Michele Kosiewicz, Ph.D.

Students

Jing Ma (Ph.D. Candidate)

 

Research Interests

Immunoregulation, Tolerance, Autoimmunity and Microbiota

My laboratory studies the mechanisms governing the development and maintenance of immunoregulation and self-tolerance in health and disease.  Our focus is on T cells and antigen presenting cells and the role these cells play in pathogenesis, immunoregulation and tolerance in the context of autoimmune disease, including (but not limited to) type 1 diabetes (T1D) and systemic lupus erythematosus (SLE).  We use several mouse models of disease in our studies, including the NOD and (NZBxNZW)F1 mouse strains which spontaneously develop T1D and SLE, respectively.  We have also studied and maintain an interest in other autoimmune diseases including experimental autoimmune encephalomyelitis (EAE; a model for human multiple sclerosis), inflammatory bowel diseases (particularly Crohn’s disease), autoimmune gastritis (a model for human pernicious anemia), ocular immunity/tolerance, and autoimmune ovarian dysgenesis. We have a long-standing interest in the biology of an important subset of CD4 cells, the CD4 regulatory cells (CD4+CD25+Foxp3+), that is critical for the maintenance of peripheral tolerance and control of potentially autoreactive T cells.  Maintaining the proper balance between fully functional regulatory CD4 cells and non-regulatory (effector) T cells is extremely important in the maintenance of an effective well-controlled immune system that protects against infectious pathogens but does not inflict damage on the host. More recently, we have become interested in role that the gut microbiota plays in immunoregulation, and the development of and/or protection from autoimmune disease.


Projects

Sex-based differences in immunoregulation, autoimmunity and the gut microbiota. Females have a significantly higher incidence of autoimmune diseases than males.  For lupus, the bias is 9:1 in “favor” of females in humans (i.e., 9 females develop disease for every 1 male). The reason(s) for this disparity in susceptibility is poorly understood.  However, sex hormones have a significant impact on the immune system, and consequently, the types and quantity of sex hormones that are differentially produced by females and males almost definitely contribute to the differing susceptibility of the sexes to autoimmune disease. Interestingly, we have found that the composition (i.e., Next Gen/deep sequencing analysis) and function (i.e., metabolomic analysis) of the gut microbiota differ between female and male lupus-prone mice. In ongoing studies in our laboratory, we are examining the effect that gender, sex hormones, and the gut microbiota have on antigen-presenting cell function, and T cell (both regulatory and non-regulatory, effector) development and function in normal and lupus-prone mice.

Mechanisms involved in the maintenance of the regulatory CD4 cell:effector T cell balance. The thymus is the primary site for both regulatory and effector T cell development. However, we and others have found previously that conversion of non-regulatory T cells (CD4+CD25- cells) into regulatory T cells (CD4+CD25+Foxp3+) can occur spontaneously in the periphery in the absence of the thymus.  Thymic production and output, peripheral expansion (proliferation), and survival/death of regulatory and non-regulatory CD4 cells, and conversion of non-regulatory T cells (CD4+CD25- cells) into regulatory T cells can all have a significant impact on the peripheral regulatory CD4 cell:effector T cell balance, and subsequently to susceptibility to autoimmune disease, cancer and infectious diseases.  We are interested in understanding how each of these components contributes to the development and maintenance of the peripheral regulatory CD4 cell:effector T cell balance, and how each is regulated in both normal healthy and autoimmune-prone strains of mice at the systemic and/or local (i.e., draining lymph node, target organ) levels.

Modulation of immunoregulation and tolerance to prevent/treat autoimmune disease, cancer and infectious diseases.  We are interested in utilizing our knowledge of immunoregulation and tolerance to develop specific therapeutic strategies that can eventually be used in the clinic to treat human disease. We are examining the efficacy of using antigen presenting cells (APC) that have been rendered tolerogenic by treatment with "immunosuppressive" cytokines or genetic engineering as therapeutic modalities to treat autoimmune disease in our animal models.  Interestingly, the same natural mechanisms (i.e., immunoregulation and tolerance) that keep pathogenic autoreactive T cells in check can also hamper the development of an effective immune response against tumors and infectious organisms.  For this reason, we plan to explore experimental approaches that will allow us to selectively target and modify the immunoregulatory and/or tolerance-mediating mechanisms that impair the development/maintenance of effective immunity against tumors or infectious organisms.  The goal of the latter studies is to discover strategies that can be used in conjunction with immunotherapies to enhance their efficacy in preventing/treating cancer or infectious diseases.

 

Publications

Shuang Liang, Pascale Alard, Yuan Zhao, Sarah Parnell, Sherry L. Clark, and Michele M. Kosiewicz. 2005.  Conversion of CD4+CD25- cells into CD4+CD25+ regulatory cells in vivo requires B7 co-stimulation, but not the thymus.  J. Exp. Med.  201:127-137.

Pascale Alard, Jean N. Manirarora, Sarah A. Parnell, Jason L. Hudkins, Sherry L. Clark and Michele M. Kosiewicz.  2006.  Deficiency in NOD APC function may be responsible for sub-optimal CD4+CD25+ T cell-mediated regulation and Type 1 diabetes development in NOD mice.  Diabetes.  55:2098-2105.

Michele M. Kosiewicz, Dominick L. Auci, Paolo Fagone, Katia Mangano, Salvatore Caponnetto, Colleen F. Tucker, Nabeel Azeem, Steven K. White, James M. Frincke, Christopher L. Reading, and Ferdinando Nicoletti.  2011.  HE3286, an orally bioavailable synthetic analogue of an active DHEA  metabolite suppresses spontaneous autoimmune diabetes in the non‑obese  diabetic (NOD) mouse.  Eur J Pharmacol.  658(2-3):257-62.

Colleen F. Tucker, Doreen L. Nebane-Ambe, Anita Chhabra, Sarah A. Parnell, Yuna Zhao, Pascale Alard, and Michele M. Kosiewicz.  2011.  Decreased frequencies of CD4+CD25+Foxp3+ cells and the potent CD103+ subset in peripheral lymph nodes correlate with autoimmune disease predisposition in some strains of mice.  Autoimmunity.  Sep;44(6):453-64.

MM Kosiewicz, AY Chhabra, AL Zirnheld, P Alard.  2011.  CD8+ suppressor cells resurrected and vindicated. Immunotherapy. Mar;3(3):316-7.

MM Kosiewicz, AY Chhabra, AL Zirnheld, P Alard.  2011.  Beta-catenin: does it have a role in tolerance?  Immunotherapy. Mar;3(3):314-6.

MM Kosiewicz, AY Chhabra, AL Zirnheld, P Alard.  2011.  Commensal flora:  friends or foes?  Immunotherapy. Mar;3(3):313-4.

MM Kosiewicz, Arin L Zirnheld, and Pascale Alard.  2011. Gut microbiota, immunity and disease: a complex relationship.  Front Cell Infect Microbiol.  2011;2:180.

MM Kosiewicz, Arin L Zirnheld, and Pascale Alard.  2013. Tuning of skin immunity by skin commensal bacteria.  Immunotherapy. Jan;5(1):23-5.

Z. Gu*, A.Y. Chhabra*, P. Alard, D.R. Warner, and M.M. Kosiewicz.  FcgammaRI is required for TGFbeta-treated macrophage-induced tolerance.  2013. Immunobiology.  April;218:1200-1206. (*co-first authors)

M.M. Kosiewicz, GW Dryden, A.Y. Chhabra, P. Alard. 2014. Relationship between gut microbiota and development of T cell associated disease. FEBS Letters.  Nov 17;588(22):4195-206.

Korte EA, Caster DJ, Barati MT, Tan M, Zheng S, Berthier CC, Brosius FC 3rd, Vieyra MB, Sheehan RM, Kosiewicz M, Wysoczynski M, Gaffney PM, Salant DJ, McLeish KR, Powell DW. 2017. ABIN1 Determines Severity of Glomerulonephritis via Activation of Intrinsic Glomerular Inflammation. Am J Pathol. 2017 Dec;187(12):2799-2810.

Zhao, Y, P Alard, and MM Kosiewicz. High Thymic Output of Effector CD4+ Cells May Lead to a Treg:T Effector Imbalance in the Periphery in NOD Mice. J Immunol Res.,  2019 Jun 11;2019:8785263, 2019. doi.org/10.1155/2019/8785263. 

A. Zirnheld, M. Villard, S. A. Parnell, M. Martin, J. N. Manirarora, M.M. Kosiewicz*, P. Alard*. -catenin stabilization in NOD dendritic cells increases IL-12 production and subsequent induction of IFNg-producing T cells. J Leukoc Biol.  2019 Dec;106(6):1349-1358. doi: 10.1002/JLB.3A0919-244R. (*co-corresponding authors)

F. Yuan*, J. Harder*, J. Ma, X. Yin, X. Zhang and M.M. Kosiewicz. Using multiple analytical platforms to investigate the androgen depletion effects on fecal metabolites in a mouse model of systemic lupus erythematosus. (*co-first authors) J Proteome Res. 2020 Feb 7;19(2):667-676. 10.1021/acs.jproteome.9b00558

J.N. Manirarora, M.M. Kosiewicz* and P. Alard*. Feeding lactobacilli impacts lupus progression in (NZBxNZW)F1 lupus-prone mice by enhancing immunoregulation. Autoimmunity, 2020 Sep;53(6):323-332.  doi: 10.1080/08916934.2020.1777282 (*co-corresponding authors)