Pascale Alard, Ph.D.

Research Interests

  • Enhancing immunoregulation in autoimmune-prone mice using components of the normal gut flora in order to prevent and/or ameliorate lupus and type 1 diabetes development.
  • Understanding the contribution of elevated beta-catenin expression by cells from diabetes-susceptible mice to pathogenic cell induction in order to develop novel strategy to control disease development.

A balance between pathogenic and regulatory cells is crucial for the control of autoimmune disease development.  Indeed, a dysregulation of the immune response, including aberrant regulatory cell and antigen presenting cell (APC) function, plays a major role in the induction of diabetes in NOD mice and lupus in (NZWxNZB)F1 mice.  In these mice, the deficiency in CD4+CD25+ regulatory T cell number and function, as well as the presence of APC exhibiting pro-inflammatory characteristics, lead to the induction of pathogenic  cells.  Therefore, developing strategy that enhance the levels and activity of this regulatory T cell population and that inhibit pro-inflammatory APC could lead to the prevention and amelioration of these autoimmune diseases.

Hygiene hypothesis and type 1 diabetes/lupus. The "Hygiene Hypothesis" links the prevalence of autoimmune and allergic diseases with higher hygiene.   Microorganisms have been shown to prevent diabetes and lupus development, and are capable of evading immune response via induction of tolerogenic APC and regulatory cells.   Our goals are to characterize the molecules involved in induction of tolerance by microorganisms, especially bacteria from the normal flora, and ultimately to design novel therapeutic strategy to enhance immunoregulation in these two autoimmune disease-prone mouse strains, and prevent and/or treat disease development using microparticle technology.

Importance of APC in type 1 diabetes development. On one hand, our study indicates that inappropriate activation by NOD APC is in part responsible for the dysfunction of CD4+CD25+ regulatory T cells in NOD mice.  Our goals are to characterize the potential defect in APC leading to non-functional CD4+CD25+ regulatory T cells in NOD mice, and to restore functional regulation in these mice.  On the other hand, we have found that APC from NOD mice express abnormally high levels of beta-catenin, a molecule involved in cell proliferation and cancer.  Our study shows that beta-catenin influences pro-inflammatory cytokine production by APC, and thereby leads to the induction of pathogenic cells that destroy the pancreatic beta cells.  Our goals are to characterize the molecular mechanisms leading to this defect and to examine whether potential treatment targeting this molecule can impact disease development.

Selected Publications:

A. Zirnheld, M. Villard, M.M. Kosiewicz*, P. Alard*. 2019. Beta-catenin stabilization in NOD dendritic cells increases IL-12 production and subsequent induction of IFNgamma-producing T cells.  (* co-corresponding authors). Journal of Leukocyte Biology 106(6):1349-1358. doi: 10.1002/JLB.3A0919-244R.

 M.M. Kosiewicz, A.Y. Chhabra, P. Alard. 2014. Interactions of gut microbiota and inflammatory responses. FEBS Letters. 588:4195-4206.PMID: 24681103.

J. N. Manirarora, S. A. Parnell, Y-H. Hu. M. M. Kosiewicz, and P. Alard.  2011.  NOD dendritic cells stimulated with lactobacilli preferentially produce IL-10 versus IL-12 and decrease diabetes incidence.  Clin. Dev. Immunol.  2011:630187.

M. M. Kosiewicz,  A. L. Zirnheld and P. Alard.  2011.  Gut microbiota, immunity and disease: a complex relationship.  Frontiers in Cellular and Infection Microbiology. 2(190):1-11.

J. N. Manirarora, S. A. Parnell, M. M. Kosiewicz, and P. Alard.  2009.  Analysis of modulation of Foxp3 expression in CD4+CD25+ regulatory cells from NOD mice.  J. Ky Acad. Sci. 70(2):145-151.

J. N. Manirarora, M. M. Kosiewicz, S. A. Parnell, and P. Alard.  2008.  APC activation restores functional CD4+CD25+ regulatory T cells in NOD mice that can prevent diabetes development.  PLoS ONE 3 (11):e3739.