Beta2 integrins separate graft-versus-host disease and graft-versus-leukemia effects.
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 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 beta2 integrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.
Liang
Yaming
Y
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Liu
Chen
C
Djeu
Julie Y
JY
Zhong
Bin
B
Peters
Thorsten
T
Scharffetter-Kochanek
Karin
K
Anasetti
Claudio
C
Yu
Xue-Zhong
XZ
D000818:Animals; D016026:Bone Marrow Transplantation; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006801:Humans; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous
D018821:CD18 Antigens; D016207:Cytokines