Journal
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
Volume 157, Issue 1, Pages 104-118Publisher
WILEY
DOI: 10.1111/j.1365-2249.2009.03933.x
Keywords
GVHD; humanized mice; Hu-PBL-scid; IL-2r gamma chain; NOD-scid; xenogeneic
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Funding
- National Institutes of Health [AI46629, DK53006, HL077642]
- institutional Diabetes Endocrinology Research Center (DERC) [DK32520]
- Cancer Center [CA34196]
- Viacell, Inc.
- Beta Cell Biology Consortium
- Juvenile Diabetes Foundation, International
- American Diabetes Association
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Immunodeficient non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)-2 receptor gamma chain gene (IL2r gamma(null) ) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft-versus-host-like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD-scid IL2r gamma(null) mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 x 10(6) PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor-alpha signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly.
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