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PubMed1998

[Mutations in the genes of the HNF-family cause maturity-onset diabetes of the young (MODY)].

Maturity-onset diabetes of the young (MODY) is a monogenic form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by an early age of onset, often in childhood or adolescence and usually < 25 years of age, and autosomal dominant inheritance. Clinical characterization of patients with MODY indicates that impaired insulin secretion is the primary defect responsible for the hyperglycemia in these patients. Genetic studies have thus far identified five MODY susceptibility genes, four of which encode transcription factors; HNF (hepatocyte nuclear factor)-1 alpha, HNF-1 beta, HNF-4 alpha, and IPF1. The association of mutations in the genes for these transcription factors with early-onset familial diabetes indicates the importance of the HNF-regulatory network in determining pancreatic beta-cell function.

Adolescent↗
PubMed1981

The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation.

The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was investigated in six patients. In five patients in whom acidosis failed to lower the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pCO2) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pCO2 normally with the administration of phosphate, demonstrating that this patient's distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone deficiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion ion response to stimulation with sodium sulfate or acetazolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement (C3) along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection.

Acidosis, Renal Tubular↗
PubMed1994

Endocytosis is required for the growth of vacuolar H(+)-ATPase-defective yeast: identification of six new END genes.

Yeast mutants that are defective in acidification of the lysosome-like vacuole are able to grow at pH 5.5, but not at pH 7. Here, we present evidence that endocytosis is required for this low pH-dependent growth and use this observation to develop a screen for mutants defective in endocytosis. By isolating mutants that cannot grow when they lack the 60-kD vacuolar ATPase subunit (encoded by the VAT2 gene), we isolated a number of vat2-synthetic lethal (Vsl-) mutant strains. Seven of the Vsl- mutants are defective in endocytosis. Four of these mutant strains (end8-1, end9-1, end10-1, and end11-1) show altered uptake of the endocytosed ligand, alpha-factor, and three (end12-1, end12-2, and end13-1) are probably defective in transfer of internalized material to the vacuole. Most of the mutations also confer a strong Ts- growth defect. The mutants defective in uptake of alpha-factor sort newly synthesized vacuolar proteins correctly, while those which may be defective in subsequent transport steps secrete at least a fraction of the newly synthesized soluble vacuolar proteins. The mutations that result in a defect in alpha-factor uptake are not allelic to any of the genes previously shown to encode endocytic functions.

Carboxypeptidases↗
PubMed2005

Munc18c heterozygous knockout mice display increased susceptibility for severe glucose intolerance.

The disruption of Munc18c binding to syntaxin 4 impairs insulin-stimulated GLUT4 vesicle translocation in 3T3L1 adipocytes. To investigate the physiological function and requirement for Munc18c in the regulation of GLUT4 translocation and glucose homeostasis in vivo, we used homologous recombination to generate Munc18c-knockout (KO) mice. Homozygotic disruption of the Munc18c gene resulted in early embryonic lethality, whereas heterozygous KO mice (Munc18c(-/+)) had normal viability. Munc18c(-/+) mice displayed significantly decreased insulin sensitivity in an insulin tolerance test and a >50% reduction in skeletal muscle insulin-stimulated GLUT4 translocation when compared with wild-type (WT) mice. Furthermore, glucose-stimulated insulin secretion was significantly reduced in islets isolated from Munc18c(-/+) mice compared with those from WT mice. Despite the defects in insulin action and secretion, Munc18c(-/+) mice demonstrated the ability to clear glucose to the same level as WT mice in a glucose tolerance test when fed a normal diet. However, after consuming a high-fat diet for only 5 weeks, the Munc18c(-/+) mice manifested severely impaired glucose tolerance compared with high-fat-fed WT mice. Taken together, these data suggest that the reduction of Munc18c protein in the Munc18c(-/+) mice results in impaired insulin sensitivity with a latent increased susceptibility for developing severe glucose intolerance in response to environmental perturbations such as intake of a high-calorie diet rich in fat and carbohydrate.

Animals↗
PubMed2001

New antidiabetic medications. Clinical evidence, clinical practice and pharmacoeconomics.

BACKGROUND: Type 2 diabetes is a progressive and complex disease with underlying defects in insulin sensitivity, insulin secretion and hepatic glucose production. There is a range of antidiabetic treatment options now available to address these defects. Determination of which therapy for which patient is not always apparent from the clinical literature or the product information. OBJECTIVE: To summarise the extent and use of clinical evidence, clinical practice and pharmacoeconomics in positioning antidiabetic agents in Australian clinical practice. DISCUSSION: This paper summarises the introduction of new agents into the options for treatment of type 2 diabetes through the Pharmaceutical Benefits Scheme. Combining evidence based medicine, accepted clinical practice and decision analysis, allows the controlled introduction of new therapies in a climate of limited resources and a population with increasing therapeutic needs.

Australia↗
PubMed2000

Nonatopic wheezy children have reduced interferon-gamma.

Viruses cause asthmatic exacerbations in schoolchildren. We tested the hypothesis that children who wheezed with viral respiratory tract infections secrete higher levels of the type 1 cytokine interferon-gamma (IFN-gamma) in the peripheral circulation than children who had never wheezed. Blood was taken from 13 children (eight atopic) with episodic wheeze and 11 controls. CD4 and CD8 cells were separated from peripheral blood mononuclear cells and stimulated with phorbol 12-myrisate 13-acetate (PMA) and ionomycin for 24 h. IFN-gamma, IL-4, and IL-5 were measured in the supernatant by ELISA. IFN-gamma production by CD4 and CD8 cells was lower in children with a history of wheeze (CD4, P = 0.046; CD8, P = 0.037). These children were then analysed according to atopic status. CD4 and CD8 IFN-gamma production in nonatopic wheezy children was reduced (CD4, P=0.009; CD8, P=0.003). IFN-gamma production by atopic wheezy children was lower than by controls, but the differences were not significant (CD4, P = 0.2831; CD8, P = 0.1372). CD8 IL-5 was lower in children who wheezed (P=0.012). Release of IL-4 and IL-5 by CD4 cells did not differ between the three groups. We propose that defective IFN-gamma secretion by CD4 and CD8 cells may contribute to viral-induced wheeze in nonatopic children.

CD4-Positive T-Lymphocytes↗
PubMed2005

Tetramethylpyrazine stimulates cystic fibrosis transmembrane conductance regulator-mediated anion secretion in distal colon of rodents.

AIM: To investigate the effect of tetramethylpyrazine (TMP), an active compound from Ligustium Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved. METHODS: The short-circuit current (I(SC)) technique in conjunction with pharmacological agents and specific inhibitors were used in analyzing the electrolyte transport across the distal colon of rodents. The underlying cellular signaling mechanism was investigated by radioimmunoassay analysis (RIA) and a special mouse model of cystic fibrosis. RESULTS: TMP stimulated a concentration-dependent rise in I(SC), which was dependent on both Cl(-) and HCO(3)(-), and inhibited by apical application of diphenylamine-2,2'-dicarboxylic acid (DPC) and glibenclamide, but resistant to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS). Removal of Na(+) from basolateral solution almost completely abolished the I(SC) response to TMP, but it was insensitive to apical Na(+) replacement or apical Na(+) channel blocker, amiloride. Pretreatment of colonic mucosa with BAPTA-AM, a membrane-permeable selective Ca(2+) chelator, did not significantly alter the TMP-induced I(SC). No additive effect of forskolin and 3-isobutyl-1-methylxanthine (IBMX) was observed on the TMP-induced I(SC), but it was significantly reduced by a protein kinase A inhibitor, H(89). RIA results showed that TMP (1 mmol/L) elicited a significant increase in cellular cAMP production, which was similar to that elicited by the adenylate cyclase activator, forskolin (10 micromol/L). The TMP-elicited I(SC) as well as forskolin- or IBMX-induced I(SC) were abolished in mice with homozygous mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) presenting defective CFTR functions and secretions. CONCLUSION: TMP may stimulate cAMP-dependent and CFTR-mediated Cl(-) and HCO(3)(-) secretion. This may have implications in the future development of alternative treatment for constipation.

Adrenergic beta-Agonists↗
PubMed1999

Metabolic characteristics of individuals with impaired fasting glucose and/or impaired glucose tolerance.

With the release of the new 1997 American Diabetes Association diagnostic criteria, a new category was introduced, termed "impaired fasting glucose" (IFG). The metabolic abnormalities of individuals with IFG, compared with those with impaired glucose tolerance (IGT) (World Health Organization criteria), remain to be elucidated. We assessed insulin action (hyperinsulinemic clamp), insulin secretion (25-g intravenous glucose tolerance test), and endogenous glucose output (EGO) (3-(3)H-glucose) in 434 nondiabetic Pima Indians with either normal (NFG; <6.1 mmol/l) or impaired (IFG; 6.1-7.0 mmol/l) fasting glucose and with either normal (NGT; 2-h glucose <7.8 mmol/l) or impaired (IGT; 2-h glucose 7.8-11.1 mmol/l) glucose tolerance: NFG/NGT (n = 307), IFG/NGT (n = 11), NFG/IGT (n = 98), and IFG/IGT (n = 18). Compared with the NFG/NGT group, individuals with IFG/NGT had lower maximal insulin-stimulated glucose disposal (M; -20%, P < 0.01), a lower acute insulin response (AIR) to intravenous glucose (-33%, P < 0.05), and higher EGO (8%, P = 0.055). Individuals with NFG/IGT also had lower M (-21%, P < 0.001) and lower AIR (-8%, P < 0.05), but normal EGO (-1%, NS). Individuals with IFG/IGT showed the most severe abnormalities in M (-27%), AIR (-51%), and EGO (+13%) (all P < 0.001 compared with NFG/NGT). These group differences could be explained by the observation that AIR and EGO, but not M, were more strongly related to the fasting than to the 2-h glucose concentration. Thus, Pima Indians with isolated IFG and isolated IGT show similar impairments in insulin action, but those with isolated IFG have a more pronounced defect in early insulin secretion and, in addition, increased EGO. More severe metabolic abnormalities are present in Pima Indians with combined IFG and IGT.

Adult↗
PubMed1989

Type II diabetes, glucose "non-sense," and islet desensitization.

A universal finding in hyperglycemic patients with type II (non-insulin-dependent) diabetes mellitus is that all share a common defect in glucose recognition resulting in abnormal insulin secretion by pancreatic islet beta-cells. This defect is 1) specific for glucose signals rather than global, 2) related to chronic hyperglycemia, and 3) partially reversible after brief treatment with insulin to induce normoglycemia and through use of other pharmacological agents without normalizing glucose levels. My perspective is that an essential component of this defect is secondary and may represent a state of homologous desensitization of the beta-cell secretory apparatus to glucose. Elucidation of the biochemical mechanism(s) of defective recognition of glucose signals by beta-cells--or glucose "non-sense"--in these patients will provide key insights into the pathogenesis of type II diabetes mellitus.

Diabetes Mellitus, Type 2↗
PubMed2000

The Tetrahymena homolog of bacterial and mammalian 4-hydroxyphenylpyruvate dioxygenases localizes to membranes of the endoplasmic reticulum.

The expression and intracellular localization of the Tetrahymena homolog of 4-hydroxyphenylpyruvate dioxygenase (HPPD) were investigated in wild-type Tetrahymena thermophila strain B1868 VII and the mutant strains IIG8, defective in food vacuole formation, MS-1, blocked in secretion of lysosomal enzymes, and SB 281, defective in mucocyst maturation. Immunoelectron microscopy and confocal laser scanning microscopy demonstrated that Tetrahymena HPPD primarily localized to membranes of the endoplasmic reticulum. In addition, Tetrahymena HPPD was detected in association with membranes of the Golgi apparatus, and transport vesicles in exponentially growing wild-type and mutant strains. In starved cells, Tetrahymena HPPD localized exclusively to membranes of small vesicles. Since no de novo synthesis of Tetrahymena HPPD takes place in cells starved for more than 30 min, these results suggest that there is a flow of Tetrahymena HPPD from the endoplasmic reticulum to small vesicles, possibly via the Golgi apparatus, and that Tetrahymena HPPD contains a signal for vesicle membrane retrieval or retention.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1986

T and B cell function in alcoholic liver disease.

Increased in vivo synthesis of immunoglobulin in patients with alcoholic liver damage has been attributed to direct activation of B cells, although other defects of lymphocyte function have been identified suggesting a more generalised defect. In the present study we have investigated the role of T cell regulation of immunoglobulin production in alcoholic liver disease analysed according to the presence or absence of alcoholic hepatitis. Spontaneous production of IgG and IgA was elevated and co-culture experiments confirmed hyper-reactivity of B cells, but also suggested impaired T cell function. Suppressor cell activity for IgG and IgA was impaired. Similarly, the response to pokeweed mitogen for IgG and IgA was defective, although this was more marked for secretion than for proliferation suggesting an associated T helper defect. No differences in the immunological abnormalities were identified between those with alcoholic hepatitis and those with other alcoholic liver diseases. This study demonstrates a broad defect of T cells and a hyper-reactivity of B cells in patients with alcoholic liver disease, irrespective of the severity of hepatic inflammation.

Adult↗
PubMed1997

Effect of anion transport inhibition on mucus secretion by airway submucosal glands.

To model the airway glandular defect in cystic fibrosis (CF), the effect of anion secretion blockers on submucosal gland mucus secretion was investigated. Porcine distal bronchi were isolated, pretreated with a Cl- secretion blocker (bumetanide) and/or a combination of blockers to inhibit HCO3- secretion (dimethylamiloride, acetazolamide, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid), and then treated with acetylcholine (ACh), a glandular liquid and mucus secretagogue. Bronchi were then fixed, sectioned, and stained for mucins. Each gland duct was ranked for mucin content from zero (no mucin) to five (duct completely occluded with mucin). Untreated bronchi, bronchi treated only with ACh, and ACh-treated bronchi that received either bumetanide or the HCO3- secretion blockers all exhibited low gland duct mucin content (1.18 +/- 0.34, 0.59 +/- 0.07, 0.65 +/- 0.03, and 0.83 +/- 0.11, respectively). However, pretreatment with both Cl- and HCO3- secretion blockers before ACh addition resulted in substantial and significant ductal mucus accumulation (3.57 +/- 0.22). In situ videomicroscopy studies of intact airways confirmed these results. Thus inhibition of the anion (and presumably liquid) secretion response to ACh leads to mucus obstruction of submucosal gland ducts that resembles the early pathological changes observed in CF.

Acetylcholine↗
PubMed1991

Alterations in function and phenotype of monocytes from patients with septic disease--predictive value and new therapeutic strategies.

Recently we described the predictive value of the proportion of HLA-DR+ peripheral blood monocytes for the clinical outcome of septic disease in immunosuppressed patients (allograft recipients) and surgical patients mostly with peritonitis as septic focus (following perforation of gastrointestinal tract). The experiments described here show that the loss of HLA-class II antigen expression and other phenotypical abnormalities of monocytes from septic patients with fatal outcome are associated with functional defects (antigen presentation, formation of reactive oxygen species, cytokine secretion). The picture of phenotypical and functional defects of monocytes was termed "immunoparalysis" (leading parameter: loss of HLA-DR antigen expression less than 20%). Interferon-gamma as well as GM-CSF normalized in vitro the surface antigen expression on monocytes derived from septic patients with "immunoparalysis". However, sera from patients with "immunoparalysis" prevented the cytokine-mediated effects on HLA-DR antigen expression. The inhibitory activity in septic sera was not dialysable. In order to remove such factors we started a plasmapheresis study in septic patients selected for "immunoparalysis". The preliminary data of this clinical trial suggest an improved survival rate.

Antibodies, Monoclonal↗
PubMed1989

LHRH pulse frequency in normal and infertile men.

The aim of this study was to examine the hypothesis that decreased LHRH pulse frequency may be responsible for the preferential rise in FSH in infertile men. The LH pulse pattern was determined as an index of hypothalamic LHRH secretion in 21 infertile patients with idiopathic azoospermia or oligoasthenozoospermia and 14 fertile age-matched controls by frequent blood sampling at 10-min intervals for 24 h. The infertile patients were further divided into three groups according to their relative concentrations of FSH and LH: (1) normal FSH and LH, (2) raised FSH but normal LH, and (3) raised FSH and LH. LH pulses were detected by a computerized algorithm (Munro) validated against a threshold method. Concentrations of FSH, testosterone, sex hormone-binding globulin and oestradiol were measured in pooled plasma. Luteinizing hormone pulse frequencies in normal men were not significantly different from the infertile group as a whole. Similarly, mean LH pulse frequencies in infertile subgroups 1, 2 and 3 were not significantly lower than normal. Pulse interval, however, was increased in subgroup 1 compared with normal. Mean 24 h LH in group 2 was significantly higher than normal, but still within the normal range. The total testosterone, but not the free testosterone index was significantly decreased in the infertile group compared with normal. There was no correlation between mean FSH and LH pulse frequency or interval. In conclusion, our results show that in patients with seminiferous tubular dysfunction, the typical pattern of raised plasma FSH, increased LH pulse amplitude, raised FSH: LH ratio and normal or marginally low testosterone was not associated with any significant deviations in LHRH pulse frequency from the range observed in normal fertile men. This is not compatible with the hypothesis that decreased LHRH pulse frequency is associated with or the cause of the preferential rise in FSH in men with idiopathic infertility. Thus unlike anovulatory infertility in females, functional defects of hypothalamic LHRH secretion remain an uncommon finding in male infertility. Attempts to treat idiopathic oligozoospermia by altering LHRH pulse frequency is therefore unlikely to yield any clinical benefit.

Adult↗
PubMed1987

Glycoprotein hormone genes are expressed in clinically nonfunctioning pituitary adenomas.

Approximately 25% of patients with pituitary adenomas have no clinical or biochemical evidence for excess hormone secretion and are classified as having null cell or nonfunctioning adenomas. To characterize the cell type of these tumors, we analyzed pituitary hormone gene expression in clinically nonfunctioning pituitary adenomas using specific oligonucleotide probes for the messenger (m)RNAs encoding growth hormone, prolactin, ACTH, and the glycoprotein hormone subunits, alpha, luteinizing hormone (LH)beta, follicle-stimulating hormone (FSH)beta, and thyroid-stimulating hormone (TSH)beta. Expression of one or more of the anterior pituitary hormone genes was found in 12/14 (86%) of the patients with clinically classified nonfunctioning adenomas. Expression of one or more of the glycoprotein hormone genes (alpha, LH beta, FSH beta, TSH beta) was identified most commonly (79%) with expression of multiple beta-subunit genes in many cases. Expression of alpha-subunit mRNA was found in each of the adenomas from patients expressing one of the beta-subunit mRNAs and in three patients with no detectable beta-subunit mRNA. Although FSH beta and LH beta mRNAs were found with similar frequencies in nonfunctioning adenomas, expression of FSH beta mRNA was generally much more abundant. TSH beta mRNA was detected in only one adenoma. The levels of glycoprotein hormone subunit mRNAs were variable in different adenomas, but the lengths of the mRNAs and transcriptional start sites for the alpha- and beta-subunit genes were the same in the pituitary adenomas and in normal pituitary. Growth hormone and prolactin gene expression were not observed in the nonfunctioning adenomas, but ACTH mRNA was found in a single case. Immunohistochemistry of the adenomas confirmed production of one or more pituitary hormones in 13/14 (93%) nonfunctioning tumors, with a distribution of hormone production similar to that of the hormone mRNAs. These data indicate that pituitary adenomas originating from cells producing glycoprotein hormones are common, but are difficult to recognize clinically because of the absence of characteristic endocrine syndromes and defective hormone biosynthesis and secretion.

Adenoma↗
PubMed2001

beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms.

Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial defect in early or first-phase insulin secretion, followed by a decreasing maximal capacity of glucose to potentiate all nonglucose signals. Last, a defective steady-state and basal insulin secretion develops, leading to complete beta-cell failure requiring insulin treatment. This functional loss exceeds the expected impact of a 20-50% loss of beta-cells reported at autopsy, which has been associated with amyloid deposits. This review summarizes the nature of the amyloid deposition process and its association with disproportionate hyperproinsulinemia. It reviews recent studies in IAPP (islet-amyloid polypeptide, or amylin) transgenic mice developing islet amyloid deposits and hyperglycemia to suggest that the process of amyloid fibril formation impairs function early and leads to beta-cell failure and eventual death. Based on the known association of amyloid deposits and relative hyperproinsulinemia, it is hypothesized that fibril formation begins during impaired glucose tolerance after other factors cause the initial defects in early insulin secretion and insulin action. Thus, the process that leads to beta-cell loss is implicated in the deposition of amyloid and the late unrelenting progressive hyperglycemia now found in all patients despite current therapies.

Amyloid↗
PubMed1990

Mechanisms of impaired growth hormone secretion in genetically obese Zucker rats: roles of growth hormone-releasing factor and somatostatin.

GH secretion is markedly blunted in obesity; however, the mechanism(s) mediating this response remains to be elucidated. In the present study we examined the involvement of the two hypothalamic GH-regulatory hormones, GH-releasing factor (GRF) and somatostatin (SRIF), using the genetically obese male Zucker rat. Spontaneous GH, insulin, and glucose secretory profiles obtained from free moving, chronically cannulated rats revealed a marked suppression in amplitude and duration of GH pulses in obese Zucker rats compared to their lean littermates (mean 6-h plasma GH level, 3.9 +/- 0.4 vs. 21.5 +/- 3.8 ng/ml; P less than 0.001). Obese rats also exhibited significant hyperinsulinemia in the presence of normoglycemia. The plasma GH response to an iv bolus of 1 microgram rat GRF-(1-29)NH2, administered during peak and trough periods of the GH rhythm, was significantly attenuated in obese rats at peak (137.4 +/- 26.1 vs. 266.9 +/- 40.7 ng/ml; P less than 0.02), although not at trough, times. Passive immunization of obese rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values; the mean 6-h plasma GH level of obese rats given SRIF antiserum was not significantly different from that of obese rats administered normal sheep serum. Both pituitary wet weight and pituitary GH content and concentration were reduced in the obese group. Measurement of hypothalamic GRF immunoreactivity revealed a significant (P less than 0.05) reduction in the mediobasal hypothalamic GRF content in obese rats (503.2 +/- 60.1 pg/fragment) compared to that in lean controls (678.1 +/- 50.2 pg/fragment), although no significant difference was observed in hypothalamic SRIF concentration. Peripheral SRIF immunoreactive levels were significantly (P less than 0.01) elevated in both the pancreas and stomach of obese rats. These results demonstrate that the genetically obese Zucker rat exhibits 1) marked impairment in both spontaneous and GRF-induced GH release, which cannot be reversed by SRIF immunoneutralization, 2) significant reduction in pituitary GH concentration, 3) depressed hypothalamic GRF content, and 4) elevated gastric and pancreatic, but not hypothalamic, SRIF levels. The findings suggest that the defect in pituitary GH secretion observed in the genetically obese Zucker rat is due, at least partially, to insufficient stimulation by hypothalamic GRF, and that SRIF does not play a significant role.

Animals↗
PubMed1999

IL-13 and IFN-gamma secretion by activated T cells in HIV-1 infection associated with viral suppression and a lack of disease progression.

The immunopathology of HIV-1 infection includes immune defects in T cell cytokine secretion, resulting in decreased Ag-specific responses. In this report, IL-13 and IFN-gamma were analyzed in progressive HIV-1 disease. Both cytokines exert positive effects on Ag presentation and inhibit HIV-1 infection of macrophages. Anti-CD3/anti-CD28-activated PBMC from HIV-1-infected individuals (n = 74) compared with uninfected subjects (n = 30) secreted significantly less IL-13 (median, 0.64 ng/ml vs 2.07 ng/ml; p < 0. 001) and IFN-gamma (median, 40.96 ng/ml vs 129.5 ng/ml; p < 0.005). Decreased IL-13 and IFN-gamma secretion in HIV infection was present in sorted CD4+ and CD8+ T cell subsets, and additional analysis determined concurrent deficiency at the protein and transcriptional level. Longitudinal analysis showed that cytokine secretion levels correlated positively with CD4 count and negatively with plasma HIV-1 viral load. Patients changing to suppressive antiretroviral therapy during the study showed increases in IL-13 and IFN-gamma secretion. Overall, results show a decline in IL-13 and IFN-gamma secretion in progressive HIV-1 infection and suggest a role for both cytokines as part of T cell adaptive responses associated with a lack of disease progression.

CD4-Positive T-Lymphocytes↗