Thais Sielecki

Publications (2)11.42 Total impact

• Article: A small-molecule inhibitor of macrophage migration inhibitory factor for the treatment of inflammatory disease.

  Aaron P Kithcart, Gina M Cox, Thais Sielecki, Abigail Short, James Pruitt, Tracey Papenfuss, Todd Shawler, Ingrid Gienapp, Abhay R Satoskar, Caroline C Whitacre
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  ABSTRACT: Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) characterized by demyelination and axon loss. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be elevated in the cerebrospinal fluid of patients during relapses. The purpose of this study was to evaluate a new small-molecule inhibitor of MIF and its ability to reduce the severity of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We utilized 2 structurally related isoxazolines, which show in vitro inhibition of MIF tautomerase activity. We found that administration of an inhibitor of MIF to mice with established EAE immediately reduced the severity of clinical signs and expanded a population of regulatory T lymphocytes. We also noted that the inhibitor reduced relapses of disease in a relapsing/remitting model of EAE. An analysis of leukocyte migration into the brain revealed that administration of inhibitor reduced entry of these cells. No effects on inflammatory cytokine production or T-cell activation in the periphery were noted. From these studies, we conclude that a small-molecule inhibitor of MIF reduces the severity of EAE and prevents access of immune cells into the CNS, which could be of therapeutic relevance to MS.
  The FASEB Journal 11/2010; 24(11):4459-66. · 5.71 Impact Factor
• Article: Macrophage migration inhibitory factor is a therapeutic target in treatment of non-insulin-dependent diabetes mellitus.

  Yuriko Sanchez-Zamora, Luis I Terrazas, Alonso Vilches-Flores, Emmanuel Leal, Imelda Juárez, Caroline Whitacre, Aaron Kithcart, James Pruitt, Thais Sielecki, Abhay R Satoskar, Miriam Rodriguez-Sosa
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  ABSTRACT: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in the pathogenesis of a variety of autoimmune inflammatory diseases. Here, we investigated the role of MIF in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) using MIF(-/-) mice and a mouse model of streptozotocin (STZ)-induced NIDDM. Following single injection of STZ, MIF(+/+) BALB/c mice showed a significant increase in blood glucose levels, developed polyuria, and succumbed to disease. In contrast, no such increase in blood glucose was observed in MIF(-/-) BALB/c mice treated with STZ. These mice produced significantly less inflammatory cytokines and resistin as compared with MIF(+/+) mice and failed to develop clinical disease. Finally, oral administration of a small-molecule MIF antagonist, CPSI-1306, to outbred ICR mice following induction of NIDDM significantly lowered blood glucose levels in the majority of animals, which was also associated with a significant reduction in the levels of the proinflammatory cytokines IL-6 and TNF-alpha in the sera. Taken together, these results demonstrate that MIF is involved in the pathogenesis of NIDDM and is a therapeutic target to treat this disease.
  The FASEB Journal 03/2010; 24(7):2583-90. · 5.71 Impact Factor