Kori Wallace, MDPhD

Polymorphisms of the TL1a, a TNF superfamily cytokine member, gene are associated with Inflammatory Bowel Disease (IBD). The causes of IBD are complex and involve the environment, along with a patients own genetics, immune response, and microbiota. The immune-pathogenesis of IBD is thought to be due to T - helper cell pathways. Firstline biologic treatment in IBD is anti-TNFa therapy (i.e. Humera, Remicaide), however up to half of IBD patients do not respond to this therapy and more become… Show more

Polymorphisms of the TL1a, a TNF superfamily cytokine member, gene are associated with Inflammatory Bowel Disease (IBD). The causes of IBD are complex and involve the environment, along with a patients own genetics, immune response, and microbiota. The immune-pathogenesis of IBD is thought to be due to T - helper cell pathways. Firstline biologic treatment in IBD is anti-TNFa therapy (i.e. Humera, Remicaide), however up to half of IBD patients do not respond to this therapy and more become refractory within a year. Therefore, it is important to discover new treatments. Given the complicated causes of IBD, it is important to look at each patient as an individual and treat accordingly. In order to do this we utilize transgenic mice with constitutive expression of TL1a in lymphoid cells. These mice spontaneously will develop colitis over months. Alternatively, utilizing an adoptive transfer model of naive T-cells into Rag-/- mice, these mice will develop colitis in two to three weeks. We have crossed the TL1a transgenic mice with various cytokine deficient mice in order to determine the contribution of each T - helper pathway in IBD under TL1a driven conditions. TL1a-IFNg KO (Th1), TL1a-IFNg KO (Th2), and TL1a-IL17a KO (Th17) mice are used for experimentation. The results of these experiments will hopefully elucidate mechanisms of disease in IBD. Show less

We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A(2A) receptor (A(2A)R) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A(2A)R agonist ATL146e produced a dose-dependent reversal of pulmonary… Show more

We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A(2A) receptor (A(2A)R) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A(2A)R agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1(-/-) mice reduced pulmonary injury that was restored by adoptive transfer of 10(6) purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A(2A)R alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ε]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A(2A)Rs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation-induced exacerbation of pulmonary injury. A(2A) agonists have promise for treating diseases associated with iNKT or NK cell activation. Show less

Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69(+), interferon-gamma(+) [IFN-gamma(+)]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of… Show more

Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69(+), interferon-gamma(+) [IFN-gamma(+)]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-gamma, IFN-gamma-inducible chemokines (CXCL9, CXCL10), and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation reverses baseline pulmonary dysfunction manifested as elevated vascular permeability, decreased arterial oxygen saturation, and increased numbers of activated leukocytes. Anti-CD1d antibodies decrease pulmonary levels of IFN-gamma and CXCR3 chemokines. Neutralization of CXCR3 receptors ameliorates pulmonary dysfunction. Crossing NY1DD to lymphocyte-deficient Rag1(-/-) mice decreases pulmonary dysfunction. This is counteracted by the adoptive transfer of 1 million NKT cells. Like mice, people with SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in SCD mice by a pathway involving IFN-gamma and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease. Show less