Low Responder Group Research Articles

X-linked recessive inheritance of a defective responsiveness to T-cell-replacing factor in DBA/2Ha mice

TRF responsivity of B-cells from an F1 hybrid of the low-responder strain DBA/2Ha (♀) and the high-responder strain BALB/c (♂), or their reciprocal F1 hybrid(BALB/c(♀) ×DBA/2Ha(♂)), was analyzed. In every case the B-cells from all of the male mice of the (DBA/2Ha×BALB/c) (DC)F1 hybrid were incapable of responding to TRF, whereas B-cells from female mice of the same litter responded to TRF. In contrast, B-cells from both male and female (BALB/c×DBA/2Ha>) (CD)F1 mice were able to respond to TRF, strongly suggesting that the responsivity of B-cells to TRF is controlled by the X-chromosome of the high-response animals.To substantiate further the evidence for a X-linked B-cell defect in DBA/2Ha mice, we analyzed TRF responsivity of B-cells from back-cross (DCF1 (♀) ×DBA/2Ha(♂)) progeny and fromF2 (DCF1 ×DCF1>) progeny, respectively. In both crosses we observed segregation of TRF responsivity into high-responder and low-responder groups in a nearly1:1 ratio. These findings further indicated that a major component involved in the regulation of TRF responsivity is carried on the X-chromosome. This component is defective in DBA/2Ha mice, the defect being inherited in a recessive manner.

792 FACTOR VIII INHIBITOR RESPONSE TO CYCLOPHOSPHAMIDE (C)

Immunosuppressive therapy for Factor VIII inhibitors has been studied by different investigators with variable results. Over a 6 year period, 68 patients with Factor VIII inhibitors were randomized into 3 separate protocols: The high responder group showed 3 separate patterns: 1) reduction of inhibitor & prevention of anamnestic response as long as cyclo-phosphamide therapy was maintained; 2) disappearance of inhibitor & no recurrence when exposed to Factor VIII after cyclophos-phamide therapy termination; 3) persistence of inhibitor but in low responder range without anamnestic response to Factor VIII infusions after cyclophosphamide therapy termination. Controls developed an anamnestic inhibitor response each time they were exposed to Factor VIII. The low responder group showed 2 patterns: 1) disappearance of inhibitor without recurrence when exposed to Factor VIII; 2) persistence of inhibitor in low responder range. The low responders reacted the same during immunosuppression & after termination of the immunosuppression therapy. Controls showed the same results as the protocol group. It is evident from these results that immunosuppression was apparently unnecessary for the low responders but gave beneficial results with the high responders.

Cholesterol absorption and turnover in rhesus monkeys as measured by two methods.

We compared the absorption of cholesterol in seven rhesus monkeys (four high-responders and three low-responders) as measured by two methods: 1) the dual isotope plasma ratio method of Zilversmit (1972. Proc. Soc. Exp. Biol. Med. 140: 862) and 2) the single isotopic meal feeding technique of Borgström (1969. J. Lipid Res. 10: 331). We also compared the cholesterol pool sizes calculated by kinetic analysis of the plasma cholesterol specific activity decay curves obtained after simultaneous administration of [(3)H]- and [(14)C]cholesterol, one given intravenously and the other orally. The ratio of orally to intravenously administered cholesterol radioactivity in plasma did not attain constancy until 6 weeks after isotope administration. Therefore, the percent absorption of cholesterol was calculated by the Zilversmit method 8 weeks after the administration of isotopes. The mean percent absorption of cholesterol by the Borgström method was 66.3 +/- 5.1 (S.E.) and by the Zilversmit method was 70.3 +/- 7.4. The differences were not statistically significant. However, in two of seven monkeys the percent absorption of cholesterol calculated by the Zilversmit method was higher by 10.4 and 22.6 percentage points than the values obtained by the Borgström method. Cholesterol absorption by either method was higher in the high-responding monkeys than in the low-responding group. The sizes of the rapidly exchangeable pool or the minimum estimate of the total body pool of cholesterol were similar for all monkeys or for either the low-responding or the high-responding animals and were also similar when calculated using the data from either the orally or the intravenously administered radioactive cholesterol. Cholesterol synthesis was significantly higher in the low-responding monkeys (115 mg/day) than in the high-responding (64 mg/day). The present study and our previous studies support the hypothesis that a major factor causing the difference in response of plasma cholesterol to dietary cholesterol between the high- and low-responding rhesus monkeys is a difference in the intestinal absorption of cholesterol.-Bhattacharyya, A. K., and D. A. Eggen. Cholesterol absorption and turnover in rhesus monkeys as measured by two methods.

Suppressor Adherent Cells in Human Tuberculosis

Abstract Patients with newly diagnosed active pulmonary tuberculosis were divided into high and low responder groups on the basis of 3H-thymidine incorporation of peripheral blood mononuclear cells (PB MNC) induced by tuberculin-purified protein derivative (PPD). The group of patients with low tuberculin responses was characterized by anergy to tuberculin skin testing and larger numbers of circulating monocytes than the high responders. The groups were comparable in the extent of pulmonary tuberculosis and other clinical parameters. PB MNC from tuberculin low responders had normal phytohemagglutinin (PHA) but depressed streptokinase-streptodornase (SKSD), Candida antigen, and tetanus toxoid-induced 3H-thymidine incorporation. Depletion of adherent cells resulted in a mean 24.4-fold enhancement of T lymphocyte responses to PPD in the low responders as compared to a 2.9-fold increase in the high responders. The low response of PB MNC from low responders to nonmycobacterial antigens was not similarly augmented by adherent cell depletion. Adding back graded numbers of adherent cells to purified T lymphocyte populations resulted in greater depression of the PPD-induced proliferative response to the tuberculin low responders when compared to the high responders. These studies provide evidence for circulating suppressor adherent cells in tuberculosis patients with diminished responsiveness to PPD in vitro. This immunosuppression is not mediated by adherent cell supernatant products, nor does it involve T lymphocyte labile during culture. However, complex cellular interactions, possibly involving suppressor T cells, are implicated by the restriction of this phenomenon to PPD-induced lymphocyte activation and the depression of the PB MNC responses to nonmycobacterial antigens. The suppressor adherent cells defined in these studies may be relevant as a cause or consequence of infection in a subset of patients with tuberculosis.

IMMUNOPATHOGENICITY AND ONCOGENICITY OF MURINE LEUKAEMIA VIRUS: IV. ANTINUCLEAR ANTIBODY RESPONSE AND TUMOUR INDUCTION IN B10.A. RECOMBINANT MICE

The levels of murine leukaemia virus (MuLV) proteins p30 and gp70, antinuclear antibody (ANA), anti-soluble nuclear protein, anti-single-stranded DNA, anti-double-stranded DNA and anti-histone antibodies were measured in B10.A and B10.A recombinant mice neonatally infected with MuLV-Scripps (Lerner et al., 1972). The incidence and latency of lymphoma and the incidence of glomerulonephritis were also determined. The mice studied could be divided into high-responder and low-responder groups. Most of the high ANA antibody could be attributed to anti-histone antibody. High response was associated with the H-2b haplotype and recombinant strains on the B10 background which were identical at the I-A subregion derived from the H-2b parental stock. In contrast, low ANA response was associated with the I-A subregion derived from the H-2k haplotype. In all groups of virus-inoculated animals, most animals developed serum elevations of p30 and gp70 and at least 72% of the inoculated animals developed lymphomas. High serum p30 levels correlated inversely with latency and directly with gp70 values. From 4 to 28% of the animals in each virus-inoculated group had histological evidence of glomerulonephritis, although no clear genetic basis could be ascribed to the incidence of glomerulonephritis, serum p30 or gp70 levels, or latency of lymphoma development.

Cholesterol metabolism in groups of rhesus monkeys with high or low response of serum cholesterol to an atherogenic diet

Cholesterol metabolism has been studied in two groups of five rhesus monkeys each that were selected from the upper and lower sextile in the distribution of serum cholesterol concentration while being fed an atherogenic diet. This diet consisted of a basal commercial monkey food supplemented with saturated fat and cholesterol. To determine differences that might be related to the difference in serum cholesterol concentration, parameters of whole body cholesterol metabolism were measured while the animals were fed the supplemented diet again while they were fed the basal diet. Serum cholesterol and triglyceride concentrations were greater in the high-respoonding (HI) than in the low-responding (LO) groups during both diet periods. Percent of luminal cholesterol absorbed was also greater in the HI than in the LO group during both diet periods. The increase in fecal excretion of endogenous neutral steroids during the period when the atherogenic diet was fed was similar in the two groups; however the increase in excretion of bile acids was greater in the HI than in the LO group. The three-pool model was used for analysis of decay of serum cholesterol specific activity after a tracer pulse dose. The mean size of the total miscible body pool and of pools 1 and 3 (but not pool 2) was greater in both groups when the atherogenic diet was fed than during basal diet feeding. The distribution of the increment in total body pool between pool 1 and the peripheral pools was similar in the two groups. The distribution of the increment in cholesterol of pool 1 between serum and other tissues was also similar for the two groups. There was an indication that a constant cholesterol pool size was not attained even after feeding the atherogenic diet for 8 months. This study indicates that the difference in serum cholesterol concentration between LO and HI responders is, in part, a result of differences in rate of intestinal absorption of cholesterol.

Patterns of free fatty acids, glycerol, D-beta-hydroxybutyrate and insulin in pregnant women and their newborn infants. Effects of a low and a high insulin response to glucose in the mothers.

Twenty-eight healthy women, 17 with high and 11 with low insulin response to glucose but with normal glucose tolerance, were followed throughout pregnancy. Plasma FFA, glycerol and D-beta-hydroxybutyrate as well as plasma insulin and glucose in blood were determined before and during a glucose infusion test (GIT) in each trimester and after pregnancy. In 13 infants of high insulin responders (IHR) and 10 infants of low responders (ILR) an intravenous glucose tolerance test (IVGTT) was performed, and the above lipid parameters were studied at birth and during the IVGTT. The low responder group was postulated to consist mainly of prediabetic individuals (8). Their infants have previously been shown to have an increased glucose assimilation rate at IVGTT (12, 13), as has been shown for infants of diabetic mothers. There was little difference between the two groups of mothers except for the insulin levels during the GIT in non-pregnant and early pregnant subjects, which were considerably lower in the low responders. They all had decreased fasting levels of FFA, glycerol, and D-beta-hydroxybutyrate in mid-pregnancy and normal values in late pregnancy. The ILR showed the same changes in FFA and glycerol as the IHR, but their D-beta-hydroxybutyrate levels were higher at birth than those of the IHR and lower after birth. Another difference found, was the correlation between birth weight and fasting insulin (and to some extent the insulin level at birth) in the ILR group, which was not found in the IHR. Apart from those differences the ILR and the IHR seemed to handle their fat metabolism in a similar way in the early neonatal perinatal period.