Showing papers by "University of Texas Southwestern Medical Center published in 1978"

On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition?

Abstract: In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.

The lymphoreticular system in triggering virus plus self-specific cytotoxic T cells: evidence for T help.

Abstract: The thymus determines the spectrum of the receptor specificities of differentiating T cells for self-H-2; however, the phenotypic expression of T cell's specificity for self plus virus is determined predominantly by the H-2 type of the antigen presenting cells of the peripheral lymphoreticular system Furthermore, virus specific helper T cells are essential for the generation of virus-specific cytotoxic T cells For cooperation between mature T cells and other lymphocytes to be functional in chimeras, thymic epithelial cells and lymphohemopoietic stem cells must share the I region; killer T-cell generation also requires in addition compatibility for at least one K or D region These conclusions derive from the following experiments: A leads to (A X B)F1 chimeric lymphocytes do produce virus-specific cytotoxic T-cell activity for infected A but not for infected B cells; when sensitized in an acutely irradiated and infected recipient (A X B)F1 these chimeric lymphocytes respond to both infected A and B Therefore the predominantly immunogenically infected cells of chimeras the radiosensitive and by donor stem cells replaced lymphoreticular cells In this adoptive priming model (KAIA/DB leads to KAIA/DC) chimeric lymphocytes could be sensitized in irradiated and infected F1 against KA and DC but not against infected DB targets In contrast KBIB/DA leads to KCIC/DA chimeras' lymphocytes could not be sensitized at all in appropriately irradiated and infected F1 recipients Thus these latter chimeras probably lack functional I-specific T helper cells that are essential for the generation of T killer cells against infected D compatible targets If T cells learn in the thymus to recognize H-21 or K, D markers that are not at least partially carried themselves in other cells of the lymphoreticular system immunological interactions will be impossible and this paradox situation results in phenotypic immune incompetence in vivo

Release of vasoactive intestinal polypeptide in mast cells by histamine liberators

Abstract: VASOACTIVE INTESTINAL POLYPEPTIDE (VIP), originally isolated from porcine duodenum1, is a potent relaxant of vascular and nonvascular smooth muscle2, and a stimulant of adenylate cyclase activity3,4. The peptide has been localised in endocrine cells in the gastrointestinal tract and pancreatic islets5,6, as well as in nervous structures in these and other organs7–9, the peripheral autonomic nervous system and selected areas of the brain8–11. We report here immunological evidence that VIP, or a closely related peptide, occurs in mast cells, from which it can be released by compound 48/80 or by the Ca2+ ionophore A23187.

Morphine and beta-endorphin influence the secretion of the endocrine pancreas.

Abstract: OPIOID PEPTIDES1–3 are present in high concentrations in those areas of the brain and gastrointestinal tract4 in which opiate receptors5 are numerous and a biological response to opiates well established6. The report of immunoreactive enkephalin in the pancreas4 raised the possibility that a similar association between the presence of endogenous peptide and opiate receptors might exist in this organ and would be manifested by a biological response to these agents. We report here that an exogenous opiate and an endogenous opioid peptide both exert biological effects upon the endocrine pancreas that are compatible with the presence of opiate receptors in the islets of Langerhans.

Role of glucagon in the pathogenesis of diabetes: The status of the controversy

Abstract: The current controversy concerning the role of glucagon in the pathogenesis of diabetes is reviewed. The traditional "unihormonal abnormality concept," namely, that all of the metabolic derangements of diabetes are the direct consequence of deficient insulin secretion or activity, and the newer so-called bihormonal abnormality hypothesis, proposing that the fullblown diabetic syndrome requires, in addition to the insulin abnormality, a relative glucagon excess, are scrutinized. The relationship of insulin deficiency to the A-cell malfunction of diabetes, the conflicting evidence concerning the essential role of glucagon in mediating the marked overproduction of glucose and ketones in severe insulin deficiency and the contribution of glucagon to the endogenous hyperglycemia of diabetics without insulin deficiency are examined. Finally, the possibility that therapeutic suppression of diabetic hyperglucagonemia may make possible better control of hyperglycemia than is presently attainable by conventional therapeutic methods is considered. It is concluded that (1) although insulin lowers glucagon levels, restoration to normal of the A-cell dysfunction of diabetes requires that plasma insulin levels vary appropriately with glycemic change; (2) that glucagon mediates the severe endogenous hyperglycemia and hyperketonemia observed in the absence of insulin; (3) that in diabetics in whom insulin is present but relatively fixed an increase in glucagon causes hyperglycemia and glycosuria; and (4) that glucagon suppression could be a potentially useful adjunct to conventional antihyperglycemic treatment of diabetics.

Hepatic cytosolic non selenium-dependent glutathione peroxidase activity: its nature and the effect of selenium deficiency

Abstract: Recent work had indicated the presence of a non selenium-dependent glutathione peroxidase activity in rat liver in addition to the selenium-dependent activity. The present study was undertaken to learn whether the glutathione S-transferases are reponsible for the non selenium-dependent glutathione peroxidase activity and to study the effect of selenium deficiency on those enzymes. Glutathione S-transferase B was purified by an established method using carboxymethyl cellulose ion exchange chromatography and studied. It exhibited glutathione peroxidase activity toward cumene hydroperoxide and t-butyl hydroperoxide. A limiting Km of 0.55 mM was determined for cumene hydroperoxide. Sulfobromophthalein was found to be a competitive inhibitor with respect to cumene hydroperoxide of the glutathione peroxidase activity of glutathione S-transferase B. Selenium deficiency caused an increase in glutathione S-transferase activity. These results establish that glutathione S-transferase B contributes to the non selenium-dependent glutathione peroxidase activity in rat liver and show that it increases in selenium deficiency when the selenium-dependent glutathione peroxidase is decreased.

The critical role of iron in host-bacterial interactions.

Abstract: The ability of potential pathogens to acquire iron in a host is an important determinant of both their virulence and the nature of the infection produced. Virulent gram-negative bacteria are capable of acquiring sufficient iron from the host because their virulence (for chick embryos) is unaffected by exogenous iron. Avirulent mutants which are apparently limited in their ability to acquire iron could be isolated from the virulent strains. The lethality of these mutants was significantly enhanced by exogenous iron. Reduction of the relatively high serum iron saturation of chick embryos (to levels more closely approximating those in man) by pretreatment with iron-binding proteins or endotoxin inhibits the lethality of some virulent bacteria. Those bacteria whose virulence was reduced include the Shigella, Vibrio cholerae and strains of Neisseria gonorrhoeae, all of which are nondisseminating pathogens in the normal human host. Pathogens which produce septicemic and disseminating infections such as Neisseria meningitidis, Haemophilus influenzae type B, Escherichia coli possessing K-1 antigen, Pseudomonas aeruginosa and Salmonella typhimurium and disseminating strains of N. gonorrhoeae were, in general, unaffected by reduced serum iron saturation. These disseminating bacteria appeared to produce greater quantities of compounds (siderophores) which stimulated microbial growth in low-iron media than did the nondisseminating pathogens. Thus, the gram-negative bacteria tested can be divided into four major classes according to their responses to modifications in iron levels in the chick embryo model and these results correlate with the nature of the infections which they typically produce in man.

Effect of prostaglandin synthetase inhibitors on pressor response to angiotensin II in human pregnancy.

Abstract: Pregnant women destined to develop pregnancy-induced hypertension (PIH) lose refractorinessto the pressor effects of infused angiotensin II (AII) several weeks before the onset of hypertension. This loss of refractoriness to A-II is unrelated to plasma renin activity or circulating levels of A-II. In animal studies it has been shown that the prostaglandins are important mediators of vascular reactivity. Specifically, the uterine blood flow appears to vary directly with prostaglandin E concentrations in uterine venous effluent. The present study was designed to evaluate the effects of prostaglandin synthetase inhibitors on the pressor effects of A-II in human pregnancy. The “effective A-II pressor dose” (nanograms of A-II·kg-1·min-1 necessary to cause a 20 mm Hg rise in diastolic pressure) was determined in 14 pregnant women before and after treatment with either 25 mg indomethacin or 600 mg aspirin given twice, 6 h apart. The effective pressor dose required before treatment [22.7 ± 3.4 ng·kg-1·min-1 (mean...

The hypercalciuria of diabetes mellitus: Its amelioration with insulin

Abstract: Calcium and phosphous metabolism was investigated in 20 patients with diabetes mellitus when their diabetes was under poor metabolic control and again once optimal glycaemic control was achieved with aggressive insulin therapy. Ten of the twenty uncontrolled diabetics had hypercalciuria; insulin therapy returned calcium excretion to normal in five. Twenty-four hour calcium excretion fell in all but two patients when optimal diabetic control was achieved and calcium excretion was positively correlated with glucose excretion. Urinary cyclic AMP excretion, which was in the high normal range during poor control, decreased significantly during optimal insulin therapy. These data suggest that the hypercalciuria of uncontrolled diabetes may be a form of renal hypercalciuria which could result in parathyroid stimulation which might contribute to the development of osteopenia in patients with diabetes mellitus.

The hypercalciuria of diabetes mellitus: its amelioration with insulin.

Abstract: Calcium and phosphous metabolism was investigated in 20 patients with diabetes mellitus when their diabetes was under poor metabolic control and again once optimal glycaemic control was achieved with aggressive insulin therapy Ten of the twenty uncontrolled diabetics had hypercalciuria; insulin therapy returned calcium excretion to normal in five Twenty-four hour calcium excretion fell in all but two patients when optimal diabetic control was achieved and calcium excretion was positively correlated with glucose excretion Urinary cyclic AMP excretion, which was in the high normal range during poor control, decreased significantly during optimal insulin therapy These data suggest that the hypercalciuria of uncontrolled diabetes may be a form of renal hypercalciuria which could result in parathyroid stimulation which might contribute to the development of osteopenia in patients with diabetes mellitus

Conversion of Androgen to Estrogen by the Human Fetal Ovary

Abstract: The conversion of radiolabeled androgen to estrone and 17 beta-estradiol was assessed in tissues of human embryos that varied from phenotypically indifferent stages (1-3 cm crownrump length) to midgestation (15. 1-20 cm crownrump length). Significant rates of estrogen synthesis were demonstrated only in ovaries, liver, and brain. Estrogen synthesis was undetectable in gonads from 1-3 cm fetuses, but by the 3.1-5-cm stage it had reached an average rate of 1.9 pmol . h-1 . mg protein -1 in ovaries and remained at this level of activity through the latest stages examined. Estrogen formation was undetectable in testes at all stages examined, but the time of appearance of the capacity to form estrogens in the fetal ovary is similar to the onset of the capacity of the fetal testis to synthesize testosterone. The capacity of the fetal ovary to form estrogen develops before histological differentiation of the tissue.

The Validity of Normal Arteriography in Penetrating Trauma

Abstract: The detection of underlying arterial injury is a major problem in the management of penetrating trauma. Arteriovenous fistula and false aneurysm are late sequelae of unrepaired injuries. The diagnostic accuracy of arteriography in clinically occult injury has not been defined. One hundred and seventy-seven patients with 183 penetrating extremity wounds underwent arteriography followed by operative vessel exploration. Arteriogram/operation correlation demonstrated 36 true-positive, 132 true-negative, 14 false-positive, and one false-negative arteriogram. Arteriography is sufficiency sensitive to exclude the presence of arterial injury in patients with equivocal clinical signs of injury. The radiographic changes are often sublte and diagnostic accuracy demands attention to the details of technique and interpretation. Unequivocal clinical signs of arterial injury and any arteriographic abnormality are indications for operative exploration.

The Protein Products of the Murine 17th Chromosome: Genetics and Structure

Abstract: Publisher Summary This chapter focuses on the analysis of the protein products of the murine 17th chromosome. Many of the gene complexes that map between the centromere and TLa play an essential role in cell–cell interactions and the control of immune responsiveness, embryogenesis, and differentiation. All the products of these genes are glycoproteins, most of which are expressed on cell surfaces presumably as receptors and often in association with β-microglobulin. The chapter discusses the present state of biochemical knowledge about these glycoproteins, focusses on their common features and interrelationships, and explores the implications of these qualities for the evolutionary origins of the associated genes. This segment of chromosome 17 acts in some ways as a “super gene” in which the genes and gene complexes coding for a number of functionally interrelated molecules are closely linked, presumably as a result of selective pressures. Significant data concerning the genetics, function, and structure of the I region and its products have been obtained. There is great heterogeneity in the I region. I -region genes and products are involved in a fundamental way with the regulation of the immune response.