Publications

We demonstrate that purified interleukin 2 (IL-2) can directly upregulate IL-2 receptor expression on phytohemagglutinin-activated T lymphocytes maintained in culture until IL-2 receptor expression had markedly declined. The IL-2-induced increase in IL-2 receptor number is maximal within 12 hr, requires new RNA and protein synthesis, and is mediated by an interaction of ligand with the high-affinity receptors for IL-2. IL-2 stimulation results in increased accumulation of IL-2 receptor mRNA within 4 hr, while an increase in IL-2 receptor gene transcription is detected within 30 min in isolated nuclei. In addition, IL-2 incubation results in increased amounts of c-myc and transferrin receptor mRNA, but it does not augment levels of mRNA encoding the beta chain of the T-cell receptor for antigen. These results demonstrate that IL-2 can directly upregulate transcription and expression of its own receptor and, therefore, indicate that IL-2 may regulate IL-2-dependent immune responses, in part, by influencing the expression of IL-2 receptors.

Adult T cell leukemia (ATL) is an almost uniformly fatal malignancy of mature T cells associated with human T cell leukemia/lymphoma virus type 1 (HTLV-1) infection. Cells from this leukemia are characterized by the expression of large numbers of receptors for interleukin 2 (IL-2). In an attempt to prepare an immunotoxin with selective cytotoxicity for ATL cells, we conjugated anti-Tac, a monoclonal anti-IL-2 receptor antibody, to purified ricin A chains. Although unmodified anti-Tac had no effect on the protein synthesis of these cells, anti-Tac-ricin A chain conjugates produced half-maximal inhibition of protein synthesis in HTLV-1-infected leukemic T cell lines at concentrations of 2 to 6 X 10(-10) mol/L (ID50). An essentially identical ID50 was obtained with leukemic peripheral blood T lymphocytes isolated from two patients with ATL. In contrast, half-maximal inhibition of protein synthesis in HTLV-uninfected, IL-2 receptor-negative T and B cell lines required 200- to 1,000-fold higher concentrations of anti-Tac-ricin A chain conjugates. Both unconjugated anti-Tac and immunoaffinity-purified IL-2 completely inhibited the toxic effects of anti-Tac-ricin A, confirming the specificity of the conjugate-IL-2 receptor interaction. Clonogenic assays demonstrated that anti-Tac-ricin A chain was able to eliminate greater than 99.9% of an HTLV-1-infected T cell population at concentrations only marginally affecting IL-2 receptor-negative cells. The data presented demonstrate that anti-Tac-ricin A is selectively cytotoxic for HTLV-1-infected leukemic T cells in vitro and raises the future possibility of specific therapeutic intervention with immunotoxins in this disease.

It is uncertain if respiratory heat loss or respiratory water loss is the stimulus for bronchoconstriction induced by isocapnic hyperpnea or exercise with dry air in subjects with asthma. We partially separated these 2 stimuli by having 18 subjects with asthma breathe dry air (0 mg/L water content) at increasing ventilations by isocapnic hyperpnea while we measured the increase in specific airway resistance (SRaw). The study was divided into 2 phases. In Phase 1, we used an apparatus with a single respiratory valve and evaluated the subjects' responses at 3 different inspired temperatures (-8.4, 20.5, and 39.4 degrees C). Seven of the subjects had esophageal catheters with 2 thermocouples in place to measure retrocardiac and retrotracheal temperatures. In this phase, we found that there were no significant differences in the ventilation required to cause a 100% increase in SRaw among the 3 different inspired temperatures (48.4 L/min, cold; 47.5 L/min, room temperature; 44.2 L/min, hot), even though the retrotracheal temperature fell more when the subjects breathed cold air at 40 L/min (2.1 degrees C) than when they breathed hot air (1.2 degrees C), suggesting greater airway cooling with the cold air. In Phase 2, in order to accurately measure inspired and exhaled temperatures and exhaled water content, we used 2 separate systems for delivering the inspired air and collecting the exhaled air at 2 different inspired temperatures (-21.4 and 38.9 degrees C). Again, we found that there was no significant difference in the ventilation required to cause a 100% increase in SRaw between the 2 different inspired temperatures (28.3 L/min, cold; 33.6 L/min, hot). When the subjects inhaled cold air, exhaled temperature was warmer than previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

The population pharmacokinetics of racemic warfarin was evaluated using 613 measured warfarin plasma concentrations from 32 adult hospitalized patients and 131 adult outpatients. Warfarin concentrations were measured in duplicate using a high-performance liquid chromatographic procedure. The pharmacokinetic model used was a one-compartment open model with first-order absorption (absorption rate constant set equal to 47 day-1) and first-order elimination. The extent of availability was assumed to be one. A linear regression model was used to evaluate the influence of various demographic factors on warfarin oral clearance. Age appeared to be an important determinant of warfarin clearance in this adult population. There was about a 1%/year decrease in oral clearance over the age range of 20-70 years. Smoking appeared to result in a 10% increase in warfarin clearance, while coadministration of the inducers phenytoin or phenobarbital yielded about a 30% increase in clearance. This study has yielded a predictive model that, when combined with appropriate pharmacological response data, may be useful in the design and adjustment of warfarin regimens.