Persistance of endocrine cells in immuno-induced carcinoma of the exocrine pancreas: insulin, glucagon, and somatostatin cells]

In immuno-induced exocrine pancreatic carcinomas, which keep their exocrine secretory specificity through their different evolution stages [(1), (2)], normal B, A and D endocrine cells are still found, demonstrated by immunochemical techniques. They are localized in the islets of Langerhans. B and A cells are scattered in adenomatous pancreatic remains, and in the anaplasic carcinoma; D cells are found in the ductular and adenomatous remains. The three types of endocrine secretion granules are analyzed by electron microscopy at the early and late stages of carcinogenesis. The origin of the persisting endocrine cells and the nature of undifferentiated cells proliferating from the ductular epithelium are discussed.     

Presence of "pancreatic polypeptide" cells, and gastrin immunoreactivity in immuno-induced exocrine pancreas carcinoma]

1) In electively immuno-induced carcinomas of the exocrine pancrease in Mice, where A (glucagon) and B (insulin) endocrine cells persist, cells with a pancreatic polypeptide immunoreactivity are also detected, even in late evolution stages. These cells, like D cells, containing somatostatin, are localized only in the pancreatic remains surrounding the anaplasic carcinomatous tissue: islets, adenomatous parenchyma, and ductular epithelium. Ultrastructure of these cells shows their active elaboration of numerous chracteristic secretion granules. (2) Immunocytoenzymatic detection of gastrin is negative in the exocrine and endocrine pancreatic tissues. However one of the anti-gastrin sera used gives a positive reaction, in some carinomatous cells only. Does this immunoreactivity characterize a polypeptide specific to the pancreatic carcinomatous cell?     

Demonstration of tissue-specific antigens shared by normal pancreas and pancreatic neoplasms

Summary Xenoantiserum raised against extracts of normal hamster pancreas, after absorption with normal tissues, reacted specifically with normal hamster and human pancreas by immunodiffusion. Absorbed antiserum also reacted with hamster and human pancreatic carcinoma but not with other neoplasms. Immunization of hamsters with normal pancreas extracts prevented growth of transplantable pancreatic carcinomas.     

Demonstration of tissue-specific antigens shared by normal pancreas and pancreatic neoplasms

Xenoantiserum raised against extracts of normal hamster pancreas, after absorption with normal tissues, reacted specifically with normal hamster and human pancreas by immunodiffusion. Absorbed antiserum also reacted with hamster and human pancreatic carcinoma but not with other neoplasms. Immunization of hamsters with normal pancreas extracts prevented growth of transplantable pancreatic carcinomas.     

Pancreatic polypeptide: A possible role in the regulation of food intake in the mouse. Hypothesis

Summary Pancreatic polypeptide (PP) is a recently identified hormone produced by pancreatic endocrine cells. The islets of genetically obese mice (ob/ob, C57 BL/6J), which are suspected to lack a circulating satiety factor, contain relatively few of the PP-producing cells. Administration of bovine pancreatic polypeptide (bPP) reduces food intake and suppresses body weight gain in the hyperphagic obese mice. It is postulated that PP participates in the regulation of food intake in a manner as yet undefined.This work was supported by grant No. 3.553.75 from Swiss National Science Foundation. We thank Mrs M. Eissler and Mr R. Cuche for their valuable help.     

Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes

Autoimmune diseases result from a combination of genetic, immunologic, hormonal, and environmental factors. Infectious agents may induce the breakdown of immunological tolerance and the appearance of autoreactivity. However, the specific relationship between infection and autoimmunity is still unclear. One of the mechanisms responsible could be molecular mimicry between the infectious agent and self. The concept of molecular mimicry is a viable hypothesis in the investigation of the etiology, pathogenesis, treatment, and prevention of autoimmune disorders. Immune-mediated (type 1) diabetes in humans and in non-obese diabetic (NOD) mice is polygenic and characterized by autoimmune destruction of insulin-producing pancreatic beta cells in islets of Langerhans. In NOD mice, a T-helper 1 (Th1)-based autoimmune response arises spontaneously against glutamate decarboxylase (GAD) concurrently with the onset of insulitis. Subsequently. this Th1-type autoreactivity spreads intra- and intermolecularly to other beta cell autoantigens, suggesting that a Th1-type response is responsible for the progression of the disease, whereas Th2 responses when experimentally induced are protective. In humans, a homology between GAD and the P2-C protein of Coxsackie B make a cause-and-effect molecular mimicry an attractive hypothesis. Evidence to support the concept of molecular mimicry in diabetes is reviewed.     

Effect of pancreatic duct ligation on exocrine pancreatic function and structure in the rabbit

Summary 4 weeks after pancreatic duct ligation in the rabbit, fecal and luminal chymotrypsin were detected in concentrations similar to the control group. Pancreatic changes in the ligated group were marked dilatation of the main pancreatic duct, proliferation and distention of ductules and fibrosis. Despite pancreatic duct ligation and fibrosis, proteolytic enzymes continued to secrete into the duodenal lumen. These results suggest that pancreatic duct ligation in the rabbit is not associated with total pancreatic insufficiency.This study was supported by the Kansas University Endowment Association (Grant No. 73-2550), General Research Support (Grant No. 2553 and 1522-14) and a grant from Kaw Valley Heart Association.     

Endocrine and exocrine pancreatic function after camostate-induced growth of the organ

It is well known that oral administration of camostate induces hyperplasia and hypertrophy of the rat pancreas. It is not clear, however, whether pancreatic hormone and enzyme secretion are affected by camostate treatment.In rats, daily administration of 200 mg camostate/kg b. wt for 14 days significantly increased pancreatic weight and pancreatic content of DNA, protein, amylase, lipase, trypsin and chymotrypsin, as well as the amount of insulin, glucagon and somatostatin. In the intact animal, blood glucose levels and serum concentrations of insulin and glucagon in response to an oral glucose load were not impaired after camostate treatment. In the isolated perfused pancreas, however, insulin and glucagon secretions were reduced, whereas somatostatin release was not affected. The volume of pancreatic juice produced by the unstimulated isolated perfused organ, as well as protein and enzyme secretion, were increased after camostate treatment. Likewise, the isolated perfused pancreas from camostate-treated rats secreted a larger volume of pancreatic juice and more protein in response to cholecystokinin (CCK), while enzyme secretion was affected in a non-parallel manner: amylase release was markedly reduced, lipase release was unchanged, and release of trypsin and chymotrypsin was increased.     

In vitro secretion of ecdysteroids by Y-organs of the crayfish,Procambarus clarkii

It was demonstrated that excised Y-organs of the crayfish,Procambarus clarkii, synthesize in vitro 3-dehydroecdysone (3-DHE) as the major product, together with small amounts of ecdysone. Both were identified by immunological and spectroscopic methods. The increase of ecdysteroidogenesis in the Y-organs was accompanied by an increase of the major free ecdysteroid, 20-hydroxyecdysone, in the hemolymph. This suggests a physiological role of 3-DHE, the details of which are still to be elucidated.     

Evidence of an ileal hormone inhibiting pancreatic secretion (ACP anticholecystokinine peptide)]

The contact of long and medium chain fatty acids with the ileal mucosa inhibits basal or stimulated pancreatic protein secretion of Man, Dog, Cat and Rat. This inhibition is due to an inhibitory factor transmitted by cross-circulation. We isolated from partially purified extracts of Pig ileum a peptide which inhibits strongly volume and protein pancreatic output of the conscious Rat. We propose to call this factor ACP, anticholecystokinine peptide.     

Functional inhibition of isolated pancreatic cells, new technic for the detection of macrophage cytotoxicity]

It is usually accepted that macrophages "activated" by lymphokines may be found cytotoxic against tumoral target cells but show no detectable cytotoxicity in in vitro tests using normal non tumoral cells as target cells. These data have been obtained mainly with the chromium-release test. The present paper describes a new test using normal isolated pancreatic cells as target cells and evaluating the effect of activated or non-activated macrophages on the insulin secretion response to glucose stimulation. The results show a striking decrease in this response following an 18-hr incubation of pancreatic islet cells with activated macrophages, as compared to that of the same cells incubated with control macrophages. This is clear evidence that activated macrophages may alter normal cells and suggests that their cytotoxic properties are not restricted to tumoral target cells.     

Immunological memory ≠ protective immunity

So-called ‘immunological memory’ is, in my view, a typical example where a field of enquiry, i.e. to understand long-term protection to survive reexposure to infection, has been overtaken by ‘l’art pour l’art’ of ‘basic immunology’. The aim of this critical review is to point out some key differences between academic text book-defined immunological memory and protective immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is that ‘immunological memory’ of course exists, but only in particular experimental laboratory models measuring ‘quicker and better’ responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection. Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection—as documented by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and maintaining a level of protection in the population to deal with old and new infectious diseases.     

Ontogenic development of peptide hormones in the mammalian fetal pancreas

The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human, pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal beta-cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.     

Role of the pituitary in cyproheptadine-induced pancreatic beta-cell toxicity

Summary Hypophysectomized rats given cyproheptadine (40 mg/kg) for 10 days exhibited a loss of pancreatic immunoreactive insulin and ultrastructural changes in the cytoplasm of beta-cells. Sham-operated animals given cyproheptadine showed identical changes in pancreatic beta-cells except that cytoplasmic involvement progressed to the formation of large vacuoles. The pituitary is not directly involved with the cyproheptadine-induced depletion of pancreatic insulin but plays a role in the formation of large cytoplasmic vacuoles.Acknowledgments. This work was supported by U. S. Public Health Service, grant GM 12675.     

Exocrine pancreas: difference in the amylase content of the dorsal and ventral regions

Summary The amylase content of the acinar tissue is higher in the splenic region of the rat pancreas containing glucagon-rich islets than in the duodenal region harboring pancreatic polypeptide-rich islets.This work was supported by a grant from the Belgian Ministry of Scientific Policy.     

Measles and temporary increase in masculine births: coincidence or causality?]

Data from three West-African populations shows significant increase of sex-ratio. In two of them a considerable excess of male births came from conceptions the year following an epidemic of measles. This is limited to the villages affected by this epidemic. These facts seem to be similar to those related to hepatitis and sex-ratio. They suggest similarities between measles virus and surface antigens of Y sperms. This hypothesis could be tested by immunological investigation.     

The influence of different nutrients on plasma cholecystokinin levels in the rat

Summary Isocaloric and isovolemic amounts of protein (casein), fat (intralipid) and carbohydrate (saccharose) and an isovolemic control solution of water were administered intragastrically to conscious rats. The plasma CCK levels, determined by a sensitive and specific radioimmunoassay, showed an increment of 6.3±0.6, 2.7±0.5, 1.7±0.4 and –0.9±0.4 pM, respectively (basal value 2.5±0.3 pM). The threshold increment of plasma CCK to stimulate pancreatic enzyme secretion by exogenous CCK was found to be 1.5 pM. It is therefore concluded that casein is a potent stimulus for CCK secretion and pancreatic secretion, but that fat and even carbohydrate, although less potent, also produce a CCK increment above the threshold for pancreatic secretion.Supported by Grant IKW 86-16 from the Netherlands Cancer Foundation KWF.     

Ontogenic development of peptide hormones in the mammalian fetal pancreas

Summary The ontogeny of insulin, glucagon, PP and somatostatin in the mammalian fetal pancreas has been examined in recent years largely by immunocytochemistry and in some instances by radioimmunoassay. Complete ontogenic data are available only for the rat, human pig and sheep. Figure 3 compares the time of appearance of the endocrine cell-types within the fetal pancreas when the periods of gestation of the four species are converted to a uniform scale. The striking ontogenic difference in the rat probably reflects the immaturity of the rodent fetus at birth compared with the human, pig and sheep. In the fetal pancreas, differences in cell number of glucagon and PP cells in the dorsal and ventral lobes become apparent from an early gestational period. Factors responsible for the functional and structural maturation of the fetal pancreatic endocrine cells and the processes involved in pancreatic organogenesis are poorly understood. Studies in these areas would have clinical implications since it may be possible in the future to employ agents for selective replication of fetal -cells for transplantation in patients with Type I diabetes, bearing in mind that such cells must have the capacity to respond to normal stimuli and repressors when transplanted. The presence of the other islet cell-types may be obligatory for these appropriate responses. This would require a more complete knowledge of those factors which produce the normal selectivity of the four hormonal cell-types.     

The glucose dependence of pancreatic endocrine responses to 2-deoxyglucose in the calf

Summary The initial plasma glucose concentration of unanesthetized calves with cut splanchnic nerves, given 2-deoxyglucose (1.2 mmoles/kg, i.v.), was either lowered by prior starvation, or raised by a continuous infusion of exogenous glucose. Raising the initial plasma glucose concentration completely suppressed the release of pancreatic glucagon and pancreatic polypeptide but substantially enhanced the release of insulin in response to 2-deoxyglucose.This work has been supported by the Medical Research Council and the Leverhulme Trust. We are also indebted to Mr P.M.M. Bircham and Mr G.P. Macgregor for their skilled technical assistance.     

Regional distribution of pancreatic polypeptide cells in the 21-day fetal rat pancreas

Summary 21-day fetal rat pancreata were stained with the unlabeled antibody peroxidase-antiperoxidase technique using bovine pancreatic polypeptide as the primary antibody. Total counts of pancreatic polypeptide cells were made over the entire pancreas. It was found that the head region contained the greatest number of pancreatic polypeptide cells with the body next and the tail having the smallest number. The pancreatic polypeptide cells of the body were concentrated in the portion closest to the distal duodenum. This distribution pattern seems to support the suggested role of pancreatic polypeptide on the physiological function of the digestive tract.The authors wish to express their appreciation to Dr R. McEvoy, T. Whittlsey, G. Wassilchenko and D. Wilson for their assistance in this study. To whom reprint requests should be addressed.