A distinctive feature of malignant adrenocortical neoplasms is decreased major histocompatibility complex (MHC) class II molecule expression. However, it is unknown whether there exists a restriction ...to certain MHC genotypes and whether this involves alterations of the Fas/Fas ligand system and thereby affects tissue homeostasis.
Therefore, MHC class II phenotype and genotype and expression patterns of the Fas/Fas ligand system were investigated in 24 adrenocortical tumors (nAdenomas = 14, nCarcinomas = 10) and an adrenal cancer cell line (NCI-H295). No MHC class II antigen expression was detected in carcinomas. The DRB1*01 genotype was found in 54.5% of patients with carcinoma (P = 0.046). No prevalence of any genotype could be detected in patients with adenomas, which exhibited varying levels of antigen expression. Fas receptor expression was 75.0% in adenomas compared with 20.0% in carcinomas (P = 0.0196), whereas ligand expression was 37.7% in adenomas and reached almost 100% in the carcinomas investigated in this study (P = 0.0033).
In summary, the DRB1*01 genotype may be correlated to a higher risk for malignancy. Additional studies on MHC class II genotype and phenotype and the altered Fas/Fas ligand system in adrenal neoplasms may help to identify mechanisms of immune escape and suggest new diagnostic approaches.
Tissue Remodelling in the Adrenal Gland Wolkersdörfer, Gernot W; Bornstein, Stefan R
Biochemical pharmacology,
07/1998, Letnik:
56, Številka:
2
Journal Article
Recenzirano
Adaptation of the adrenal gland to the demands of the organism is regulated functionally and structurally. Three common hypotheses on zonation in the adrenal gland, the migrational, zonal, and ...transformation field theories, try independently to reconcile the findings on structure, proliferation, and cell death. The classical theories on zonation are revisited in the light of recent data on cell death and renewal. In accordance with data on cell death as immunoreactivity against FAS (CD 95), an apoptosis-inducing receptor,
in situ end labelling of fragmented DNA, and ultrastructural analyses, programmed cell death (PCD) occurs throughout the whole organ. The angiotensin II receptor subtypes described in the adrenal allow an additional regulation of tissue homeostasis by proliferative and even by the antiproliferative effects of the angiotensin II type 2 receptor. Proto-oncogenes are involved in the regulation of cell cycle and PCD, and adrenocorticotropin asserts its tissue integrating and differentiating effects by regulating proto-oncogenes such as c-
jun, c-
fos,
jun-
B and c-
myc. Polypeptides involved in proliferation and DNA repair, such as proliferating cell nuclear antigen and Ki-67, have been found within zones of expected cell senescence. The expression of the class II major histocompatibility complex on normal adrenocortical cells allows cell-to-cell communication with the immune system and may trigger the Fas/Fas-ligand system to permit tissue regression and decreasing activity in both systems. In summary, new data allow us to reappraise and to reconcile the classical theories. Apoptosis is a physiological process in the adrenal gland. There is a differential regulation of apoptosis in the different zones. An investigation of this process may elucidate the basic mechanisms of adrenal zonation.
Background. Current therapies for adenocarcinoma of the pancreas do not improve the life expectancy of patients. Methods. In a non-randomized pilot trail we tested whether a local therapy based upon ...an adenoviral gene transfer of wild type p53 in combination with gemcitabine administration would be safe in patients with liver metastases due to pancreatic carcinoma. We report on the clinical course of three patients with respect to safety, tolerability and tumor response. Results. Transient grade III toxicities occurred with fever, leucopenia, elevation of AP, ALT, AST, GGT, while grade IV toxicity occurred for bilirubin only. Laboratory tests suggested disseminated intravascular coagulation in all three patients, but fine needle biopsies of liver did not show any histological evidence of thrombus or clot formation. Progression of liver metastases was documented in one and stable disease in another patient two months after treatment. However, a major improvement with regression of the indexed lesion by 80% occurred in a third patient after a single administration of 7.5×1012 viral particles, and time to progression was extended to six months. Conclusion. The combination therapy of viral gene transfer and chemotherapy temporarily controls and diminishes tumor burden. Improvement of the toxicity profile is necessary. Further trials are warranted to improve treatment and life expectancy of patients suffering from fatal diseases such as pancreatic carcinoma.
Adrenal cortical activation in murine colitis Franchimont, Denis; Bouma, Gerd; Galon, Jerome ...
Gastroenterology (New York, N.Y. 1943),
12/2000, Letnik:
119, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background & Aims: Proper adrenal glucocorticoid secretion is crucial in the course of inflammatory diseases. However, the function and structure of the adrenal glands have not been examined in ...inflammatory bowel diseases. Methods: After induction of trinitrobenzene sulfonic acid (TNBS) colitis in SJL/J mice, plasma hormone and cytokine levels were measured, adrenal structure was analyzed by immunohistochemistry and electron microscopy, and adrenal cytokine/cytokine receptor expression were studied by RNase protection. Results: Adrenals of colitic animals were enlarged and hypervascularized. These animals had a marked increase in plasma corticosterone levels during the course of colitis (270 ± 34 vs. 16 ± 11 ng/mL; P < 0.0001) but only a modest elevation of their concurrent adrenocorticotropin levels (57 ± 13 vs. 29 ± 9 pmol/L; NS). On electron microscopy, adrenocortical cells showed ultrastructural signs of marked stimulation, and intra-adrenal lymphocytes were frequently found in direct contact with these cells. Concurrent plasma levels of interleukin (IL)-6, the major cytokine activating the hypothalamic-pituitary-adrenal axis, were markedly increased (495 ± 131 vs. 20 ± 1.5 pg/mL; P < 0.0001), and this cytokine directly stimulated corticosterone secretion by adrenocortical cells in vitro. Intra-adrenal expression of IL-6 in animals with colitis was increased 80-fold, and the IL-6 receptor subunits IL-6Rα and gp130 were present in the adrenal cells. Treatment of animals with neutralizing anti–IL-6 antibody reduced the TNBS-induced growth and activation of the adrenal cortices. Conclusions: Colitis is associated with a profound stimulation of adrenocortical cell function and glucocorticoid release. Direct immune-adrenal interactions seem to contribute to this activation of the adrenal glands during colitis.
GASTROENTEROLOGY 2000;119:1560-1568
To measure the effect of experimental endotoxemia and anti-inflammatory therapy on plasma dehydroepiandrosterone (DHEA) levels in humans.
Controlled, randomized, single-blind, prospective clinical ...study.
Monitored unit in research hospital.
Twelve healthy volunteers served as their own controls and were randomized to receive intravenous endotoxin (Escherichia coli) or saline separated by 1 wk. Six were randomized to receive ibuprofen, a cyclooxygenase inhibitor, and six were given placebo.
Measurement of vital signs and hormones during a 24-hr period.
All subjects given endotoxin had a significant increase in plasma DHEA, cortisol, and adrenocorticotropic hormone (ACTH) levels (all p = .02). DHEA levels were maximum at 2 hrs and returned to baseline values by 6 hrs. Ibuprofen administration significantly blunted the endotoxin-induced increase in DHEA secretion (p = .001), whereas the increase in cortisol and ACTH was not affected.
Acute endotoxemia leads to a rise in plasma DHEA levels in humans. Maximum levels of DHEA but not cortisol or ACTH were blunted by ibuprofen, suggesting a different regulation of these synthetic pathways in the adrenal cortex inner zone during acute inflammation.
Adrenal androgen production was reduced by 80% in patients receiving T lymphocyte-suppressive medications compared to that in age-matched controls. In vitro, however, neither tacrolimus nor ...cyclosporin A reduced dehydroepiandrosterone (DHEA) release by adrenocortical cells. Therefore, we examined the potential role of lymphocytes in adrenal androgen production, using cocultures of human T lymphocytes and adrenocortical primary or transformed cells. Co-cultures led to a 4-fold elevation of DHEA levels (490.4 +/- 94.8% over basal), which was greater than the increase observed after the addition of maximal concentrations of ACTH (117.4 +/- 14.8%). Separation of cells by semipermeable membranes abolished this effect, and transfer of leukocyte-conditioned medium had little androgen-stimulating effect. These data suggested that the observed stimulation of androgen secretion required cell contact rather than soluble paracrine factor(s). Furthermore, we examined human adrenal glands for the presence of T lymphocytes and contact between these cells and steroid-secreting cells of the zona reticularis. Indeed, T lymphocytes expressing CD4 and CD8 antigens were present within human adrenal zona reticularis by immunohistochemical subtyping. Electron microscopic analyses demonstrated direct cell-cell contact between T lymphocytes and adrenocortical cells in situ. This study provides evidence for a novel mechanism of immune-endocrine interactions of direct T lymphocyte-adrenocortical cell contact-mediated stimulation of adrenal androgen secretion.
Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to ...the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/ Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% +/- 2.78 (mean +/- SEM), in adult adrenals 18.63% +/- 3.14 (third decade), and 15.15% +/- 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.
One in seventy randomly selected individuals is supposed to host an adrenal mass. The increasing number of incidentally detected adrenocortical adenomas requires the effective and reliable evaluation ...of dignity. So far this has been determined through a difficult multi-parametric analysis. Since MHC class II antigens are expressed in the normal adrenal cortex with a restriction to the zona reticularis, we examined 28 adrenocortical incidentalomas, 10 adenomas, 13 cortical carcinomas, 2 metastases, 10 controls as well as the adrenocortical carcinoma cell line NCI-H295 immunohistochemically for the expression of HLA class II antigens. We showed, that the majority of the adenomas still express class II antigens, whereas the expression is abrogated in all carcinomas examined. Our results indicate, that the detection of HLA class II positive tumour cells excludes malignancy. Therefore, MHC class II antigens may serve as a novel tumour marker in the evaluation of dignity in adrenocortical tumours. These findings could change the strategy for the assessment of adrenal masses.
PDF
