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
Immune responses to pathogens are tightly regulated. During acute viral infections, a strong immune response is necessary to clear the pathogen followed by a contraction phase that prevents overwhelming immune mediated pathology. However, some viruses are able to circumvent the immune response and establish persistence in the host. In several chronic virus infections, such as HCV in humans or chronic LCMV in mice, viral persistence is associated with exhausted T cell responses that facilitate persistence on the one hand but prevent immune mediated pathology on the other hand. I am interested in the mechanisms that govern the magnitude of the virus-specific effector T cell response during chronic viral infections. Currently, I am looking at the role of immunoregulatory and co-stimulatory pathways in a murine model of a chronic virus infection and whether modulation of these pathways could open novel paths for therapeutic interventions.
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
Aims: To visualize the immune attack that is
responsible for the death of insulin-producing beta cells in type 1
diabetes. We are involved in a unique, nationwide project (nPOD or the
network for Pancreatic Organ Donors) that aims to improve our
understanding of type 1 diabetes by the procurement and distribution of
human pancreas tissue from deceased patients. We apply advanced
microscopy techniques to these samples to study ongoing aberrations of
the immune system. We also take these types of investigations to a new
level in animal models of the disease, where we observe islet
destruction by the immune system by video (‘two-photon') microscopy.
More
Georgia Fousteri - Research Scientist
Central and peripheral tolerance of insulin-reactive CD4 T cells
Type 1 diabetes (T1D) is a complicated autoimmune disorder, in which both genetic and environmental factors can modify the risk for disease development. Due to its increasing incidence worldwide in young adolescents and children, understanding T1D pathogenesis is vital for generating effective immune intervention strategies. Currently, most of these strategies are developed and tested in the non-obese diabetic (NOD) mouse model of T1D, which seems to share many genetic and mechanistic features of the human disease. For example, a number of similar autoantigens have been identified as targets, and insulin is evidently a primary target for both CD4 and CD8 autoreactive T cells in humans and mice. In our lab one of our major goal is to understand how tolerance to insulin is lost, which control checks are bypassed and how these can be reset to prevent and/or cure T1D. 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.
Jeremy Pettus - Postdoctoral Fellow
My research interest centers around better understanding the pathogenesis of type 1 diabetes with the ultimate aim to discover therapies for prevention and reversal of the disease. I am currently working on a collaboration with Northwestern University in studying type 1 patients post islet cell transplant. This therapy has the potential to offer a cure for the disease but is plagued by difficulties with reactive autoimmunity requiring potent immunosuppressive agents. In my study I will be analyzing post islet cell transplant blood samples longitudinally and looking at antigen specific changes in auto-reactive CD8 cells and their respective cytokine profile. Using Elispot analysis, we will study changes in IFN-G production in response to auto-antigens over time in an attempt to identify an assay that can ultimately predict clinical outcome IE which patients will do well and which will ultimately lead to rejection. This information could be used to fine-tune immunosuppressive regimens if for example; our assay shows that they are shifting to a more pro-inflammatory milieu.
Tom Van Belle - Research Scientist
tomvb@liai.orgProject Summary IL-21
Type I diabetes mellitus (T1D) is a chronic autoimmune disorder of the pancreas that precipitates in genetically susceptible individuals by environmental factors. Current symptomatic treatments require daily blood glucose monitoring and injections of insulin. It is critical to develop therapies that can specifically induce long-lasting control over the auto(self)-immune response. The mouse studies we are doing in the lab will lead to crucial insight in diabetes etiology that can hopefully be translated to clinical therapies for T1D patients.
Currently under study is the cytokine interleukin-21 (IL-21) that is produced at higher levels in the pancreas as diabetes develops. We already that two genetically diverse and mechanistically distinct mouse models rendered deficient in the IL-21 receptor are completely diabetes resistant. Therefore, we are currently investigating the mechanisms responsible for this crucial contribution of IL-21 signaling to T1D, and exploring the therapeutic potential of IL-21 blockade in vivo. Given the pleiotropic nature of IL-21, we postulate that the complete absence of diabetes in IL-21R deficient mice is due to several defects, which encompass trafficking, expansion, differentiation, CD4 help and APC function. More
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.
Darius Schneider - Postdoctoral Fellow
Technicians:
Natalie Amirian - Research Technician I
natalie@liai.org
Mira Bel Hani - Graduate Student
amira@liai.org
Audrey Briscoe - Visiting Scientist
abriscoe@liai.org
Yulia Manenkova - Research Technician II
Malina McClure - Research Technician II
Jackie Miller - Lab Assistant
Shaida Omid - Lab Assistant
Sonal Phatak - Visiting Scientist
Sowbarnika Sachithanantham - Research Technician II