Th2-like response and anti-tumor effect of anti-lL-4 mAb in mice bearling renal cell carclinoma

1994 Fiscal Year Final Research Report Summary

• Project/Area Number: 05807144
• Research Category: Grant-in-Aid for General Scientific Research (C)
• Allocation Type: Single-year Grants
• Research Field: Urology
• Research Institution: University of Tokyo
• Principal Investigator: TAKEUCHI Takumi University of Tokyo, Department of Urology, consultant urologist, 医学部・附属病院, 助手 (90167487)
• Co-Investigator(Kenkyū-buntansha): OSHI Masaya University of Tokyo, Department of Urology, assistant professor, 医学部・附属病院, 講師 (60143468)
• Project Period (FY): 1993 – 1994
• Keywords: Th1 / Th2 / cytokine / anti-IL-4-mAb / renca

Research Abstract

Tumor regr ession 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 IL-4 & 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*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. Fourteen days later, Th2 cytokine (IL-4 and IL-10) mRNAs as well as TGF-b1 mRNA assesed by RT-PCR were up-regulated in the spleen of hosts upon naive renca tumor acceptance, while Th1 cytokine (IL-2 and IFN-g) mRNAs were almost undetectable. in the renca tumor, IL-10 mRNA was detected but IL-2, IFN-g, and IL-4 mRNA 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 acceptan ce rate of the tumor (p=0.18). However, prior depletion of CD4+ or CD8+ cells with monoclonal antibodies abrogated the anti-tumor effects of anti-IL-4 mAb. Additionally, the significant anti-tumor 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,RencaH : low or high lL-4 producing, respectively) and control renca cells (RencaC) were obtained, RencaL cells, RencaH cells, or RencaC cells (1*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 inoculated into syngeneic Balb/c hosts, tumor volume was marginally suppressed (p=0.03) and tumors tended to be rejected (p=0.06) were observed 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 lL-4 mAb to Balb/c mice significantly suppressed renca tumor growth by a CD4+ and CD8+ T cell dependent mechanism. On the contrary, 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.