Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID beta2mnull mice.
OBJECTIVE
Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Models of immunodeficient mice that consistently and efficiently reconstitute with xenoreactive human T cells would be a valuable tool for the in vivo study of GVHD, as well as other human immune responses.


METHODS
We developed a consistent and sensitive model of human GVHD by retro-orbitally injecting purified human T cells into sublethally irradiated nonobese diabetic/severe combined immunodeficient (NOD/SCID)-beta2m(null) recipients. In addition, we characterized for the first time the trafficking patterns and expansion profiles of xenoreactive human T cells in NOD/SCID-beta2m(null) recipients using in vivo bioluminescence imaging.


RESULTS
All NOD/SCID-beta2m(null) mice conditioned with 300 cGy total body irradiation and injected with 1 x 10(7) human T cells exhibited human T-cell engraftment, activation, and expansion, with infiltration of multiple target tissues and a subsequent >20% loss of pretransplantation body weight. Importantly, histological examination of the GVHD target tissues revealed changes consistent with human GVHD. Furthermore, we also showed by in vivo bioluminescence imaging that development of lethal GVHD in the NOD/SCID-beta2m(null) recipients was dependent upon the initial retention and early expansion of human T cells in the retro-orbital sinus cavity.


CONCLUSIONS
Our NOD/SCID-beta2m(null) mouse model provides a system to study the pathophysiology of acute GVHD induced by human T cells and aids in development of more effective therapies for human GVHD.
Nervi
Bruno
B
Division of Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA.
Rettig
Michael P
MP
Ritchey
Julie K
JK
Wang
Hanlin L
HL
Bauer
Gerhard
G
Walker
Jon
J
Bonyhadi
Mark L
ML
Berenson
Ronald J
RJ
Prior
Julie L
JL
Piwnica-Worms
David
D
Nolta
Jan A
JA
DiPersio
John F
JF
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D006086:Graft vs Host Disease; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000166:cytology*; D001613:beta 2-Microglobulin / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D001613:beta 2-Microglobulin