Research Associates:
Carmen Baca Jones - Postdoctoral Fellow
carmen@liai.orgImmune Regulation in Chronic Viral Infection: Induction and maintenance of systemic IL10 in chronic LCMV infection
Elevated levels of systemic IL10 have been associated with several chronic viral infections including, HIV, EBV, HCMV and LCMV. IL10 receptor blockade has previously been demonstrated to resolve chronic LCMV infection. Studies are currently underway to more fully explore the induction and maintenance of the IL10 production loop in vivo. To this end, a naturally selected LCMV mutant, Clone 13, which preferentially establishes a persistent infection is being used in combination with the Armstrong strain in a variety of in vitro and in vivo assays.
Tobias Boettler - Postdoctoral Fellow
Development of novel therapeutic strategies for chronic viral infections based on the IL-10 receptor blockade
Interleukin-10 has a crucial role in persistent viral infections and blockade of the IL-10 receptor has been shown to resolve chronic LCMV clone 13 infection in mice when administered early in infection. After establishment of the chronic infection, however, viral clearance cannot be achieved although IL-10 receptor blockade is still beneficial. Thus, new approaches need to be developed to establish paradigms of synergism between IL-10 receptor blockade and therapies that induce immune activation or decrease viral loads.
Damien Bresson - Research Scientist
Helping to find cures for autoimmune diseases, such as type 1 diabetes (T1D) or autoimmune thyroiditis, has been the main focus of my research since 2000 when I started my graduate studies in Montpellier, France. I joined Matthias von Herrath's lab in 2003 with the objective to develop antigen-specific immune interventions to cure new-onset T1D. At that time, we hypothesized that anti-CD3 antibody with the capacity to generate in vivo regulatory T cells (Tregs) could function in synergy with islet-autoantigen (aAg) immunizations (expressed as peptides, proteins or DNA vaccines) to expand islet-specific Tregs which is believed to be safest approach for inducing long-term protection from T1D in vivo. We have studied the efficacy of several islet-aAgs in conjunction with low-dose anti-CD3 to reverser new-onset T1D and showed that (i) synergy was dependent upon the aAg used in combination with anti-CD3 and (ii) genetic background can influence the capacity to generate protective aAg-specific Tregs. Overall, our approach opened a new avenue to induce long-term antigen-specific tolerance by expanding aAg-specific Tregs in vivo. Future studies are aiming at devising therapeutic protocols to improve the efficacy/side effect ratio and eventually move our findings from bench to bedside.
Ken Coppieters - Research Scientist
Imaging cellular events leading to type 1 diabetes
There is a broad consensus among investigators on the fact that particular cell types of our immune system are responsible for the destruction of beta cells in type 1 diabetes. Numerous reports indicate that these cells, which are somehow aberrantly activated against the body's own beta cells, accumulate around the islets and cause them to die. The traditional way to study the principal cell type involved, namely ‘T cells', is either to make sections of pancreas tissue (see picture 1 below) or to analyze the cells present in blood drawn from patients at diagnosis.
Unfortunately, in both cases the information that can be derived from such samples has limitations. Given the relative inaccessibility of pancreas tissue, most studies have to be done on organs from deceased patients and these may represent only the final stage of the disease process. When analyzing the blood, one can easily imagine that it remains questionable as to how relevant the cells are to the disease process that's actually going on around the pancreatic islets. In addition, both approaches only yield insight into how cells look like at a given time point, while the dynamics of their interactions remain elusive. More
Philippe Pagni - Postdoctoral Fellow
ppagni@liai.org
Potential means to prevent Type 1 Diabetes: Virally Induced immunomodulatory mechanisms such as TLR stimulation enhancing regulatory T cell function.
Type 1 diabetes (T1D) is an autoimmune disorder in which lymphocytes destroy pancreatic beta-cells that produce insulin. In addition to T1D susceptibility genes, environmental factors such as viral infections have also been suggested to contribute to disease incidence both in animal models and humans. However, the role of viral infections in T1D onset remains controversial, as accumulating evidence has revealed protective effects as well, fitting the "hygiene hypothesis". Previous work from the laboratory has strongly contributed to the hypothesis that viral infections can enhance the function of CD4+CD25+ regulatory T cells (Tregs), which can help protect the host from autoreactive immune attacks in T1D (Filippi et al., J Clin Invest. 2009;119(6):1515-23). Nonetheless, the underlying mechanisms mediating this protection are not completely understood and deserve further investigation.
We propose that innate immune pathogen-recognition receptors such as Toll-like receptors (TLRs) represent one molecular bridge between viral infections and enhancement of Treg function leading to prevention of autoimmune processes. This is supported by preliminary data indicating that TLR2 signaling can enhance Treg function and delay hyperglycemia in diabetes-prone mice. Studies underway aim at determining how signaling by other TLRs can influence Treg biology in the context of viral infections and T1D. This may ultimately help to define or refine strategies to induce Tregs for the treatment of T1D and other autoimmune diseases.
Shyam Sarikonda - Postdoctoral Fellow
My main goal is to understand the progression of autoimmune diabetes in pediatric T1D patients. To achieve this goal, currently I am working on analyzing CD4+ T –cell responses in two subsets of pediatric human patients, as stated below. These projects utilize a combination of genetic analysis, flow cytometry to assess the expression levels of certain markers, and ELISPOT assays to determine the number of T-cell producing a particular cytokine (IFN-g or IL-10) in response to stimulation with a peptide.
Project 1: Analysis of CD4+ T cell responses in obese vs lean pediatric T1D patients. Our hypothesis is that the obese children (body mass index= BMI greater than 95%) with new onset diabetes mellitus (DM) have reduced numbers of regulatory T-cells (CD4+CD25+FoxP3+CD127-) as assessed by flow cytometry compared to lean patients (BMI<85%) with new onset DM. Amongst a subgroup of obese patients who are antibody positive we predict that numbers of regulatory T-cells will be similar to lean patients and will predict clinical outcomes as measured by need for insulin and hemoglobin A1C.
Project 2: Analysis of regulatory T-cells in pediatric T1D patients in a longitudinal fashion. The specific aim of this project is to characterize the immunology of regulatory T-cells in children with type 1 diabetes as they progress through the partial remission phase of type 1 diabetes (aka the honeymoon phase) in a longitudinal fashion. Based on our prior data we hypothesize that patients will experience a reduction in regulatory T-cells (as measured by numbers of CD4/CD25/FoxP3/CD127- cells through flow cytometry) from diagnosis over time but that numbers of regulatory cells at diagnosis will be predictive of glucose control over time.
Tom Van Belle - Research Scientist
The role of cytokines in type 1 diabetes
Cytokines are my main angle in diabetes research. IL-21 is a type 1 cytokine that mediates signaling to a variety of immune cells and plays an important role in immune responses involved in viral infection, tumors and autoimmune diseases. One of our recent studies demonstrated an essential prodiabetogenic activity of IL-21 using animal models with diverse genetic backgrounds. We showed that loss of IL-21 signaling, via knockout of the IL-21 receptor, completely abrogates diabetes development on the NOD background. In addition, we demonstrated the pathogenic role of IL-21 via over-expression of IL-21 in pancreatic beta-cells, which induces a high incidence of spontaneous Type 1 diabetes on the normally diabetes-resistant C57BL/6 background. While we are currently further unraveling the mechanisms, this study established the critical role of IL-21 in Type 1 diabetes development in animal models and indicated a potentially therapeutic role of IL-21 in human Type 1 diabetes.
Further interests are: therapeutic potential of Flt3-ligand in type 1 diabetes, the role of Th17 in type 1 diabetes, combination therapy involving NKG2D blockade.
Technicians:
Natalie Amirian - Research Technician I
natalie@liai.org
Audrey Briscoe - Visiting Scientist
abriscoe@liai.org
Mira Bel Hani - Graduate Student
amira@liai.org
Yang Cheng - Graduate Student
ycheng@liai.org
Amy Dave - Lab Assistant
Sibel Durlanik - Grad Student
Wilhem Leconet - Graduate Student
Yulia Manenkova - Research Technician II
Malina McClure - Research Technician II
Bret Morin - Research Technician I
bret@liai.org
Shaida Omid - Lab Assistant
Sowbarnika Sachithanantham - Research Technician I
Jeremy Weng - Lab Assistant