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Interleukin 2 in the in Vitro Generation and in Vivo Effectiveness of Tumor Specific T Lymphocytes [microform]

出版	Thesis (Ph.D.)--University of Alberta, 1984
ISBN	03151937949780315193796
URL	http://books.google.com.hk/books?id=k_a50AEACAAJ&hl=&source=gbs_api

註釋In order to respond to a foreign challenge, cells of the immune system must recognize the pathogen as foreign and must also receive a "second signal'. Both signals are required to induce the proliferation and differentiation of effector cells. Malignant disease in the otherwise immunocompetent host could escape immune control through failure to recognize tumor cells as foreign or through lack of the required "second signal". Previous work suggested that Interleukin 2 may be one of the second signals stimulating immune cells. Failure of Interleukin 2 production or action may allow malignant cells to escape the immune system. Therefore, an attractive method of immunotherapy would be to increase the positive immunoregulatory action of IL2 in vivo. Unfortunately, methods for modulating Interleukin action in vivo are not available. Therefore, removing lymphocytes from tumor-bearing mice, culturing them with exogenous Interleukin 2 and, subsequently, reinfusing the programed cells into tumor-bearing mice was explored as a model of a possible immunotherapeutic technique. Spleen cells from tumor-bearing mice contain populations of precursor cells reactive to autologous tumor. Culture of these cells with exogenous Interleukin 2 generated a population of helper lymphocytes able to recruit host anti-tumor activity. Culture with IL2 also generated two populations of lymphocytes directly cytotoxic to tumor cells. One of the populations of cytotoxic lymphocytes, generated by culture with Interleukin 2 and autologous tumor, was relatively specific to the sensitizing tumor. These are probably "classical" cytotoxic T lymphocytes. The second population of cytotoxic cells, generated by culture with Interleukin 2 alone, demonstrated a broader spectrum of anti-tumor reactivity. Identifying the origin of the cell responsible for this non-specific activity has proven to be difficult. The broad spectrum of activity, the lack of requirement for antigen sensitization, and the lack of H2 restriction are appropriate for "natural killer" cells; whereas, the time course of activation and the surface marker phenotype are appropriate for "classical" cytotoxic lymphocytes. The precursors of both cytolytic cell populations, described above, are significantly increased in tumor-bearing animals. This suggests that tumor recognition occurs in tumor-bearing animals but that the "second signal" required for proliferation and differentiation is not present or not received. Interleukin 2 can provide this signal at least in vitro. Culture of peripheral blood cells from ovarian cancer patients with either human IL2 or murine IL2 generated cytotoxic lymphocytes which were active against autologous tumor. In the immunotherapy of murine tumors, the cytotoxic lymphocyte containing populations were most effective if given shortly after injection of the tumor. The response was dose related. Repeated injections were more effective than single injections. The cultured cells homed poorly to the tumor, therefore injection directly into the tumor site was more effective than intravenous administration. Therapy with cytotoxic lymphocytes was synergistic with surgical therapy of CaD2 tumors. Therapy with cytotoxic lymphocyte containing populations consistently improved the survival of mice with intraperitoneal P815 tumors. Despite the improved survival of mice following therapy, there were few long term survivors. Therapy with cytotoxic lymphocyte containing populations cured some mice with subcutaneous P815 tumors. The mice that died of the tumor did not demonstrate an improvement in survival times compared to untreated mice. Mice cured of the P8 15 tumor by treatment with cytotoxic lymphocyte containing preparations remain tumor-immune. There were no significant detrimental side effects of therapy with cytotoxic lymphocytes.