| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1994: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1993: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| 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
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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. Less
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