Graft versus host disease in the bone marrow, liver and thymus humanized mouse model.

TitleGraft versus host disease in the bone marrow, liver and thymus humanized mouse model.
Publication TypeJournal Article
Year of Publication2012
AuthorsGreenblatt MB, Vrbanac V, Vbranac V, Tivey T, Tsang K, Tager AM, Aliprantis AO
JournalPLoS One
Volume7
Issue9
Paginatione44664
Date Published2012
ISSN1932-6203
KeywordsAnimals, Bone Marrow, CD4-Positive T-Lymphocytes, Cytokines, Disease Models, Animal, Graft vs Host Disease, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Humans, Interleukin-2, Liver, Macrophages, Mice, Mice, Inbred NOD, Mice, SCID, Risk, Skin, Spleen, Thymus Gland
Abstract

Mice bearing a "humanized" immune system are valuable tools to experimentally manipulate human cells in vivo and facilitate disease models not normally possible in laboratory animals. Here we describe a form of GVHD that develops in NOD/SCID mice reconstituted with human fetal bone marrow, liver and thymus (NS BLT mice). The skin, lungs, gastrointestinal tract and parotid glands are affected with progressive inflammation and sclerosis. Although all mice showed involvement of at least one organ site, the incidence of overt clinical disease was approximately 35% by 22 weeks after reconstitution. The use of hosts lacking the IL2 common gamma chain (NOD/SCID/γc(-/-)) delayed the onset of disease, but ultimately did not affect incidence. Genetic analysis revealed that particular donor HLA class I alleles influenced the risk for the development of GVHD. At a cellular level, GVHD is associated with the infiltration of human CD4+ T cells into the skin and a shift towards Th1 cytokine production. GVHD also induced a mixed M1/M2 polarization phenotype in a dermal murine CD11b+, MHC class II+ macrophage population. The presence of xenogenic GVHD in BLT mice both presents a major obstacle in the use of humanized mice and an opportunity to conduct preclinical studies on GVHD in a humanized model.

DOI10.1371/journal.pone.0044664
Alternate JournalPLoS One
PubMed ID22957096
Grant ListP01AI078897 / AI / NIAID NIH HHS / United States
P30AI060354 / AI / NIAID NIH HHS / United States
K08AR054859 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

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