title: 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.
authors.affiliation: Department of Urology, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takeuchi
authors.forename: T
authors.initials: T
authors.lastname: Ueki
authors.forename: Y
authors.initials: Y
authors.lastname: Sasaki
authors.forename: T
authors.initials: T
authors.lastname: Kajiwara
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Moriyama
authors.forename: K
authors.initials: K
authors.lastname: Kawabe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015847:Interleukin-4