Year: 2007
Type: article
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. Beta2 integrins, a group of heterodimeric molecules including CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18 and CD11d/CD18, are of critical importance 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 (BMT) 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. A cell-dose titration experiment indicated that the ability of CD18-/- T cells had more than 4-fold reduction compared to that of WT T cells in the induction of GVHD. Analysis of alloreactive 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 beta2 intergrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.
Authors: Y. Liang, C. Anasetti, X.-Z. Yu
Institution: Moffitt Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W1998946910