Role of cytokines in GVL (ESb lymphoma) and GVHD after adoptive transfer of allogeneic T lymphocytes in mice.
ESb lymphoma cells injected i.v. into DBA/2 (H-2d) mice multiply rapidly in the liver and kill all mice in a few days. Adoptive transfer of allogeneic C57B1/6 (H-2b) tumor-immune or normal splenic lymphocytes to sublethally irradiated DBA/2 mice induced a marked antitumor state, graft-versus-leukemia (GVL), increasing the mean survival time 2-3-fold, but also induced an acute and lethal graft-versus host disease (GVHD). We have undertaken experiments to try to dissociate GVL from GVHD. Transfer of immune spleen cells induced a greater GVL than transfer of normal spleen cells with an equivalent to GVHD. Three to five million immune or normal CD8+ T lymphocytes were sufficient to induce both GVL and GVHD. Individual DBA/2 mice were labeled and followed. In mice undergoing GVHD, the spleens were repopulated by donor (H-2b) lymphocytes, and tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were present in the sera of 26 of 27 and 18 of 20 mice, respectively, together with increased amounts of TNF-alpha and IL-6 mRNA in their spleens. This was in contrast to DBA/2 mice receiving allogeneic cells but not developing GVHD. Both interferon-alpha/beta (IFN-alpha/beta) and IL-12, which had proven very effective in association with adoptive transfer of syngeneic immune T lymphocytes in inhibiting ESb metastases, enhanced GVHD when administered with allogeneic immune or normal spleen cells, and >90% of mice died. Intensive IL-2 treatment inhibited GVHD while maintaining GVL.
Gresser
I
I
Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy.
Greco
G
G
Santini
S M
SM
Woodrow
D
D
Mecchia
M
M
Parlato
S
S
Logozzi
M
M
Venditti
M
M
Maunoury
M T
MT
Belardelli
F
F
D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D006086:Graft vs Host Disease; D020350:Graft vs Tumor Effect / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009362:Neoplasm Metastasis; D015996:Survival Rate; D013601:T-Lymphocytes / Q000637:transplantation*; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
D016207:Cytokines