Laura Cooney
e-mail address: ltesmer@umich.edu

Mentor: David Fox, MD

Research Description

CD4+ T helper cells are now known to differentiate into three effector
subclasses: Th1 (characterized by the production of gamma IFN), Th2
(characterized by the production of IL-4), and Th17 (characterized by
the production of IL-17). IL-17 is an extremely potent pro-inflammatory
cytokine that has been shown to be important in several mouse models of
autoimmunity. Notably, blocking or knocking out IL-17 significantly
reduced the onset and severity of collagen-induced arthritis, while
adding back IL-17 exacerbated inflammation and joint destruction.
Specific inhibition of IL-17 production or activity is quickly becoming
a therapeutic goal for the treatment of several immunopathologies,
including rheumatoid arthritis. Th17 development has been shown to be
inhibited by Th1 and Th2 cytokines, including IL-12, gamma IFN, and
IL-4. We have observed a strong downregulation of IL-17 production by
IL-4 during ex vivo antigen rechallenge of spleen cells from mice with
collagen-induced arthritis. Interestingly, however, Th17 cells from
end-stage arthritis or long term culture are no longer susceptible to
downregulation by IL-4, suggestive of maturation of the Th17 phenotype.
These mature Th17 cells lose the ability to phosphorylate STAT6 in
response to IL-4, possibly as a result of upregulation of inhibitors of
cytokine signaling. We are currently working to understand the signals
involved in the maturation of Th17 cells from an IL-4-sensitive to an
IL-4-resistant state as well as the underlying mechanism for the loss of
IL-4 responsiveness. We also hope to determine what role Th17 maturation
plays in the development and progression of arthritis.

Publications

Sarkar S, Tesmer LA, Hindnavis V, Endres JL, and Fox DA: IL-17
as a Molecular Target in Immune-Mediated Arthritis - Immunoregulatory Properties of Genetically-Modified Dendritic Cells that Secrete IL-4. Arthritis and Rheumatism, 2007, 56(1):89-100.

Tran CN, Davis MJ, Tesmer LA, Endres JL, Motyl CD, Smuda C, Somers EC, Chung KC, Urquhart AG, Lundy SK, Kovats S and Fox DA: Presentation of Arthritogenic Peptide to Antigen Specific T cells by Fibroblast-Like Synoviocytes. Arthritis and Rheumatism. 2007, 56(5):1497-506.

Lundy SK, Sarkar S, Tesmer LA, and Fox DA: Cells of the Synovium
in Rheumatoid Arthritis: T lymphocytes. Arthritis Res. Ther. 2007, 9(1):202.

Lu Q, Wu A, Tesmer L, Ray D, Yousif N, and Richardson B: Demethylation of CD40LG on the Inactive X in Women with Lupus. J. Immunol., 2007, 179(9):6352-8.

Tesmer LA*, Lundy SK*, Sarkar S, and Fox DA: Th17 cells in Human Disease. Immunological Reviews. Immunol Rev. 2008 Jun; 223: 87-113. (*Co-first authors)

Snider NT, Nast JA, Tesmer LA, Hollenberg PF: A cytochrome P450-derived epoxygenated metabolite of anandamide is a potent cannabinoid receptor 2-selective agonist. Mol. Pharmacol., 2009, Apr;75(4):965-72.

Waldorff E, Christenson KB, Cooney LA, Goldstein SA. 2009. Microdamage repair and remodeling requires mechanical loading. J. Bone Mineral Res. In revision.

Cooney LA, Sarkar S, Fox DA. The role of Th17 cells in arthritis. Immunological Reviews. In revision.

Sarkar S*, Cooney LA*, White P, Endres JL, and Fox DA: Differential Regulation of IL-17 Responses by Th1 and Th2 Cytokines in Collagen-Induced Arthritis. Arthritis Res. Ther. In revision. (*co-first authors)

Abstracts

Lu Q, Tesmer L, Yousif N, Wu A, Ray D, and Richardson B: Demethylation of the Inactive X Chromosome Predisposes Women to the Development of Lupus. Arthritis and Rheumatism, (suppl) 52(9), 2005.

Ding D, Mehta H, Tesmer L, McCune WJ, and Kaplan MJ: Lupus Myeloid Dendritic Cells Display an Aberrant Phenotype and Induce Abnormal T cell Function. Arthritis and Rheumatism, (suppl) 52(9), 2005.

Tran CN, Davis MJ, Tesmer LA, Endres JL, Motyl CD, Smuda C, Somers EC, Chung KC, Urquhart AG, Lundy SK, Kovats S, and Fox DA: Presentation of Arthritogenic Peptide to Antigen Specific T cells by Fibroblast-like Synoviocytes. Arthritis and Rheumatism, (suppl) 52(9), 2005.

Tesmer LA, Sarkar S, and Fox DA: Regulation of IL-17 Production During Antigen-Specific Responses in the Mouse. Journal of Immunology, (suppl) 176, 2006.

Tesmer LA, Sarkar S, and Fox DA: Regulation of IL-17 Production by Th1 and Th2 Cytokines During Collagen-Induced Arthritis. Arthritis and Rheumatism, (suppl) 54(9), 2006.

Lundy SK, Tesmer LA, Moore TB, and Fox DA: Characterization of the ThIL-17 Response to the Arthritogenic Antigens, HCgp39 and Type II Collagen, in DR4 Transgenic Mice. Arthritis and Rheumatism, (suppl) 54(9), 2006.

Lu Q, Tesmer L, Wu A, Ray D, and Richardson B: Women and Lupus: the Inactive X Awakens. Arthritis and Rheumatism, (suppl) 54(9), 2006.

Tesmer LA, Sarkar S, and Fox DA.: Regulation of IL-17 Production in Collagen-Induced Arthritis by IL-4. Cytokine, (suppl) 39(1), 2007.

Tesmer LA, Sarkar S, and Fox DA.: Regulation of IL-4R Signaling in Th17 Cells. Cytokine, (suppl) 40(1), 2008.

Sarkar S, Tesmer LA, and Fox DA: Regulation of IL-17 Responses by CTLA4-Ig. Arthritis and Rheumatism, (suppl) 56(9), 2008.

Kovsky S, Tesmer LA, Endres J, Lee J, Ryu MJ, Sommers EC, and Fox DA: A Genetic Mechanism for the Determination of Severity of RA: A Polymorphism in the IL-4 Receptor Controls the Ability of IL-4 to Regulate Th17 Cells. Arthritis and Rheumatism, (suppl) 56(9), 2008.

Tesmer LA, Sarkar S, and Fox DA: Regulation of IL-4R Signaling in Th17 Cells. Arthritis and Rheumatism, (suppl) 56(9), 2008.

Tesmer LA, Sarkar S, and Fox DA: Regulation of IL-4R Signaling in Th17 Cells. Keystone Symposium: Th17 Cells in Health and Disease, 2009.

Awards

American College of Rheumatology REF/Abbott Medical and Graduate Student Achievement Award

Regenerative Sciences Training Grant

Rackham Pre-Doctoral Fellowship

University of Michigan Rheumatology Division Alfred Grant Scholastic Award