Date of Award

1996

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Abstract

It was previously reported from our laboratory (Chakrabarti et al., Cell. Immunol. 142:54, 1992, ibid 144:455, 1992) that in a murine B-lymphoma model, 2C3, idiotype-specific cytotoxic T cells (CTLs) are generated in mice following hyperimmunization with irradiated tumor cells, and that they are effective in tumor rejection. The present study focused on the following: (a) does live tumor evoke CTL response as does the killed tumor (b) how does cell-mediated immunity during tumor growth differ from that induced by vaccination with killed tumor and (c) what is the nature of antigenic idiotype recognized by CTL? The present study reveals that tumor-specific CD8+ CTLs are indeed induced in the spleens of mice during in vivo progression of 2C3 lymphoma. These T-cells produce high levels of IL-4, IL-10 and IFN-$\gamma$ at the early stage of tumor growth, but both their CTL activity and cytokine production sharply decline with increase in tumor burden, as does the anti-idiotypic humoral response. The most notable decline, (20-fold) however, at the late stage of tumor growth is observed in IL-4 secretion by CD4+ T-cells. Surprisingly, in about 20% of the animals that survive and show no sign of tumor growth, neither the CTL activity nor IL-4 secretion is affected. Our results also demonstrate that the cytotoxicity of the CTLs from the late tumor-bearers can be restored by the addition of IL-4 or anti-IFN-$\gamma$, but not by IFN-$\gamma$ and IL-10. Furthermore, only the IL-4 activated CD8+ T-cells from the late tumor-bearers are found by the Winn assay to be protective in vivo. It appears that IL-4 and IFN-$\gamma$ regulate the differentiation of different CD8+ T-cells and that the down-regulation of antitumor immune response may be due to the decline in IL-4 secreting CD4+ T-cells. The CTLs from the vaccinated animals as well as those from tumor-bearing animals proliferate similarly in response to mitogens. However, they differ in their cytokine secretion profile as well as in V$\beta$ gene usage suggesting involvement of heterogeneous population of CTLs at different stages of tumor growth. With regard to epitopes recognized by CTLs, seven antigenic peptides were isolated from the 2C3 tumor. One of these peptides appear to be derived from 2C3 idiotype and is responsible for CTL induction following vaccination.

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