Activation of T lymphocytes involves a preprogrammed alteration in lymphocyte responsiveness to informational signals transmitted by a variety of regulatory molecules. These signals are channeled to the cell via stereospecific receptor proteins. In studies performed in our laboratory, we have found that the process of human T lymphocyte activation sets in motion a process in which a series of receptor and other functionally important membrane proteins are expressed de novo in a reproducible, non-synchronous manner. The stages of T cell activation can be defined, in large part, by using the sequential de novo expression of functionally important proteins as a roadmap of the activation sequence. We will map the kinetic expression of the phenotypic markers of T cell activation for each subset by use of a multibeam laser activated cell sorter in concert with fluorochrome labelled antibodies, hormones, and growth factors, and stains that detect changes in ion flux and intracellular pH. We will determine the stimuli required to direct T cells from one stage to the next of the activation sequence and hence determine the sequence of signals required for proliferation and activation of the functional program of each subset. These efforts are made possible by our access to cloned cell lines and our ability to purify lymphokines by HPLC. These data should provide a framework by which autoimmune and immunodeficiency states may be dissected and perhaps ameliorated by use of lymphokines. A series of activation antigens of particular interest have been identified by flow cytometric probes (4 monoclonal antibodies and fluoresceinated insulin) these proteins appear on essentially all activated human T cells until cycles of replication cease. These include the transferrin, insulin, and interleukin-2 (IL-2) receptors. The monoclonal antibodies which recognize the IL-2 and another T cell specific activation, respectively, are of special interest. We will ascertain if they neatly define the entire antigen activated T cell population. Universal probes of activation represent an attractive therapy by which to manipulate only those T cell clones that are activated by antigens, particularly as the heterogeneity of therapeutic probes needed is minor as compared to idiotype or anti-idiotype specific agents. Accordingly, the utility of a monoclonal antibody directed against a murine early activation antigen will be tested in vivo for therapy in transplantation, autoimmunity, and lymphoma.

National Institute of Health (NIH)
National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIADDK)
Research Project (R01)
Project #
Application #
Study Section
Immunobiology Study Section (IMB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Heagy, W; Strom, T B; Kelley, V E et al. (1989) Recombinant human gamma interferon enhances in vitro activation of lymphocytes isolated from patients with acquired immunodeficiency syndrome. Infect Immun 57:3619-28
Kelley, V E; Gaulton, G N; Hattori, M et al. (1988) Anti-interleukin 2 receptor antibody suppresses murine diabetic insulitis and lupus nephritis. J Immunol 140:59-61
Diamantstein, T; Osawa, H; Kirkman, R L et al. (1987) Interleukin 2 receptor--a target for immunosuppressive therapy. Transplant Rev (Orlando) 1:177-96
Knudsen, P J; Dinarello, C A; Strom, T B (1987) Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 139:4129-34
Melton, L B; Lakkis, F G; Deloria, D et al. (1987) Requirements for primary T cell activation. Transplant Proc 19:331-2
Kelley, V E; Gaulton, G N; Strom, T B (1987) Inhibitory effects of anti-interleukin 2 receptor and anti-L3T4 antibodies on delayed type hypersensitivity: the role of complement and epitope. J Immunol 138:2771-5
Kelley, V E; Strom, T B (1987) Immunosuppression by anti-interleukin-2 receptor antibody but not anti-L3T4 requires terminal complement components. Transplant Proc 19:617
Kelley, V E; Farber, N M; Williams, J M et al. (1986) Inability of autoimmune mice with the lpr gene to spontaneously produce interleukin 3. Eur J Immunol 16:464-7
Kelley, V E; Strom, T B (1986) Spleen cell factor inhibits lymphoproliferation, abnormal Ia expression and overt autoimmunity in MRL-lpr mice. Clin Immunol Immunopathol 41:145-53
Kelley, V E; Naor, D; Tarcic, N et al. (1986) Anti-interleukin 2 receptor antibody suppresses delayed-type hypersensitivity to foreign and syngeneic antigens. J Immunol 137:2122-4

Showing the most recent 10 out of 13 publications