Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis.
Human risk allele HLA-DRB1*0405 predisposes class II transgenic Ab0 NOD mice to autoimmune pancreatitis.
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DOI：
10.1053/j.gastro.2010.03.038
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发表时间：
2010-07
期刊：
影响因子：
29.4
通讯作者：
Sønderstrup G
中科院分区：
文献类型：
--
作者：
Freitag TL;Cham C;Sung HH;Beilhack GF;Durinovic-Belló I;Patel SD;Bronson RT;Schuppan D;Sønderstrup G
Autoimmune pancreatitis (AIP) underlies 5%–11% of cases of chronic pancreatitis. An association between AIP and the HLA-DRB1* 0405/DQB1*0401 haplotype has been reported, but linkage disequilibrium has precluded the identification of predisposing HLA gene(s). We studied the role of single HLA genes in the development of AIP in transgenic mice. CD4+ T cell-negative I-Aβ chain−/− (Ab0) mice develop AIP spontaneously, likely due to dysregulation of CD8+ T cell responses. We generated Ab0 NOD mice transgenic for HLA-DR*0405, leading to rescue of CD4+ T cells; we compared their susceptibility to AIP with HLA-DQ8 or HLA-DR* 0401 (single) transgenic, or HLA-DR*0405/DQ8 (double) transgenic mice. CD4+ T cell-competent HLA-DR*0405 transgenic Ab0 NOD mice develop AIP with high prevalence after sublethal irradiation and adoptive transfer of CD90+ T cells, leading to complete pancreatic atrophy. HLA-DR* 0405 transgenic mice can also develop unprovoked AIP, whereas HLA-DR* 0401, HLA-DQ8 and HLA-DR*0405/DQ8 transgenic Ab0 NOD controls all remained normal, even after irradiation and adoptive transfer of CD90+ T cells. Pancreas histology in HLA-DR*0405 transgenic mice was characterized by destructive infiltration of the exocrine tissue with CD4+ and CD8+ T cells, B cells and macrophages. Mice with complete pancreatic atrophy lost weight, developed fat stools, and had reduced levels of serum lipase activity. Since HLA-DR*0405 expression fails to protect mice from AIP, the HLA-DRB1*0405 allele appears to be an important risk factor for AIP on the HLA-DRB1*0405/DQB1*0401 haplotype. This humanized mouse model should be useful for studying immunopathogenesis, diagnostic markers, and therapy of human AIP.
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DOI：
10.1084/jem.20050693
发表时间：
2005-09-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jiang W;Anderson MS;Bronson R;Mathis D;Benoist C
通讯作者：
Benoist C
影响因子：
29.4
作者：
Kawa, S;Ota, M;Kiyosawa, K
通讯作者：
Kiyosawa, K
影响因子：
4.1
作者：
SHINDO, Y;INOKO, H;OHNO, S
通讯作者：
OHNO, S
影响因子：
4.4
作者：
Meagher, Craig;Tang, Qizhi;Bluestone, Jeffrey A.
通讯作者：
Bluestone, Jeffrey A.
影响因子：
15.9
作者：
Wen, L;Chen, NY;Wong, FS
通讯作者：
Wong, FS