Showing papers by "John C. S. Harding published in 2011"

Clinical presentation, case definition, and diagnostic guidelines for porcine periweaning failure to thrive syndrome

Abstract: Porcine periweaning failure to thrive syndrome (PFTS) is a clinical condition characterized by anorexia, lethargy, and progressive debilitation of pigs occurring within 2 to 3 weeks after weaning. In affected populations, there is a striking contrast between the clinically affected pigs, which progress from being normally active to lethargic within days of weaning, and the unaffected members of their cohort, which grow and behave normally. The etiology, pathophysiology, and pathogenesis of PFTS have not been determined, although several infectious agents have been identified in affected pigs. Histopathologic lesions of chronic active rhinitis, superficial gastritis, atrophic enteritis, superficial colitis, and thymic atrophy are observed in most PFTS-affected pigs. The basis for a presumptive diagnosis of PFTS includes the age of onset, the presence of typical clinical signs, the presence of the collective histopathologic lesions, and, importantly, the ruling out of other known swine diseases (for example, porcine circovirus associated disease, swine influenza, porcine reproductive and respiratory syndrome, and bacterial infections). The objectives of this paper are to propose a clinical case definition, describe the characteristic clinical progression, signs, and observed lesions of PFTS, and to make recommendations for investigation of PFTS-suspected farms

Tet-inducible lymphoma in a new Tax transgenic mouse model

Abstract: The sufficiency of Tax in cancer initiation is evident in a variety of animal models, but the role Tax plays in cancer maintenance is less well understood. Tax is often undetectable in freshly obtained ATLL cells and while Tax promotes proliferation and protects cells from apoptosis it is also highly immunogenic and cytotoxic. We developed a mouse model in which Tax is expressed in the Tet-On system in vivo. These mice carry 4 transgenes. Tax, under the TET-promoter (TET-TAX) was provided by Warner Greene. The reverse tet activator, coupled to the granzyme B promoter (GZB-rtTA) , drives Tax in activated T and NK cells in a doxycycline (dox)-inducible manner. Two additional transgenes were included for non-invasive imaging. TET-GFP, which is regulated by the same promoter as Tax in this model, serves as a readout for Tax gene expression and firefly luciferase driven by the HTLV-1 LTR (LTR-LUC) serves as a bioluminescent readout for Tax activity. Quadruple transgenic mice were maintained with or without dox-diet for 18 months. Over that time, 6 of 8 animals receiving dox-diet developed marked lymphadenopathy and splenomegaly, compared to 2 of 9 on normal diet. 1 of 9 mice lacking the GZB-rTA transgene and 0 of 7 mice lacking the TET-TAX trangene developed lymphoma. Discontinuation of dox after lymphadenopathy resulted in a decrease in lymph node size and bioluminescence, but remission was transient. This mouse model allows us to regulate and detect Tax activity non-invasively and will enable targeted interrogation of the role of Tax in lymphoma.

IL-15 deficiency promotes tumor growth in tax transgenic mice

Abstract: IL-15 is an NFkB activated cytokine with structural similarity to IL-2 that has been implicated as a promoter of ATLL. Proposed mechanisms include; i) establishment of an autocrine loop in tumor cells that express both IL-15 and the IL-15 receptor, ii) IL-15 mediated protection from apoptosis, and iii) IL-15 mediated immune regulation that promotes tumor growth. IL-15 blockade is being considered as a therapeutic approach to HTLV-1 malignancies. To examine the effects of IL-15 deficiency on HTLV-1 malignancy in vivo, we developed IL-15-/- TAX-LUC mice in which firefly luciferase under the HTLV-1 LTR serves as a reporter of Tax expression driven by the granzyme B promoter. Unexpectedly, the absence of IL-15 resulted in a significantly enhanced tumor phenotype in TAX-LUC mice which developed markedly larger, more numerous, and more aggressive tumors. IL-15 deficiency also resulted in severe osteolytic disease, platelet and bone marrow abnormalities. Administration of soluble IL-15 slowed tumor growth in vivo. Characteristics of cell lines derived from IL-15-/- Tax tumors were indistinguishable from tumor cells derived from IL-15+/+ Tax tumors. RNA harvested from malignant and infiltrating cells within tumors indicated that tumor immunity is significantly affected by IL-15 loss. NK and gamma-delta T cells are diminished in tumor infiltrates in the absence of IL-15 and the malignant cells express elevated levels of IL-1alpha. These findings reveal a profound of effect of tumor immunity in TAX malignancies, implicate IL-1alpha as an important factor in the immune response to ATLL, and caution against IL-15 blockade as an ATLL therapy.