Aly/Aly mice: A unique model of biliary disease

Tsuneyama, Koichi; Kono, Naoko; Hoso, Masahiro; Sugahara, Hiroyuki; Yoshida, Kazuharu; Kawakami, Kazuyoshi; Gershwin, M. Eric; Saito, Katsuhiko; Nakanuma, Yasuni

doi:10.1002/hep.510270606

Cited by 9 publications

(5 citation statements)

References 29 publications

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“…Histological examination revealed that virtually all organs were infiltrated with mononuclear cells. Consistent with results obtained from Nik aly/aly mice (33), these infiltrates contained CD3 + T-cells (Fig. 1F and G); importantly, however, the infiltrates also contained eosinophilic granulocytes, as confirmed by MBP staining, which were dominating in all organs investigated (Fig.…”

Section: Resultssupporting

confidence: 90%

NIK Prevents the Development of Hypereosinophilic Syndrome-like Disease in Mice Independent of IKKα Activation

Chi

Rehg

Redecke

2012

The Journal of Immunology

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Immune cell-mediated tissue injury is the common feature of different inflammatory diseases, yet the pathogenetic mechanisms and cell types involved vary significantly. Hypereosinophilic Syndrome (HES) represents a group of inflammatory diseases that are characterized by increased numbers of pathogenic eosinophilic granulocytes in the peripheral blood and diverse organs. Based on clinical and laboratory findings, various forms of HES have been defined, yet the molecular mechanism and potential signaling pathways that drive eosinophil expansion remain largely unknown. Here we show that mice deficient of the serine/ threonine-specific protein kinase NF-κB inducing kinase (NIK) develop a HES-like disease, reflected by progressive blood and tissue eosinophilia, tissue injury and premature death at around 25–30 weeks of age. Similar to the lymphocytic form of HES, CD4+ T-cells from NIK-deficient mice express increased levels of T-helper 2 (Th2)-associated cytokines, and eosinophilia and survival of NIK deficient mice could completely be prevented by genetic ablation of CD4+ T-cells. Experiments based on bone marrow chimeric mice, however, demonstrated that inflammation in NIK-deficient mice depended on radiation-resistant tissues, implicating that NIK-deficient immune cells mediate inflammation in a non-autonomous manner. Surprisingly, disease development was independent of NIKs known function as IkappaB kinase (IKK)-α kinase, as mice carrying a mutation in the activation loop of IKKα, which is phosphorylated by NIK, did not develop inflammatory disease. Our data show that NIK activity in non-hematopoietic cells controls Th2-cell development and prevents eosinophil-driven inflammatory disease, most likely using a signaling pathway that operates independent of the known NIK substrate IKKα.

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Section: Resultssupporting

confidence: 90%

NIK Prevents the Development of Hypereosinophilic Syndrome-like Disease in Mice Independent of IKKα Activation

Chi

Rehg

Redecke

2012

The Journal of Immunology

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“…We could not evaluate the liver for GVHD because aly/aly mice develop spontaneous hepatic inflammation that is difficult to distinguish from GVHD. 40 Taken together, these data show that GVHD can develop in the complete absence of LN and PP, as well as in recipients without LN, PP, and spleen. However, that GVHD is markedly reduced in aly/aly Spl Ϫ recipients relative to mice that have either LN, PP, or spleen indicates that these are important sites for donor T-cell priming that are redundant among themselves.…”

mentioning

confidence: 60%

Effects of donor T-cell trafficking and priming site on graft-versus-host disease induction by naive and memory phenotype CD4 T cells

Anderson

Taylor

McNiff³

et al. 2008

Blood

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Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic stem cell transplantation. Effector memory T cells (T(EM)) do not cause GVHD but engraft and mount immune responses, including graft-versus-tumor effects. One potential explanation for the inability of T(EM) to cause GVHD is that T(EM) lack CD62L and CCR7, which are instrumental in directing naive T cells (T(N)) to lymph nodes (LN) and Peyer patches (PP), putative sites of GVHD initiation. Thus T(EM) should be relatively excluded from LN and PP, possibly explaining their inability to cause GVHD. We tested this hypothesis using T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN and PP or LN, PP, and spleen. Surprisingly, CD62L and CCR7 were not required for T(N)-mediated GVHD. Moreover, in multiple strain pairings, GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). Conversely, enforced constitutive expression of CD62L on T(EM) did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that T(EM) fail to induce GVHD because of inefficient trafficking to LN and PP.

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“…24 Spontaneous multiorgan disease, including biliary and portal tract destruction, occur in MRL/lpr mice and aly/aly mice, 25,26 but it is unclear that inflammation in these mice is initiated by T-cell recognition of biliary antigens. Nonsuppurative inflammatory cholangitis and portal inflammation is seen in mdr2 knockout mice, apparently because the biliary tree is exposed to bile salts uncomplexed with phospholipid.…”

Section: Discussionmentioning

confidence: 99%