The objectives of this study were to undertake a clonal analysis of cellular immune response mediated by cytotoxic T cells (CTL) and by natural killer (NK) cells in an autologous human melanoma system and to examine the cellular and molecular basis of cytotoxic unresponsiveness against autologous melanoma cells. To test the hypothesis that cytotoxic unresponsiveness against autologous melanoma cells may result from antigen-specific suppression, we planned to clone autoreactive CTL after in vitro autologous-mixed lymphocyte-tumor cell interaction (MLTI) and then use the clones in cytotoxicity assays to search for putative cellular and/or humoral suppression factor. Using several autologous melanoma systems, including a melanoma line (VIP) and an autologous in vitro-transformed fibroblast line (VIP-F:T), several major goals have been accomplished. (1) In the VIP system we demonstrated that CTL clones expressing cytotoxicity restricted to autologous melanoma cells can be generated. The cytotoxicity of the CTL clone, however, could not be modulated with autologous serum or with blood lymphocytes. (2) We were able to establish functional human-mouse CTL hybrids that appeared to express the cytotoxic specificity of the hybridized CTL. (3) Using the in vitro-transformed fibroblast system, we demonstrated the operational existence of autologous NK cells activities that express target receptor specificity and protect nude mice from tumorigenic challenge of the transformed cells. (4) Multiple colonies and clones generated in other systems are under analysis. Finally, in two of our autologous systems, we have clearly identified the existence of both suppressor and inducer cells (isolated from tumor-affected lymph nodes) that are capable of suppressing the generation of cytotoxic immune response in MLTI against the autologous melanoma cells. (IS)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030461-07
Application #
3169255
Study Section
Experimental Immunology Study Section (EI)
Project Start
1981-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Okino, T; Chakraborty, N G; Stabach, P et al. (1993) Inhibition of interleukin-2 synthesis and interleukin-2 receptor alpha expression on T cells by a cell-free factor derived from a CD4+ regulatory T cell clone. Clin Immunol Immunopathol 68:256-62
Chakraborty, N G; Sporn, J R; Pasquale, D R et al. (1991) Suppression of lymphokine-activated killer cell generation by tumor-infiltrating lymphocytes. Clin Immunol Immunopathol 59:407-16
Chakraborty, N G; Okino, T; Stabach, P et al. (1991) Adoptive transfer of activated human autologous macrophages results in regression of transplanted human melanoma cells in SCID mice. In Vivo 5:609-14
Sivanandham, M; Chakraborty, N G; Robbins, G R et al. (1991) Clonal expansion of T cells following in vitro stimulation with autologous melanoma cells and interleukin-2 studied by molecular analysis of a T cell receptor. Immunol Lett 28:155-9
Chakraborty, N G; Twardzik, D R; Sivanandham, M et al. (1990) Autologous melanoma-induced activation of regulatory T cells that suppress cytotoxic response. J Immunol 145:2359-64
Mukherji, B; Chakraborty, N G; Sivanandham, M (1990) T-cell clones that react against autologous human tumors. Immunol Rev 116:33-62
Sivanandham, M; Mukherji, B (1989) Functionally different HTLV I-infected T cell lines with the same phenotype derived from a patient with melanoma. Immunol Lett 23:149-54
Mukherji, B; Guha, A; Chakraborty, N G et al. (1989) Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma. J Exp Med 169:1961-76
Spencer, R P; Mukherji, B (1988) Utilization of tumour-sensitized ('educated') and radiolabelled lymphocytes for tumour localization. Nucl Med Commun 9:783-6
Mukherji, B; Arnbjarnarson, O; Spitznagle, L A et al. (1988) Imaging pattern of previously in vitro sensitized and interleukin-2 expanded autologous lymphocytes in human cancer. Int J Rad Appl Instrum B 15:419-27

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