Publications

Murine lupus in BXSB mice is associated with B cell hyperactivity, monocyte proliferation, and impaired T cell function. However, the significance of these abnormalities, and the relationship among them, has not been clearly established. To examine the role of T cells in the pathogenesis of autoimmune disease in BXSB mice, we depleted specific T cell subsets from BXSB males by using rat IgG2b monoclonal antibodies (MAb) to either Thy-1.2 (on all T cells) or L3T4 (on "helper/inducer" T cells). A single injection of anti-Thy-1.2 (6 mg i.v.) at age 3 mo produced a sustained 40 to 50% reduction in circulating T cells for 6 mo. Treatment prevented monocytosis, reduced anti-DNA antibody concentration, and retarded renal disease, but it did not prolong life. Repeated injections of rat MAb to Thy-1.2 were precluded by the development of a host immune response to rat immunoglobulin (Ig) that can cause anaphylaxis in BXSB mice. In contrast, rat MAb to L3T4 stimulated little or no immune response to rat Ig. We therefore were able to treat BXSB mice weekly with anti-L3T4 (2 mg i.p.) from age 3 to 12 mo. Treatment reduced circulating L3T4+ cells beneath the level of detection by fluorescence analysis. It also significantly reduced monocytosis, anti-DNA antibody production, renal disease, and mortality. These findings establish that monocytosis and autoimmunity in BXSB mice are promoted by T cells. They extend our previous observation that MAb to L3T4 retard autoimmunity in NZB/NZW F1 mice. Our finding that treatment with MAb to L3T4 is effective in two strains of lupus-prone mice suggests that treatment with MAb to Leu-3/T4, the human homologue for L3T4, may be effective in people with systemic lupus erythematosus.

The DNA sequence encoding all of the putative intracytoplasmic domain and most of the trans-membrane domain of the human IL 2 receptor was deleted from a full length receptor cDNA. After expression in mouse L cells, the resultant "anchor minus" cDNA was found to direct the synthesis of a secreted rather than membrane-associated form of the IL 2 receptor. The secreted receptor protein (44,000 to 46,000 Mr) retained the capacity to bind both IL 2 and the monoclonal anti-Tac antibody, as evidenced by retention on IL 2 and anti-Tac affinity columns, inhibition of [3H]-anti-Tac binding to HUT 102B2 cells, and partial inhibition of IL 2-induced CTLL proliferation. Removal of these domains from the IL 2 receptor did not alter the posttranslational processing or rate of export of the truncated receptor protein. These data confirm the proposed membrane orientation of the IL 2 receptor (NH2 terminus out, COOH terminus in) and underscore the anchoring function of this carboxy terminal receptor segment. The availability of such anchor minus receptor cDNA constructs may facilitate purification of large quantities of receptor protein for further analysis of receptor structure, valency, and localization of the IL 2 binding site(s).

To determine whether the combination of an agent thought to inhibit mediator release (cromolyn) and an agent that inhibits parasympathetic pathways inhibits sulfur dioxide-induced bronchoconstriction more than either agent alone, we measured the bronchomotor response of 9 asthmatic subjects to inhalation of sulfur dioxide after treatment with cromolyn sodium (200 mg by spinhaler), with atropine sulfate (2.0 mg by nebulizer), and with the 2 drugs given together. Then, to determine whether the combination of cromolyn and a parasympathetic antagonist would similarly inhibit bronchoconstriction provoked by a different nonallergic stimulus, we measured the bronchomotor response of another group of asthmatic subjects to eucapnic hyperpnea of dry air at room temperature after treatment with cromolyn (200 mg), with ipratropium bromide (100 and 200 micrograms by metered-dose inhaler), and with cromolyn (200 mg) and ipratropium bromide (200 micrograms) given together. In both studies, we found that the combination treatment provided greater protection than that obtained with either agent alone. The concentration of sulfur dioxide required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and atropine (2.58 ppm, geometric mean) than after cromolyn alone (0.84 ppm), after atropine alone (0.78 ppm), or after placebo (0.43 ppm). Similarly, the rate of ventilation with dry air required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and ipratropium (106 +/- 22 L/min, mean +/- SD) than after cromolyn alone (65 +/- 19 L/min), after 200 micrograms of ipratropium alone (64 +/- 13 L/min), or after placebo (43 +/- 10 L/min).(ABSTRACT TRUNCATED AT 250 WORDS)