Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes

Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.     

Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon- gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN- gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

Primary signet ring cell carcinoma of the eccrine sweat gland in the eyelid. Immunohistochemical and ultrastructural study of a case

We report a case of a 45-year-old woman who exhibited a primitive eccrine sweat gland carcinoma of the eyelid. Histological study showed cellular proliferation with an Indian file pattern and some signet ring cells with sialomucin secretion. Immunohistochemical study demonstrated these cells to be positive with the anticytokeratin, anti-EMA, anti-HMFG, antiestrogen receptor and antiprogesterone receptor antibodies. Ultrastructural study showed intracytoplasmic vacuoles with numerous microvilli at the apical side. Differential diagnosis with a metastasis from a mammary adenocarcinoma is difficult and a complete staging is necessary to confirm the primitive origin of the tumor. The behavior of this tumor is marked by locoregional recurrence.     

Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I

Cardiac function was measured in 16 prepubertal Ecuadorean patients with growth hormone receptor deficiency given insulin-like growth factor I (IGF-I) during part of a clinical trial. The IGF-I was given subcutaneously twice daily at a dose of 40 μg/kg on days 1 and 2, 80 μg/kg on days 3 and 4, and 120 μg/kg thereafter. Heart rate was determined at baseline (pretreatment) and on days 1–7 by repeated palpation of the radial artery and at baseline and on days 2, 4 and 7 by continuous portable Holter monitoring. Heart rate measured by both methods rose progressively with increasing doses of IGF-I. The mean palpated pulse exceeded baseline on each treatment day and was significantly higher on day 5 than day 4 and significantly higher on day 3 than day 2. The mean Holter heart rate was significantly higher on day 4 than on day 2 and significantly higher on day 2 than at baseline. Non-significant glucose and electrolyte changes did not appear to be associated with the cardiac events.     

Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins

The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30–35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs.     

IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy

Results of second-line chemotherapy regimens against lymphoma have usually been poor. In this study, we used a combination of ifosfamide, methotrexate, and VP-16 to treat 52 patients with lymphoma who had either relapsed or who had failed to attain a complete remission on front-line treatment. Thirty-two patients (62%) responded (CR 37%, PR 25%) and 10 (19%) had a minor response. The median relapse-free interval of the responding patients was 12 mo, and the median survival of the whole group was 15 mo. Of the 18 patients who achieved complete remission, 10 still remain free of any evidence of disease. The factor that best predicted for response to IMVP-16 was the quality of the remission achieved on front-line therapy. In view of the poor prognosis associated with recurrent lymphoma, the results obtained with this study are considered most encouraging. Patients with recurrent lymphoma can be successfully salvaged by the use of this combination regimen, especially if introduced early after relapse or preferably before progressive disease develops.     

Regression of mediastinal Hodgkin disease after therapy: evaluation of time interval

Ninety-one patients with Hodgkin disease of the upper torso who had mediastinal masses were studied to determine the frequency of residual mass and the time required for resolution or stabilization of the mass. In 72 of these patients, radiographs from sufficient intervals were available for determination of the rate of regression. In 62 patients (86%), the mediastinum returned to normal width within 11 months, regardless of the size of the mass. The mediastinum returned to normal in all but one patient with small masses. The intrathoracic relapse rate did not correlate with the regression time of the masses, but relapse occurred more than twice as often in patients with residual mediastinal widening.