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

Author:

Liang Yaming1,Liu Chen2,Djeu Julie Y.13,Zhong Bin1,Peters Thorsten4,Scharffetter-Kochanek Karin4,Anasetti Claudio13,Yu Xue-Zhong13

Affiliation:

1. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;

2. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville;

3. Department of Interdisciplinary Oncology, University of South Florida, Tampa; and

4. Department of Dermatology and Allergic Diseases, University of Ulm, Maienweg, Germany

Abstract

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. β2 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 β2 integrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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