β2 integrins separate graft-versus-host disease and graft-versus-leukemia effects

被引:41
|
作者
Liang, Yaming [1 ]
Liu, Chen [2 ,3 ]
Djeu, Julie Y. [1 ,4 ]
Zhong, Bin [1 ]
Peters, Thorsten [5 ]
Scharffetter-Kochanek, Karin [5 ]
Anasetti, Claudio [1 ,4 ]
Yu, Xue-Zhong [1 ,4 ]
机构
[1] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA
[2] Univ Florida, Dept Pathol Immunol, Gainesville, FL USA
[3] Univ Florida, Lab Med, Gainesville, FL USA
[4] Univ S Florida, Dept Interdisciplinary Oncol, Tampa, FL USA
[5] Univ Ulm, Dept Dermatol & Allerg Dis, Maienweg, Germany
关键词
D O I
10.1182/blood-2007-05-089573
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. beta(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 the 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 wild-type (WT) donor T cells. Analysis of alloreactivity 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 the in vivo GVL effect of CD18(-/-) donor T cells was largely preserved, because mortality of the recipients who received transplants of CD18(-/-) T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target beta(2) integrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.
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页码:954 / 962
页数:9
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