The Journal of immunology : official journal of the American Association of Immunologists
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Comparative Study
Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury.
Overwhelming evidence suggests that ischemia-reperfusion injury of the kidney is an inflammatory disease mediated by innate and adoptive immune systems. The neuronal guidance molecule netrin-1 was shown to modulate inflammatory responses. Given that ischemic kidney is particularly prone to reperfusion-elicited inflammation, we sought to determine the function of netrin-1 and its receptor UNC5B in ischemia-reperfusion-induced inflammation. ⋯ Neutralization of UNC5B receptor reduced netrin-1-mediated protection against renal ischemia-reperfusion injury, and it increased monocyte and neutrophil infiltration, as well as serum and renal cytokine and chemokine production, with increased kidney injury and renal tubular cell apoptosis. Finally, investigation into netrin-1's effect on CD4 T cell stimulation showed suppression of Th1/Th2/Th17 cytokine (IL-2, IL-6, IL-10, IL-13, IL-17, IFN-gamma, IL-4, and TNF-alpha) production in vitro. Our studies demonstrate that netrin-1 acting through UNC5B receptor reduces renal ischemia-reperfusion injury and its associated renal inflammation.
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Allogeneic hematopoietic stem cell transplantation represents the most effective form of immunotherapy for chemorefractory diseases. However, animal models have been missing that allow evaluation of donor-patient-specific graft-versus-leukemia effects. Thus, we sought to establish a patient-tailored humanized mouse model that would result in long-term engraftment of various lymphocytic lineages and would serve as a donor-specific surrogate. ⋯ Phenotypical and functional analyses of lymphoid lineages revealed that >20 wk posthematopoietic stem cell transplantation, the majority of T lymphocytes consisted of memory-type CD4(+) T cells capable of inducing specific immune functions, whereas CD8(+) T cells were only present in low numbers. Analysis of NSG-derived NK cells revealed the expression of constitutively activated CD56(bright)CD16(-) killer Ig-like receptor(negative) NK cells that exhibited functional impairments. Thus, the data presented in this study demonstrate that humanized NSG mice can be successfully used to develop a xenotransplantation model that might allow patient-tailored treatment strategies in the future, but also highlight the need to improve this model, for example, by coadministration of differentiation-promoting cytokines and induction of human MHC molecules to complement existing deficiencies in NK and CD8(+) T cell development.
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Comparative Study
B and T lymphocyte attenuator suppresses IL-21 production from follicular Th cells and subsequent humoral immune responses.
We recently showed that mice lacking B and T lymphocyte attenuator (BTLA), a third inhibitory coreceptor expressed on B cells and T cells, exhibit an increased Ag-specific IgG response and gradually develop hyper-gamma-globulinemia and autoantibody production. Recent studies revealed that follicular Th (Tfh) cells, which are non-Th1, non-Th2 effector T cells that express CXCR5 and provide help for B cells to produce Ig, also express BTLA. However, the role of BTLA in Tfh cell function remains unknown. ⋯ Moreover, the development of IL-21-producing CXCR5(+) Tfh-like cells was significantly increased in BTLA(-/-) CD4(+) T cells compared with WT CD4(+) T cells. Furthermore, Tfh-like cell-mediated IgG responses were abolished when IL-21R(-/-) mice were used as recipients. These results suggest that BTLA signaling suppresses IL-21 production from Tfh cells and subsequent Tfh cell-mediated IgG responses.
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Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus (RV)-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated OVA-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. ⋯ We conclude that augmented airway eosinophilic inflammation and hyperresponsiveness in RV-infected mice with allergic airways disease is directed in part by eotaxin-1. Airway macrophages from mice with allergic airways disease demonstrate a change in activation state characterized in part by altered eotaxin and IL-4 production in response to RV infection. These data provide a new paradigm to explain RV-induced asthma exacerbations.