Inhibition of tumor growth in immunocompromised hosts by restoring type-2 immunity using infusion of G-CSF-treated allogeneic CD8+ leukocytes.
Since recombinant human granulocyte colony-stimulating factor (rhG-CSF)-treated donor leukocyte infusion (G-DLI) has been shown to downregulate type-1 immunity in a heart transplant model, we examined influences of G-DLI on tumor growth in immunosuppressed hosts. F344 rats were treated with tacrolimus (8 mg/kg i.m.) and syngeneic colon adenocarcinoma RCN-9 cells (3 x 10(6)) were inoculated subcutaneously. For G-DLI, allogeneic DA rats were pretreated with rhG-CSF (250 microg/kg, days -5 to 0) and isolated leukocytes or sorted CD8(+) cells were injected intravenously to the hosts on day 0. Tumors in tacrolimus-treated hosts continuously grew over 5 weeks. G-DLI of 100 x 10(6) leukocytes attenuated tumor growth rate while direct host pretreatment with rhG-CSF did not. Notably, G-DLI of 10 x 10(6) CD8(+) cells blocked tumor expansion after day 14. Tacrolimus-induced inhibition of lymphocyte infiltration into tumors was recovered by the G-DLIs. Flow cytometry showed no detectable donor-type T cells in the tumor and circulation. Quantification of intratumor transcription levels using reverse transcription-real-time polymerase chain reaction showed recovery from tacrolimus-induced downregulation of interleukin-4 but not interferon-gamma levels. In vivo rhG-CSF-treated CD8(+) allogeneic cells demonstrate potent anti-tumor effects by restoring type-2 immunity of immunosuppressed hosts.
Ohmori
Ichiro
I
Department of Surgery, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8551, Japan.
Hayamizu
Keisuke
K
Oishi
Koichi
K
Yoshimitsu
Masanori
M
Itamoto
Toshiyuki
T
Asahara
Toshimasa
T
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000637:transplantation*; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016867:Immunocompromised Host / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D015847:Interleukin-4 / Q000235:genetics; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D021122:Protein Subunits / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D014184:Transplantation, Homologous
C508858:IL12A protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016559:Tacrolimus