Submitted May 8, 2007
Accepted September 28, 2007
2 integrins separates graft-versus-host disease and graft-versus-leukemia effect
Yaming Liang, Chen Liu, Julie Y. Djeu, Bin Zhong, Thorsten Peters, Karin Scharffetter-Kochanek, Claudio Anasetti, and Xue-Zhong Yu*
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
Department of Pathology, University of Florida, Gainesville, FL, United States
Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL, United States
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Maienweg, Germany
* Corresponding author; email: yuxz{at}moffitt.usf.edu.
Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. 
2 integrins are critically important for leukocyte extravasation through vascular endothelia and for T cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing graft-versus-leukemia (GVL) effect. In murine allogeneic bone marrow transplantation models, we found that recipients of CD18-/- donor T cells had significantly less GVHD morbidity and mortality compared with recipients of WT donor T cells. Analysis of allo-reactivity showed that CD18-/- and WT T cells had comparable activation, expansion and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor-T cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that in vivo GVL effect of CD18-/- donor T cells was largely preserved, because mortality of the recipients transplanted with CD18-/- T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target 2 intergrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.
