glucose levels to normal. However, within weeks of diagnosis, the amount of insulin required is substantially reduced in many patients. This period, called the 'honeymoon period', can last from weeks to over a year. Treatment of new onset TID patients with drugs aimed at reversing TID are most effective when given during the honeymoon period. Therefore, designing protocols to prolong the honeymoon period might be beneficial to patients by reducing the dose of insulin that they require, and by improving responsiveness to therapy.
A new immune cell subset called CD4+ CD44v.low has recently been discovered in the mouse model for TID. These cells are present when the mice first become diabetic, but are lost 2-3 weeks after diagnosis. They delay disease progression when injected into diabetic mice, and they induce a significant increase in the cells that make insulin when injected into mice that have a deficient immune system. In a human TID pilot study that was funded by an ADA Innovation Award, investigators found that the same cell subset is present in significantly greater numbers in TID patients who have a long honeymoon period compared to patients who have a shorter honeymoon period suggesting that CD4+ CD44v.low cells might also delay disease progression in human TID. The goal of this study is to confirm this finding by increasing the number of patients to the study.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project will focus on type I diabetes in children. Patients who are newly diagnosed with type I diabetes (TID) are required to take a large dose of insulin to reduce the blood glucose levels to normal. However, within weeks of diagnosis, the amount of insulin required is substantially reduced in many patients. This period, called the ‘honeymoon period’, can last from weeks to over a year. Treatment of new onset TID patients with drugs aimed at reversing TID are most effective when given during the honeymoon period. Therefore, designing protocols to prolong the honeymoon period might be beneficial to patients by reducing the dose of insulin that they require, and by improving responsiveness to therapy. Prolonging the honeymoon period would also reduce the requirement for exogenous insulin reducing the risk of complications later.
The goal of this study is to confirm our finding that novel immune cell subsets can be used to predict the length of the honeymoon period. We anticipate that this new information will identify novel targets for prolonging and inducing the honeymoon period in TID. Moreover, the data will justify additional mechanistic studies aimed at developing strategies to expand or enhance the function of these immune cell subsets to reduce the rate of disease progression in both newly diagnosed TID patients and in individuals at risk of developing diabetes.
Future studies: A significant association between the length of honeymoon period and frequency of the immune cell subsets tested will provide a tool for us to test the hypothesis that patients who go on to have a longer honeymoon period will be the most responsive to immunotherapy. Such a test will allow physicians to select those patients most likely to respond to therapy. In addition, using archived samples from TrialNet (Type I Diabetes TrialNet Natural History Study), we plan to test the hypothesis that these cell subsets can be used to predict which at risk individuals will progress to disease and therefore be used for early diagnosis of TID, an unprecedented development in this therapeutic area. Early diagnosis might identify an at risk population who would greatly benefit from early therapy.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The goal of this project is to determine whether novel immune cell subsets previously identified by our group can be used to predict the rate of disease progression indicated by the length of the honeymoon period. Although this information will not immediately benefit persons with diabetes, if our hypothesis is correct, in the longer term we hope to manipulate these cell subsets in newly diagnosed (and at risk individuals) to i) delay disease progression, and ii) increase the sensitivity of these individuals to immunotherapy. Ongoing research in our lab in addition to the proposed ADA study is designed to identify strategies to enhance the relevant cell subset numbers and function for the treatment and prevention of type I diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have worked in the field of type I diabetes for over 10 years. My academic interest is in understanding how the immune system causes and prevents autoimmune-mediated diabetes. The idea is that if we understand how the body naturally protects from diabetes we might exploit that information to re-establish immune competence and protection in patients who either have type I diabetes or are at risk of becoming diabetic. My personal goal is to contribute to enhancing the quality of life for patients with type I diabetes by providing new knowledge that can be used to guide the design of novel therapeutics and strategies to treat and prevent type I diabetes.
The goal of this study is to test the hypothesis that the novel immune cell markers that we have identified in both mouse and human type I diabetes can be used to predict the rate of disease progression indicated by length of honeymoon period. While this information on its own will not directly benefit the patients, if our hypothesis is correct, in the longer term we hope to manipulate these immune cell subsets in newly diagnosed and at risk individuals to both delay disease progression and increase the sensitivity of these individuals to immunotherapy.
In what direction do you see the future of diabetes research going?
Enormous research and clinical effort has been invested in designing and testing therapies for the treatment of newly diagnosed patients with type I diabetes in an attempt to prevent disease progression and reverse diabetes. Although some of these therapies have had a statistically significant effect on disease progression, none have proven highly effective. The future success of type I diabetes treatment is likely to depend on a careful analysis of type I diabetic patient immunology to determine whether patients can be stratified into separate groups with like-characteristics. This will allow the physician to identify a treatment strategy that bests suits specific groups of patients increasing the chance of the therapy being effective. In addition, understanding mechanisms of action of individual and combined therapies will allow a more effective match between the therapy selected and the target patient population. The ADA commitment to promoting innovative research in type I diabetes is likely to play a critical role in the speed with which the field progresses towards a cure for type I diabetes. Thank you ADA!
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