title: Donor CD8+ T cells mediate graft-versus-leukemia activity without clinical signs of graft-versus-host disease in recipients conditioned with anti-CD3 monoclonal antibody.
abstract: Donor CD8(+) T cells play a critical role in mediating graft-vs-leukemia (GVL) activity, but also induce graft-vs-host disease (GVHD) in recipients conditioned with total body irradiation (TBI). In this study, we report that injections of donor C57BL/6 (H-2(b)) or FVB/N (H-2(q)) CD8(+) T with bone marrow cells induced chimerism and eliminated BCL1 leukemia/lymphoma cells without clinical signs of GVHD in anti-CD3-conditioned BALB/c (H-2(d)) recipients, but induced lethal GVHD in TBI-conditioned recipients. Using in vivo and ex vivo bioluminescent imaging, we observed that donor CD8(+) T cells expanded rapidly and infiltrated GVHD target tissues in TBI-conditioned recipients, but donor CD8(+) T cell expansion in anti-CD3-conditioned recipients was confined to lymphohematological tissues. This confinement was associated with lack of up-regulated expression of alpha(4)beta(7) integrin and chemokine receptors (i.e., CXCR3) on donor CD8(+) T cells. In addition, donor CD8(+) T cells in anti-CD3-conditioned recipients were rendered unresponsive, anergic, Foxp3(+), or type II cytotoxic T phenotype. Those donor CD8(+) T cells showed strong suppressive activity in vitro and mediated GVL activity without clinical signs of GVHD in TBI-conditioned secondary recipients. These results indicate that anti-CD3 conditioning separates GVL activity from GVHD via confining donor CD8(+) T cell expansion to host lymphohemological tissues as well as tolerizing them in the host.
authors.affiliation: Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Jingwei
authors.initials: J
authors.lastname: Lou
authors.forename: Nainong
authors.initials: N
authors.lastname: Li
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Chia-Lei
authors.initials: CL
authors.lastname: Lin
authors.forename: Yu-An
authors.initials: YA
authors.lastname: Cao
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Contag
authors.forename: Fouad
authors.initials: F
authors.lastname: Kandeel
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D006086:Graft vs Host Disease / Q000276:immunology*; D007938:Leukemia / Q000276:immunology* / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology / Q000473:pathology; D051379:Mice; D013997:Time Factors; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000276:immunology; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex