Absence of beta7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine.
The alpha4beta7 integrin plays a central role in the homing of T cells to the gut. We hypothesized that absence of the beta7 subunit would result in a reduction of intestinal graft-versus-host disease (GVHD) and an improvement in overall GVHD morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT). Analysis of alloreactive beta7-/- T cells showed intact activation, proliferation, cytokine production, and cytotoxicity. However, recipients of beta7-/- donor T cells in murine HSCT models experienced less GVHD morbidity and mortality than recipients of wild-type (WT) T cells, associated with a decrease in donor T-cell infiltration of the liver and intestine and with an overall significant decrease in hepatic and intestinal GVHD. In graft-versus-tumor (GVT) experiments, we demonstrated intact or even enhanced GVT activity of beta7-/- donor T cells. In conclusion, beta7-/- donor T cells caused less GVHD morbidity and mortality than WT donor T cells because of selectively decreased T-cell infiltration of the liver and intestines. Our data suggest that strategies to target the beta7 integrin have the clinical potential to alleviate or prevent GVHD while sparing or potentiating GVT activity.
Waldman
Elisha
E
Memorial Sloan-Kettering Cancer Center, Kettering 406D, Mailbox 111, 1275 York Ave, New York, NY 10021, USA.
Lu
Sydney X
SX
Hubbard
Vanessa M
VM
Kochman
Adam A
AA
Eng
Jeffrey M
JM
Terwey
Theis H
TH
Muriglan
Stephanie J
SJ
Kim
Theo D
TD
Heller
Glenn
G
Murphy
George F
GF
Liu
Chen
C
Alpdogan
Onder
O
van den Brink
Marcel R M
MR
D000818:Animals; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D017353:Gene Deletion; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018928:Immunity, Mucosal; D039641:Integrin beta Chains / Q000235:genetics*; D034801:Mastocytoma / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology*
D039641:Integrin beta Chains; C091368:integrin beta7