With a knowledge that immunogenic tumors evoke the generation of an antitumor immune response that is down-regulated by CD4+ suppressor T cells after the tumors reach a certain size, attempts will be made to further characterize suppressor T cells. The specificity of suppression will be tested by reciprocal passive transfer experiments designed to ensure that the suppression being tested does not decay because of the absence of an adequate quantity of tumor antigen in recipient mice. The time course of production of suppressor T cells, their life-span after passive transfer, and their ability to expand in number in vivo in response to exogenous IL-2 will be investigated. Suppression will also be studied in vitro to determine the conditions for growing suppressor T cells with the aim of cloning them for functional analysis. The immune response that is down-regulated by suppressors will be studied in terms of the production and distribution of effector T cells and their entry into the tumor. The cellular events associated with tumor regression will be studied to determine whether T cells can destroy a tumor by themselves, or whether, instead, they require the participation of other host cells. This will require the use of highly enriched effector/helper T cells from immunized donor mice, and tumor-bearing recipient mice that have been-rendered deficient in their capacity to contribute monocytes, neutrophils and NK cells to the regression process. In vitro expanded TIL and freshly harvested tumor-specific T cells will be compared in terms of their ability to destroy tumor deposits in the lung and to extravasate and destroy truly extravascular tumors.

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National Cancer Institute (NCI)
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Experimental Immunology Study Section (EI)
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Trudeau Institute, Inc.
Saranac Lake
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Rakhmilevich, A L (1994) Failure of anti-T cell monoclonal antibodies to prevent acute tumor allograft rejection is associated with their inability to deplete or inactivate T cells at the site of rejection. Transplantation 58:72-80
Rakhmilevich, A L; North, R J (1994) Elimination of CD4+ T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2. Cancer Immunol Immunother 38:107-12
Rakhmilevich, A L; North, R J; Dye, E S (1993) Evidence inconsistent with a role for tumor necrosis factor in tumor allograft rejection. Transplantation 55:182-6
Rakhmilevich, A L; North, R J; Dye, E S (1993) Presence of CD4+ T suppressor cells in mice rendered unresponsive to tumor antigens by intravenous injection of irradiated tumor cells. Int J Cancer 55:338-43
North, R J; Dunn, P L; Havell, E A (1991) A role for tumor necrosis factor in poly(I:C)-induced hemorrhagic necrosis and T-cell-dependent regression of a murine sarcoma. J Interferon Res 11:333-40
Rakhmilevich, A L; North, R J (1991) Rapid acquisition of an enhanced capacity to produce tumor necrosis factor, alpha/beta interferon, and interleukin 6 after implantation of tumor cells. Cytokine 3:398-406
Dunn, P L; North, R J (1991) Effect of advanced ageing on the ability of mice to cause tumour regression in response to immunotherapy. Immunology 74:355-9
Dunn, P L; North, R J (1991) Effect of advanced aging on ability of mice to cause regression of an immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells. Cancer Immunol Immunother 33:421-3
Dunn, P L; North, R J (1991) Selective radiation resistance of immunologically induced T cells as the basis for irradiation-induced T-cell-mediated regression of immunogenic tumor. J Leukoc Biol 49:388-96
North, R J; Awwad, M (1990) Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma. Immunology 71:90-5

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