Graft versus Host Disease in the Bone Marrow, Liver and Thymus Humanized Mouse Model

• Published in: PloS one Vol. 7; no. 9; p. e44664
• Main Authors: Greenblatt, Matthew B., Vbranac, Vladimir, Tivey, Trevor, Tsang, Kelly, Tager, Andrew M., Aliprantis, Antonios O.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.09.2012; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Allografts; Analysis; Animal models; Animals; B cells; Biology; Bone marrow; Bone Marrow - pathology; Bone marrow transplantation; CD11b antigen; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; Cytokines - metabolism; Disease Models, Animal; Fetuses; Gastrointestinal tract; Genetic analysis; Glands; Graft versus host disease; Graft vs Host Disease - etiology; Graft vs Host Disease - immunology; Graft-versus-host reaction; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - metabolism; Histocompatibility Antigens Class II - metabolism; HIV; Human immunodeficiency virus; Humans; Immune system; Incidence; Infiltration; Inflammation; Interleukin 2; Interleukin-2 - metabolism; Laboratory animals; Laboratory tests; Liver; Liver - pathology; Lungs; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Major histocompatibility complex; Medicine; Mice; Mice, Inbred NOD; Mice, SCID; Phenotypes; Risk; Rodents; Scleroderma; Sclerosis; Skin; Skin - metabolism; Spleen - cytology; T cells; Thymus; Thymus Gland - pathology; Womens health; Xenografts; United States > US; Massachusetts; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0044664

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.