Th2-like response and antitumor effect of anti-interleukin-4 mAb in mice bearing renal cell carcinoma.

Abstract

Tumor regression in experimental systems has been linked to the activities of Th1 cells. It is, therefore, conceivable that Th2 cells interrupt the expression of tumor immunity since interleukin-4 (IL-4) and IL-10 inhibit the generation of Th1 from precursors and modulate the competence of antigen-presenting cells to activate this lymphocyte subpopulation. Naive murine renal cell carcinoma (renca) cells (1 x 10(5)) were implanted into the subcapsule of the left kidney of Balb/c and Balb/c nude mice at 6-8 weeks of age. After 14 days, Th2 cytokine (IL-4 and IL-10) mRNAs as well as transforming growth factor beta1 mRNA, assessed by reverse transcriptase/polymerase chain reaction were upregulated in the spleen of hosts upon naive renca tumor acceptance, while Th1 cytokine (IL-2 and interferon gamma) mRNAs were almost undetectable. In the renca tumor, IL-10 mRNA was detected but IL-2, interferon gamma, and IL-4 were not. Intraperitoneal administration of anti-(mouse IL-4) mAb (11B11) reduced the renca tumor size (P = 0.018) and prolonged host survival (P = 0.03), but did not reduce the acceptance rate of the tumor (P = 0.18). However, prior depletion of CD4+ or CD8+ cells with monoclonal antibodies abrogated the antitumor effects of anti-IL-4 mAb. In addition, the significant antitumor effect of anti-IL-4 mAb was not observed in Balb/c nude hosts. Renca cells were transfected with the mammalian expression vector pCAGGS containing murine IL-4 cDNA or vector alone, then stable IL-4 transfectants (RencaL or RencaH, low- or high-IL-4-producing respectively) and control renca cells (RencaC) were obtained. RencaL cells, RencaH cells, or RencaC cells (1 x 10(5) each) were implanted into the subcapsule of the left kidney of Balb/c, Balb/c nude, and allogenic C3H/HeJ mice, then tumor formation was evaluated 14 days later. When RencaH cells were innoculated into syngeneic Balb/c hosts, tumor volume was marginally suppressed (P = 0.03) and tumors tended to be rejected (P = 0.06) compared with RencaC cells. However, those effects were not observed in Balb/c nude mice. RencaC, RencaL, and RencaH cells were not accepted by allogeneic C3H mice with or without FK506 administration or donor-specific transfusion. The administration of anti-(mouse IL-4) mAb to Balb/c mice significantly suppressed renca tumor growth by a CD4+ and CD8+ T-cell-dependent mechanism. By contrast, relatively high levels of IL-4 production by renca cells and T cells seemed to be required to induce the rejection and growth suppression of IL-4-producing renca cells in syngeneic hosts.