Cyclophosphamide given after active specific immunization augments antitumor immunity by modulation of Th1 commitment of CD4+ T cells.
OBJECTIVE
In order to evaluate the regulatory effect of cyclophosphamide (CPA) on active specific immunization (ASI)-induced antitumor immunity, we examined the timing of CPA (100 mg/kg) with ASI, and focused on whether CPA given after ASI augments antitumor immunity by modulation of Th1 commitment of CD4+ T cells.


METHODS
We examined the effect of CPA combined with ASI using sonicated tumor supernatant (SS) and recombinant interleukin-1 beta (rIL-1 beta).


RESULTS
Survival of i.p. tumor inoculated mice after ASI (days -12, -9, and -6) followed by 100 mg/kg CPA (day -3) (ASI-CPA) was significantly prolonged compared with that of mice treated with ASI alone, whereas CPA (day -15) treatment before ASI (CPA-ASI) completely abrogated the survival prolongation by ASI alone. In early stage (day 0) after ASI-CPA treatment, the CD4+ T cells were determined to play an important role in the protective immunity for the following reasons: 1) the CD4+/CD8+ ratio of spleen cells from immunized mice was higher than that of the control or CPA alone treated group; and 2) the tumor neutralizing activity of fresh spleen cells was abrogated by CD4+ T-cell depletion in vitro. CD4+ T cells of mice treated with ASI-CPA produced more interferon (IFN)-gamma and IL-2 and less IL-4 than those of the ASI alone group.


CONCLUSIONS
These results suggest that the protective immunity induced by ASI was augmented through the modification of the Th1 and Th2 balance by CPA injection after ASI.
Li
L
L
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan.
Okino
T
T
Sugie
T
T
Yamasaki
S
S
Ichinose
Y
Y
Kanaoka
S
S
Kan
N
N
Imamura
M
M
D000818:Animals; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005434:Flow Cytometry; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010954:Plasmacytoma / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014611:Vaccination
D007376:Interleukin-2; D007371:Interferon-gamma; D003520:Cyclophosphamide