Publications

Interleukin-2 (IL-2) is a lymphokine synthesized by some T cells following activation. Resting T cells do not express IL-2 receptors but receptors are rapidly expressed on T cells following the interaction of antigens, mitogens, or monoclonal antibodies with the antigen specific T-cell receptor complex. Using anti-Tac a monoclonal antibody that recognizes the IL-2 receptor, the receptor has been purified. The receptor is a 33 kdalton peptide that is post-translationally glycosylated to a 55 kdalton mature form. Mature receptors contain both N-linked and O-linked sugars and are both sulfated and phosphorylated. Using an oligonucleotide probe, based on the N-terminal amino acid sequence, cDNAs encoding this receptor have been cloned, sequenced and expressed. The addition of anti-Tac to in vitro culture systems blocks the IL-2 induced DNA synthesis of IL-2 dependent T-cell lines and inhibits soluble auto- and alloantigen induced T-cell proliferation. Furthermore, it prevents the generation of cytotoxic and suppressor effector T cells. The anti-receptor antibody also inhibits lectin stimulated immunoglobulin synthesis and the sequential expression of late appearing activation antigens on T cells. Normal resting T cells and most leukemic T-cell populations do not express IL-2 receptors however the leukemic cells of all patients with human T-cell leukemia/lymphoma virus (HTLV-I) associated, adult T-cell leukemia (ATL) examined expressed the Tac antigen. In HTLV-I infected cells the 42 kdalton long open reading frame (LOR) protein encoded in part, by the pX region of HTLV-I may act as a transacting transcriptional activator that induces transcription of the IL-2 receptor gene thus providing an explanation for the constant association of HTLV-I infection of lymphoid cells and IL-2 receptor expression. The constant display of large numbers of IL-2 receptors which may be aberrant in the ATL cells may play a role in the uncontrolled growth of these leukemic T cells. Patients with the Tac positive ATL are being treated with an anti-Tac monoclonal antibody directed towards this growth factor receptor.

We examined the role of IL 2 and IL 2 receptors in human T lymphocyte proliferation induced by neuraminidase and galactose oxidase (NAGO)-treated autologous macrophages. T lymphocytes cultured with these aldehyde-bearing macrophages developed responsiveness to IL 2 after as few as 2 to 4 hr of activation and exhibited maximal responsiveness to IL 2 after 18 to 24 hr of activation. This early expression of IL 2 receptors was also shown by the direct binding of a monoclonal anti-IL 2 receptor antibody (anti-Tac) to the activated T lymphocytes. The production of IL 2 by T lymphocytes cultured with NAGO-treated macrophages closely paralleled the induction of IL 2 receptors on the T lymphocytes. IL 2 production began after 4 to 8 hr of activation and peaked at approximately 18 hr. Although the production of IL 2 is strictly dependent upon accessory cell function, the expression of receptors for IL 2 seems to be relatively independent of accessory cells. Despite early expression of receptors for IL 2 and early production of IL 2 by T lymphocytes during activation, T lymphocytes were not committed to proliferate in the absence of IL 2 until more than 24 hr of incubation with NAGO-treated macrophages had elapsed. The commitment to proliferate increased after 24 hr of activation until, after more than 40 hr of activation, the cells proliferated equally well in the presence or absence of IL 2. Proliferation of uncommitted, IL 2 receptor-bearing T lymphocytes was inhibited by interfering with IL 2 binding to its receptor by IL 2 receptor blockade with the anti-Tac antibody. In contrast, proliferation of T lymphocytes committed to proliferate was not affected by IL 2 receptor blockade with the anti-Tac antibody. Taken together, these data suggest three phases of T lymphocyte activation. The first phase requires mitogen (or antigen) to induce expression of IL 2 receptors and production of IL 2 by the T lymphocytes. Accessory cells are strictly required for IL 2 production during this activation phase, but they may not be necessary for expression of IL 2 receptors. The second phase is an IL 2-dependent phase that requires the interaction of IL 2 with the newly expressed IL 2 receptors. The third phase is a commitment of the activated T lymphocytes to proliferate that is independent of both mitogen and IL 2.

To determine whether treatment with atropine causes dose-dependent inhibition of histamine-induced bronchoconstriction, we constructed dose-response curves to inhaled histamine after inhalation of placebo and 0.26 and 2.08 mg of atropine in eight subjects with mild asthma. Both doses of atropine significantly inhibited histamine-induced bronchoconstriction, and 2.08 mg caused significantly greater inhibition than 0.26 mg. Baseline specific airway resistance was significantly reduced by both doses of atropine but was no different after 2.08 mg than after 0.26 mg. There were considerable differences in the efficacy of atropine among individuals. We conclude that atropine causes dose-dependent inhibition of histamine-induced bronchoconstriction and that this effect is not merely a function of the atropine-induced in baseline airway caliber. The large magnitude of the atropine effect in some subjects and the small magnitude of the effect in others suggest that there is variability in the degree of involvement of muscarinic mechanisms in the exaggerated bronchomotor response to histamine in asthmatic subjects.