Glenn T. Peake

Prostaglandin-Producing Suppressor Cells in Hodgkin's Disease

We examined the role of a prostaglandin-producing suppressor cell in the hyporesponsiveness to phytohemagglutinin seen in Hodgkins disease. Addition of indomethacin to phytohemagglutinin cultures of lymphocytes from six patients with Hodgkins disease resulted in an increase of 182 +/- 60 per cent in 3H-thymidine incorporation versus a 44 +/- 18% increase in 29 controls (mean +/- S.D., P less than 0.001). Without indomethacin the mean response of the lymphocytes in Hodgkins disease was 48% of that of control. With indomethacin it was 94% of the control value. Phytohemagglutinin cultures of Hodgkin-disease lymphocytes produced approximately fourfold more prostaglandin E2 after 48 hours than did normal lymphocytes (P less than 0.02). Removal of glass-adherent cells markedly decreased the enhancement seen with indomethacin; it reduced prostaglandin E2 production by more than 80% and eliminated the differences in response to phytohemagglutinin between Hodgkin-disease and normal lymphocytes. Thus, a glass-adherent, prostaglandin-producing suppressor cell is responsible for the hyporesponsiveness to phytohemagglutinin seen with Hodgkin-disease lymphocytes.

Prostaglandin Suppression of Mitogen-Stimulated Lymphocytes In Vitro: CHANGES WITH MITOGEN DOSE AND PREINCUBATION

In this study we further characterize the properties of the prostaglandin-producing suppressor cell. Overnight preincubation of peripheral blood mononuclear cells results in an increased response of the cells to phytohemagglutinin or Concanavalin A compared to the response of fresh cells. This increase in mitogen response with preincubation was similar in magnitude to the increase in mitogen response of fresh cells after the addition of indomethacin. The two manipulations were not additive; that is, after preincubation, indomethacin caused much less enhancement of mitogen stimulation of peripheral blood mononuclear cells (100 +/- 12% increase before preincubation vs. 12 +/- 6% after preincubation; mean+/-SEM, P < 0.001). Preincubated cells also lose sensitivity to inhibition by exogenous prostaglandin E(2). It requires the addition of 100- to > 1,000-fold more exogenous PGE(2) to produce comparable inhibition of phytohemagglutinin-stimulated preincubated cells than is required for inhibition of phytohemagglutinin-stimulated fresh cells. The enhancing effect of indomethacin increases with decreasing doses of phytohemagglutinin. Indomethacin causes a 1,059+/-134% increase in [(3)H]thymidine incorporation at the lowest dose of phytohemagglutinin (0.2 mug/ml), and a 4+/-3% increase at the highest dose (20 mug/ml). This increase in response to indomethacin with a lower dose of phytohemagglutinin is due to increased sensitivity to inhibition by PGE(2) at lower mitogen doses. The prostaglandin-producing suppressor cell assay and the short-lived suppressor cell assay measure over-lapping phenomena. The increased suppressive effect of the prostaglandin-producing suppressor at suboptimal mitogen dose must be taken into account in the interpretation of any study where the response to a range of mitogen doses is studied.

Suppressor cell function in sarcoidosis.

We investigated the role of suppressor cells in the depressed cellular immunity of patients with sarcoidosis. The mean response in 16 patients with active sarcoidosis to three concentrations of phytohemagglutinin was significantly (P less than 0.01) less than control values. Passage of the cells over glass wool resulted in a 116% increase in response to phytohemagglutinin in patients and a 39% decrease in control subjects. Addition of indomethacin to phytohemagglutinin cultures increased the response of cells in patients with sarcoidosis by 192% +/- 32% versus a 112% +/- 18%-increase for control subjects (mean +/- SEM, P less than 0.05). Patients had an increased percentage of monocytes in peripheral blood mononuclear cell preparations, and the percent monocytes correlated with the percent increase in phytohemagglutinin response after glass wool passage (r = 0.62, P less than 0.05). Thus, several factors contribute to the depressed phytohemagglutinin response in sarcoidosis patients: an increased suppression by the prostaglandin-producing suppressor cell, an increased percentage of monocytes, and an as yet undefined factor.

Exogenous growth hormone treatment alters body composition and increases natural killer cell activity in women with impaired endogenous growth hormone secretion

In order to assess the potential relationship between human growth hormone (GH) and body composition (BC) and natural immunity (NI), we measured the effects of exogenous GH on fat weight (FW), fat-free weight (FFW), and the cytotoxic activity of natural killer (NK) cells in women with impaired GH secretion. Mean peak serum concentrations of GH in response to L-dopa/arginine stimulation were 6.2 +/- 1.1 (SEM) ng/mL in 6 untreated subjects (US) and 5.4 +/- 1.5 ng/mL in 6 GH-treated subjects (TS). Moreover, the pretreatment circulating levels of IGF-I were low in both groups (US 684 +/- 121 mU/mL and TS 583 +/- 83 mU/mL), and they correlated with pretest levels of NK cell activity (r = .59, P less than .05) when both groups were combined. The TS were given 700 micrograms of human GH IM for an average of 14 days while the US were studied in parallel without GH treatment. As measured by hydrodensitometry or skinfold anthropometry, FW decreased (26.1 +/- 6.8 kg to 23.8 +/- 6.3 kg, P less than .05) and FFW increased (44.9 +/- 3.3 kg to 46.2 +/- 3.8 kg, P less than .05) in the TS. In the US, there were no significant (P less than .05) changes in either FW or FFW. Using a standard 51Cr release assay to measure the specific lytic (SL) activity of NK cells, mean SL activity increased from 24.4 +/- 7.0% to 44.1 +/- 8.9% (P less than .05) in the TS, whereas levels in the US were not altered significantly (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Osmolar control of prolactin secretion in man.

To study the effect of changing serum osmolality on serum prolactin concentration 11 volunteers were given oral and intravenous hypotonic and hypertonic fluids. Mean serum prolactin fell to 10.5 percent of baseline after oral water loading and to 15 percent of baseline after intravenous hypotonic saline infusion. Conversely, mean prolactin rose to 417 percent of baseline after intravenous hypertonic saline administration. The correlation coefficient of simultaneously determined serum prolactin and osmolality was highly significant (P 〈 .001). Isoosmolar changes in extracellular fluid volume did not consistently affect the concentration of prolactin in the serum. Thus, prolactin may be involved in the physiologic regulation of osmolar balance and the kidney may be an important farget organ for prolaction.

Body composition of oligo/amenorrheic athletes

Menstrual dysfunction in athletes may be related to low body weight or low body fat content. To investigate the relationship between body composition and menstrual function, body composition was evaluated by hydrostatic weighing in two groups of women: 14 athletes with oligo/amenorrhea and 28 athletes with regular menstruation. Age and height were similar in the two groups. In all of the weight parameters, including total body weight, percent ideal body weight, Livi Index, percent body fat, fat weight, and lean body weight, athletes with oligo/amenorrhea were significantly lighter than athletes with regular menstruation. We concluded that menstrual dysfunction in athletes is associated with low body weight, which is comprised of smaller amounts of both fat and lean body mass.

Supplemental growth hormone alters body composition, muscle protein metabolism and serum lipids in fit adults: characterization of dose-dependent and response-recovery effects

Using double-blind, placebo-controlled procedures, the effects of low and high therapeutic dosages of methionyl-human growth hormone (met-hGH) on body composition, muscle protein metabolism and serum lipids were studied in 7 fit adults without growth hormone (GH) deficiency. Dose-dependent changes in body composition were observed that in part appeared to be influenced by a response-recovery effect, as measured by responses factored according to the duration of washout between exposure to the low and high dosages of met-hGH (6 weeks vs. 12 weeks vs. 18 weeks). Increases in fat-free weight were accompanied by an increase in skeletal muscle protein metabolism. Basal levels of cholesterol were inversely related to peak levels of GH in response to exercise stimulation and IGF-I, while GH supplementation lowered levels of total cholesterol and high- and low-density lipoproteins. A dose-dependent effect occurred for total cholesterol, and the percent change in cholesterol was related to the percent change in insulin-like growth factor I (IGF-I). Endogenous levels of GH were attenuated in response to stimulation and IGF-I levels were increased after treatment with GH, but no dose-dependent changes were observed. We conclude that met-hGH alters body composition and muscle protein metabolism, and decreases stored and circulating lipids in fit adults with a pre-existing supranormal body composition. The physiological profile of the person was not as important as the treatment conditions in determining the somatic and physiological response outcomes.

Growth and somatomedin-C responses to growth hormone in dwarfed children

Nineteen children were studied because of short stature. They had in common abnormally low Sm-C values for age, and each received a ten-day course of exogenous GH therapy. Based on their endogenous GH concentrations and the response to GH therapy, in terms of Sm-C and height increments, they were classified into three groups. Group I included patients with GH insufficiency who had blunted GH responses to stimulation, but responded to therapy by normalizing the Sm-C concentration and velocity of growth. Group II patients all had normal GH responses to stimulation, but their responses to exogenous GH were similar to those observed in the GH deficient subjects. In the two children in Group III who had normal release of endogenous GH, Sm-C values and growth rate did not increase in response to GH. Group II patients may represent children with biologically inactive but immunoreactive GH, whereas the children in Group III are examples of the Laron type of dwarfism. Thus, rather than the plasma GH response to provocative stimuli, the Sm-C and growth increment responses to short-term exogenous GH therapy may more precisely identify children that will benefit from long-term GH therapy.

Direct immunochemical detection of prostaglandin-E and cyclic nucleotides in human malignant tumors.

Immunofluorescent localization of prostaglandin‐E (PGE), cyclic AMP (cAMP), and cyclic GMP (cGMP) was studied in tumor tissues from 40 patients with a variety of solid tumors. Representative normal tissues served as controls. Rabbit antisera specific for PGE or the cyclic nucleotides were used, and the reactions observed were correlated with the degree and type of lymphocytic reaction at the tumor margins. Strong PGE immunofluorescence was detected in tumor cells in 27 of 42 malignancies; by contrast nine of 13 normal tissues showed weak PGE reactions, cAMP was detected in 30 of the 42 malignancies; cGMP was noted in only seven of the 42 malignant tissues and in none of the normal tissues studied. The most common malignant tumor profile (17/42) was that of positive PGE and cAMP and negative cGMP staining. Tumors showing strong staining with anti‐PGE or cAMP demonstrated a distinct trend towards heavier lymphocytic infiltration with a predominance of T cells at their margins, although this association did not reach statistical significance in the present material.

299 A NEW SYNDROME OF SHORT STATURE DUE TO BIOLOGICALLY INACTIVE BUT IMMUNOREACTIVE GROWTH HORMONE

A 25 month old girl was first seen because of growth deceleration beginning at 3 months of age. Birth weight was 6½ lbs. and length 19″. P. examination was normal except for a height-age of 13 months. After estrogen priming a growth hormone (GH) stimulation test following sequential L-Dopa, arginine and glucagon peaked at 124 ng/ml from a base-line of 63 ng/ml. Serum somatomedin-C (Sm-C) concentration, both basal and post-stimulation, measured 0.24 U/ml. (N1. 1.5±0.5 U/ml. Measured by Dr. L. Underwood, Univ. of North Carolina, Chapel Hill). At the end of a 24 hour fast her blood glucose was 68 mg%. GH was given for 6 days and her Sm-C level increased to 0.43 U/ml. Four months later her metabolic response to the administration of GH for 6 days showed: release of FFA from 757 to 1341 μM/1 and no increase in urinary Ca++. Again her Sm-C increased from 0.19 to a peak of .73 U/ml. Prior to GH, her basal GH levels ranged from 8 to 14 ng/ml. By RIA her GH produced a parallel dose-response to pituitary GH standard. After the above study, the patient was discharged on GH, 0.1 U/kg three times a week. In the last 2 months her growth rate has increased from 0.5 to 1/cm/month. The data on this patient appear to rule out a defect in Sm-C synthesis or function, as well as factors, either inhibiting GH action or receptor function. The growth deceleration could be explained on the basis of an abnormal circulating GH molecule.