Laura Mandik-Nayak, PhD

Photo of Laura Mandik-Nayak

Email:  Mandik-Nayak@limr.org

Phone: 484.476.8427

Fax: 610.645.8533

Office: R130

Department: Faculty

Association: Resident Faculty

Education

  • BS, Biology, Bucknell University, Lewisburg, PA, 1993
  • PhD, Immunology, University of Pennsylvania, Philadelphia, PA, 1999
  • Postdoctoral Fellowship, Washington University, 1999-2006

Current Appointments

  • 2006 to 2013: Assistant Professor, Lankenau Institute for Medical Research
  • 2008 to Present: Assistant Professor, Dept. of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University
  • 2009 to Present: Adjunct Assistant Professor, Dept. of Pathology and Laboratory Medicine, Drexel University College of Medicine
  • 2013 to Present: Associate Professor, Lankenau Institute for Medical Research

Research Interests

  • Determining factors that lead to the initiation and progression of the joint-specific autoimmune response in individuals with rheumatoid arthritis
  • Google Scholar page

Lab Personnel

  • Elizabeth Pigott, Biomedical Research Assistant
  • Lauren Merlo, Post Doctoral Fellow

Awards and Honors

  • 1994 Gina Finzi Memorial Student Fellowship Award, Lupus Foundation of America
  • 1997-1998 Dr. Monica H.M. Shander Fellowship Award, The Wistar Institute
  • 1999 Saul Winegrad Award for Outstanding Dissertation, University of Pennsylvania

Lay Description


Rheumatoid arthritis (RA) affects approximately 1.2 million individuals in the United States. Classified as an autoimmune disease, it results from the immune system's attack of the joints, triggering inflammation and chronic pain. RA eventually leads to progressive and debilitating destruction of cartilage and bone. While its cause remains unclear, it is known that immune cells (T and B cells) play critical roles in RA progression.

Current treatment is not effective at controlling disease progression as it relies on the reduction of inflammation by focusing on the end stage of the disease. Dr. Laura Mandik-Nayak has taken a different approach by targeting the early stage of RA. Her lab focuses on the triggering mechanisms by which the immune system becomes activated to induce inflammation in the joints. Recently, Dr. Mandik-Nayak identified a pathway that triggers the activation of autoreactive T and B cells during the development of arthritis. This pathway involves IDO (indoleamine 2,3-dioxygenase), an enzyme implicated in immune regulation. IDO activity is elevated in arthritis patients. Dr. Mandik-Nayak's recent data demonstrated that removal of IDO activity interferes with immune cell activation and arthritis development, suggesting that IDO could instigate the disease process. 

By using an inhibitor of IDO, Dr. Mandik-Nayak is currently investigating the importance of this enzyme as a therapeutic target of RA. Her work may lead to a new approach and to novel medicines for the prevention and treatment of RA and possibly other autoimmune diseases. This research could provide some relief for millions of Americans who suffer from RA, a very incapacitating and painful disease.

Scientific Description


Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects 1.2 million Americans.  It is characterized by chronic inflammation of the synovial joints, eventually leading to progressive and debilitating destruction of cartilage and bone.  While the etiological basis for RA remains unknown, both T and B cells play critical roles in the disease process.  To study the early events in the autoimmune response leading to arthritis, my laboratory uses the K/BxN model in which mice spontaneously develop a joint inflammatory response with many features characteristic of RA.  This model is based on a T cell receptor transgene (tg), KRN, that when present in a genetic background expressing the I-Ag7 MHC Class II molecule, leads to the development of arthritis.  In this model, both T cells and B cells are essential for disease and both recognize the well-defined self-antigen glucose-6-phosphate isomerase (GPI).  Autoantibodies against GPI are key mediators in arthritis induction and by themselves can transfer disease to most naive strains of mice.

As with a variety of autoimmune disorders, there is evidence of an elevated level of tryptophan catabolism in RA patients.  This is indicative of activation of the enzyme indoleamine-2,3-dioxygenase (IDO), which initiates the breakdown of tryptophan.  Because IDO is thought to be immunosuppressive, it has been generally assumed that inhibiting IDO would exacerbate classic autoimmune disorders such as RA.  However, data from patients has suggested the opposite, that IDO activity may actually be associated with the development of disease symptoms.  Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan (1MT), we recently demonstrated that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms.  1MT treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course.  Importantly, 1MT exposure was required only during the initiation of arthritis to exert its protective effect.  In fact, starting 1MT treatment after disease initiation was no longer effective.  The alleviation of joint inflammation with 1MT was not due to a reduction in T regulatory cells or an altered T helper cell cytokine profile, but rather resulted from a diminished autoreactive B cell response.  Our data suggest that IDO plays an activating role in establishing the autoreactive B cell profile at the onset of the autoimmune response in K/BxN mice.

Our future goals are focused on the fundamental question of how an immunosuppressive enzyme can paradoxically be responsible for driving autoimmunity.  We hypothesize that IDO is not simply an immunosuppressive enzyme, but rather plays a more complex role in modulating inflammatory responses by directing the immune profile of B cell responses. To uncover the underlying mechanisms that govern the roles of IDO in B cell-mediated inflammatory responses we are using both pharmacological inhibitors and genetic null mice to identify whether targeting IDO1, the closely related IDO2, or both is responsible for the amelioration of inflammatory arthritis in K/BxN mice.  Second, we are using a combination of in vitro stimulation assays and in vivo immunization protocols to determine whether IDO1/2 directly affects B cell activation or acts indirectly through modulatory effects on the microenvironment.

Dr. Mandik-Nayak's Google Scholar page

Selected Publications

  1. Merlo, L.M.F., Pigott, E., DuHadaway, J.B., Grabler, S., Metz, R., Prendergast, G.C., and Mandik-Nayak, L. 2014. IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J. Immunol. 192(5):2082-90.
  2. Scott, G.N., DuHadaway, J., Pigott, E., Ridge, N., Prendergast, G.C., Muller, A.J., Mandik-Nayak, L. 2009. The immunoregulatory enzyme IDO paradoxically drives B cell mediated autoimmunity. J. Immunol. 182:7509-7517.
  3. Mandik-Nayak, L., Ridge, N., Fields, M., Park, A.Y., Erikson, J. 2008. Role of B cells in Systemic Lupus Erythematosus and Rheumatoid Arthritis. Curr Opin Immunol. 20(6):639-45.
  4. Mandik-Nayak, L., Racz, J., Sleckman B.P., and Allen, P.M. 2006. Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help J. Exp. Med. 203:1985-1998.
  5. Studelska, D.R., Mandik-Nayak, L., Zhou, X., Pan, J., Weiser, P., McDowell, L.M., Lu, H., Liapis, H., Allen, P.M., Shih, F.F., Zhang, L. 2009. High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis. J Biol Chem. 284(4):2354-62.
  6. Mandik-Nayak L. and Allen P.M. 2005. Initiation of an autoimmune response: insights from a transgenic model of rheumatoid arthritis. Immunol. Res. 32:5-13.
  7. Shih F.F., Mandik-Nayak L., Wipke B.T., and Allen P.M. 2004. Massive thymic deletion results in systemic autoimmunity through elimination of CD4+CD25+ T regulatory cells. J. Exp.Med. 199:323-335.
  8. Mandik-Nayak L., Wipke, B.T., Shih, F.F., Unanue, E.R., and Allen, P.M. 2002. Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node. Proc. Natl. Acad. Sci. USA. 99:14368-14373.
  9. Mandik-Nayak L., Huang G., Sheehan K.C.F., Erikson J., Chaplin D.D. 2001. Signaling through TNF Receptor p55 in TNF-a-deficient mice alters the CXCL13/CCL19/CCL21 ratio in the spleen and induces the maturation and migration of anergic B cells into the B cell follicle. J. Immunol. 167:1920-1928.
  10. Seo S., Fields M.L., Buckler J.L., Reed A.J., Mandik-Nayak L., Nish S.A., Noelle R.J., Turka L.A., Finkelman F.D., Caton A.J., and Erikson J. 2002. The Impact of T Helper and T Regulatory Cells on the Regulation of Anti-Double-Stranded DNA B Cells. Immunity. 16: 535-546.
  11. Mandik-Nayak L., Nayak S., Sokol C., Eaton-Bassiri A., Madaio M.P., Caton A.J., and Erikson J. 2000b. The origin of anti-nuclear antibodies in bcl-2 transgenic mice. Int. Immunol. 12:353-364.
  12. Mandik-Nayak L., Seo S.j., Eaton-Bassiri A., Allman D., Hardy R.R., and Erikson J. 2000. Functional consequences of the developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Immunol. 164:1161-1168.
  13. Mandik-Nayak L., Seo S.j., Sokol C., Potts K.M., Bui A., and Erikson J. 1999. MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Exp. Med. 189:1799-1814.
  14. Mandik-Nayak L., Bui A., Noorchashm H., Eaton A., and Erikson J. 1997. Regulation of anti-double-stranded DNA B cells in nonautoimmune mice: localization to the T-B interface of the splenic follicle. J. Exp. Med. 186:1257-1267.
  15. Mandik L., Katsumata M., and Erikson J. 1997. Effects of altered Bcl-2 expression on B lymphocyte selection. Ann. N.Y. Acad. Sci. 815:40-54.
  16. Mandik L., Nguyen K.A., and Erikson J. 1995. Fas receptor expression on B-lineage cells. Eur. J. Immunol. 25:3148-3154.
 
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