Publications

BALB/c mice are highly susceptible to disseminated infection with the intracellular protozoa Leishmania major. Progression of disease requires in vivo expansion of Th2 CD4+ lymphocytes and is reversed by treatment with anti-IL-4 monoclonal antibody. Inasmuch as IL-2 may be necessary for both the production of IL-4 and differentiation of Th2 cells, the possible contribution of IL-2 to progressive infection was examined. Four weekly injections of anti-IL-2 mAb (S4B6) cured more than 80% of BALB/c mice infected with L. major, as determined by diminished footpad swelling and decreased numbers of parasites in infected tissues. Multiple doses of S4B6 were necessary for benefit; a single dose given at the time of infection was ineffective. The anti-IL-2R mAb PC61 demonstrated a similar protective effect when administered twice weekly for 4 wk. Anti-IL-2-mediated cure of cutaneous leishmaniasis was associated with increased IFN-gamma and decreased IL-4 production by regional lymph node cells compared to untreated BALB/c mice with progressive illness. Both CD4+ and CD8+ T lymphocytes contributed to the increased expression of IFN-gamma mRNA in cured mice. These data suggest that levels of IL-2 suboptimal for Th2 expansion in vivo do not inhibit Th1 CD4+ and CD8+ T cell activation and IFN-gamma synthesis. Other cytokines or activation pathways that are either IL-2-independent or synergistic with low levels of IL-2 may account for the appearance of curative T cell responses during treatment with anti-IL-2 antibodies.

The cellular origin of hepatocyte growth factor (HGF), a polypeptide implicated in liver regeneration, was examined in normal liver and in hepatic regeneration induced by carbon tetrachloride. In normal liver, HGF and its mRNA were abundant in lipocytes, with smaller amounts present also in sinusoidal endothelial and Kupffer cells. In regenerating liver, HGF gene expression increased exclusively in endothelial cells. HGF mRNA levels rose sixfold in these cells, peaking at 6 h after toxin administration and returning to near normal by 24 h. The rise in HGF mRNA was accompanied by a 5.4-fold increase in HGF secretion. CCl4 did not alter HGF expression by either Kupffer cells or lipocytes; nor did it induce HGF expression by hepatocytes. Nonparenchymal liver cells contained two HGF transcripts: one predicting a full-length molecule of 728 amino acids; and the other encoding a functional five-amino acid deletion variant of HGF. The variant was less abundant than the full-length transcript, but increased in parallel with native HGF mRNA in response to CCl4. The response of nonparenchymal cells to HGF was examined by plating endothelial cells and lipocytes in the presence of recombinant human HGF. Under the conditions examined, the growth factor exerted neither mitogenic nor scatter factor activity on these cells.

Recent evidence suggests that left atrial (LA) appendage velocities may provide clues to the thrombogenic potential of this structure. Pulsed Doppler evaluation of LA appendage flow during transesophageal echocardiography was performed in 109 patients to evaluate the effects of rhythm, mitral regurgitation, and spontaneous contrast. During sinus rhythm, there was a forward LA appendage contraction wave of 46 +/- 18 cm/sec followed by a retrograde filling wave of 46 +/- 17 cm/sec. In 40% of the patients in sinus rhythm, additional forward and retrograde velocities of 23 +/- 10 and 22 +/- 11 cm/sec, respectively, were seen. In contrast, atrial fibrillation was associated with reduced forward and retrograde flows in an irregularly irregular pattern. In sinus rhythm moderate to severe mitral regurgitation did not appear to affect the LA appendage velocities. Last, although forward LA appendage velocities were found to be significantly reduced in patients with spontaneous contrast by univariate analysis, multivariate analysis demonstrated that only the presence of atrial fibrillation was a significant predictor for spontaneous contrast.