Publications

The immunosuppressive drug Cyclosporin A (CyA) inhibited the ConA-induced DNA synthesis in C57B1/6 spleen cells at a concentration of 40 ng/ml totally; this inhibition could not be overcome by the addition of highly purified interleukin-1. ConA-induced RNA synthesis was also inhibited by concentrations of 40 or 200 ng/ml CyA, although total inhibition could not be achieved. In contrast, lipopolysaccharide-induced proliferation could not be inhibited. CyA at a concentration of 40 ng/ml also inhibited the ConA-induced production of interleukin-2 by mouse spleen cells, this inhibition was not due to a toxic mechanism. On the contrary, the proliferative response of T cell blasts from a long-term T cell line (M2) to interleukin-2 containing supernatants was not inhibited by concentrations of 40 or 200 ng/ml CyA; only at 20-100-fold higher concentrations partial inhibition could be observed. One of the earliest events in the course of lymphocyte activation, the enhanced incorporation of unsaturated fatty acids into the lymphocyte plasma membranes; was also inhibited by concentrations of CyA, which abrogated the ConA-induced DNA synthesis. The inhibition of the enhanced incorporation of 14C-oleic acid and 14C-linoleic acid, which are incorporated by the membrane-bound lysolecithin-acyltransferase, thus suggests a molecular site of action for CyA.

Three strains of autoimmune mice (MRL/lpr, NZB/NZW, and BXSB) were treated with repeated injections of rat monoclonal anti-T cell antibody (anti-Thy-1.2) in order to determine 1) the extent and duration of target cell depletion, 2) the effect of T cell depletion on the course of autoimmunity, and 3) the magnitude and consequences of the host immune response to the monoclonal antibody. Mice were treated with 6 mg of anti-Thy-1.2 every 2 wk beginning early in their disease. Treatment produced a substantial reduction in circulating T cells in all three strains. Therapy was beneficial in MRL/lpr mice. It reduced lymphadenopathy, lowered autoantibody concentrations, retarded renal disease, and prolonged life. In contrast, treatment did not improve autoimmunity in NZB/NZW mice, and it caused fatal anaphylaxis in BXSB mice. These findings demonstrate that monoclonal antilymphocyte antibodies can serve as specific probes to examine the cells that contribute to autoimmunity. Moreover, they illustrate the potential therapeutic value of monoclonal antilymphocyte antibodies when a pathogeneic cell subset can be identified. However, the same antibody may have a broad range of effects, from efficacy to severe toxicity, even in diseases that share clinical features.

The failure of the blood pressure to fall during the late strain pase of the Valsalva maneuver in patients with heart failure may result from the left ventricle operating on a flat portion of its function curve or from maintenance of left ventricular volume despite decreased systemic venous return. To test these possibilities, we studied the effect of the Valsalva maneuver (40 cm H2O for 15 sec) on left ventricular volume in 12 normal subjects with a mean left ventricular ejection fraction of 0.65 +/- 0.07 (+/- SD) and in eight patients with nonischemic cardiomyopathy, evidence of pulmonary congestion, and a mean left ventricular ejection fraction of 0.23 +/- 0.09. Left ventricular volume and right ventricular area were determined by apical two-dimensional echocardiography. In both groups the right ventricular end-diastolic area decreased during the late strain phase of the Valsalva maneuver. In normal subjects it decreased from 9.3 +/- 1.5 to 5.6 +/- 1.6 cm2 (p less than .001) and in patients it decreased from 13 +/- 2.2 to 10 +/- 2.9 cm2 (p less than .001). In normal subjects, left ventricular end-diastolic volume decreased from the control level during the Valsalva maneuver, and this was apparent in both the four-chamber (96 +/- 21 to 68 +/- 18 ml, p less than .01) and two-chamber views (97 +/- 15 to 56 +/- 20 ml, p less than .01). In the patients, left ventricular end-diastolic volume was not significantly different from control in either view (199 +/- 70 to 195 +/- 78 and 214 +/- 77 to 218 +/- 86 ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)