Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory PhenotypeReportar como inadecuado




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The occurrence of Graft-versus-Host Disease GvHD is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells PBMC; -Hu-PBMC mice- are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain IL-2Rγnull, notably the NOD-scid IL-2Rγnull NSG and BALB-c-Rag2null IL-2Rγnull BRG mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45+ compartment and higher engraftment levels of CD3+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory TEM phenotype and high levels of cutaneous lymphocyte antigen CLA expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting TEM-cell driven GvHD.



Autor: Niwa Ali, Barry Flutter, Robert Sanchez Rodriguez, Ehsan Sharif-Paghaleh, Linda D. Barber, Giovanna Lombardi, Frank O. Nestle

Fuente: http://plos.srce.hr/



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