Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi, Bruno; Rettig, Michael P.; Ritchey, Julie K.; Wang, Hanlin L.; Bauer, Gerhard; Walker, Jon; Bonyhadi, Mark L.; Berenson, Ronald J.; Prior, Julie L.; Piwnica-Worms, David; Nolta, Jan A.; DiPersio, John F.

doi:10.1016/j.exphem.2007.06.007

« Previous Next »Experimental Hematology
Volume 35, Issue 12 , Pages 1823-1838, December 2007

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2m^null mice

Bruno Nervi
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
Michael P. Rettig
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
Julie K. Ritchey
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
Hanlin L. Wang
- Department of Pathology and Immunology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
Gerhard Bauer
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
Jon Walker
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
Mark L. Bonyhadi
- Xcyte Therapies, Inc., Seattle, Wash., USA
Ronald J. Berenson
- Xcyte Therapies, Inc., Seattle, Wash., USA
Julie L. Prior
- Department of Molecular Imaging Center, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
David Piwnica-Worms
- Department of Molecular Imaging Center, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
- Department of Molecular Biology and Pharmacology Washington University School of Medicine, Saint Louis, Mo., USA
Jan A. Nolta
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
John F. DiPersio
- Division of Oncology, Mallinckrodt Institute of Radiology, Saint Louis, Mo., USA
- Offprint requests to: John F. DiPersio, M.D., Ph.D., Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8007, Saint Louis MO 63110

Received 5 January 2007; received in revised form 17 May 2007; accepted 13 June 2007. published online 31 August 2007.

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.

Materials and 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)-β2m^null recipients. In addition, we characterized for the first time the trafficking patterns and expansion profiles of xenoreactive human T cells in NOD/SCID-β2m^null recipients using in vivo bioluminescence imaging.

Results

All NOD/SCID-β2m^null mice conditioned with 300 cGy total body irradiation and injected with 1 × 10⁷ 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-β2m^null recipients was dependent upon the initial retention and early expansion of human T cells in the retro-orbital sinus cavity.

Conclusion

Our NOD/SCID-β2m^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.