In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity.
Cytokine-induced killer (CIK) cells are ex vivo-expanded T lymphocytes expressing both natural killer (NK)- and T-cell markers. CIK cells are cytotoxic against autologous and allogeneic tumors. We previously showed that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD). However, the precise mechanism of reduced GVHD is not fully understood. Therefore, we evaluated the trafficking and survival of luciferase-expressing CIK cells in an allogeneic bone marrow transplant model. The initial trafficking patterns of CIK cells were similar to conventional T cells that induced GVHD; however, CIK cells infiltrated GVHD target tissues much less and transiently. CIK cells accumulated and persisted in tumor sites, resulting in tumor eradication. We evaluated different properties of CIK cells compared with conventional T cells, demonstrating a slower division rate of CIK cells, higher susceptibility to apoptosis, persistent increased expression of interferon gamma (IFN-gamma), and reduced acquisition of homing molecules required for entry of cells into inflamed GVHD target organs that lack expression of NKG2D ligands recognized by CIK cells. Due to these properties, allogeneic CIK cells had reduced expansion and caused less tissue damage. We conclude that CIK cells have the potential to separate graft-versus-tumor effects from GVHD.
Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, CA 94305, USA.
Ryosei
R
Nishimura
Jeanette
J
Baker
Andreas
A
Beilhack
Robert
R
Zeiser
Janelle A
JA
Olson
Emanuela I
EI
Sega
Mobin
M
Karimi
Robert S
RS
Negrin
D019264:Adoptive Transfer / Q000379:methods* / Q000592:standards; D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D051379:Mice; D020297:Mice, Congenic; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000628:therapy; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*
D016207:Cytokines