TCR1+ large granular lymphocyte proliferation in rheumatoid arthritis

The T-lymphoproliferative syndrome is characterized by a proliferation of large granular lymphocytes (LGL). It is often associated with neutropenia, and in 30% of cases with rheumatoid arthritis (RA). Phenotypic analysis has demonstrated that in most cases of RA with T-proliferative disease, the LGL represent T cells with a clonal rearrangement of the / T cell receptor (TCR2). Here, three patients with / TCR1⁺ LGL proliferation suffering from long-standing arthritis and neutropenia are described. The first patient with RA showed an expansion of a heterogeneous CD2⁺ CD16⁺ CD56^- LGL population, of which 30% coexpressed TCR1 with V1 rearrangement. The second patient with ankylosing spondylitis and RA was suffering from proliferation of TCR1⁺ (V9^-, V1^-), CD2⁺ CD16^- CD56^- LGL with low coexpression of CD8. The third patient with RA was suffering from a proliferation of TCR1⁺ (V1⁺, V9^-) CD4^- CE8^- CD16^- CD56^- lymphocytes. On the basis of these unusual findings, the pathogenetic role of TCR1⁺ T cells in RA is discussed.     

The effect of β-adrenergic blockade on infarct size following experimental coronary occlusion

Summary The effect of Pindolol on myocardial infarct size was studied in 10 open chest dogs. In each animal a sequential occlusion and reperfusion of 2 medium-sized branches of the left coronary artery was performed in the same heart. After occlusion and reperfusion of the control artery the initial dose of Pindolol (0.25 mg/kg body weight) was administered. Thereafter the test artery was occluded, followed by a maintenance dose of Pindolol (0.3 mg/kg body weight).The drug caused a significant decrease in LVP and LV-dp/dt but no change in heart rate. MVO₂ also decreased significantly. Regional myocardial blood flow was measured with the tracer microsphere method. Collateral flow in the perfusion area of the control artery was 11.2±5.9% and in the area of the test artery 10.0±4.4% of normal. No change in the endo/epi ratio as a result of treatment was observed.The area of infarction (p-nitroblue tetrazolium-reaction) was divided by the area of perfusion (angiography). Infarct size, expressed as the percentage of the perfusion area. was 48.2±22.2% in the region of the control artery and 43.0±23.9% in the region of the test artery. The difference was statistically not significant.With 1 table     

Experimental elimination of the splenic function by an intravenous injection of ethyl palmitate emulsion in Wistar rats

Summary Attempts were made at the experimental elimination of the sequestration function of the spleen on Wistar rats using ethyl palmitate (EP). Following an i. v. injection of EP emulsion in an amount of 0.35 g and 0.10 g/ 100 g of body weight the clearance of⁵¹Cr-labeled and heat-damaged red cells from the blood and their sequestration in the spleen and liver at 24-h, 3-, 10-, 20-, and 50-day intervals was examined. A high dose of EP caused, notably at 24 h and also after 3- and 10-day intervals, a significant decrease of radioactivity in the spleen and considerably prolonged the clearance time of the red0 cells. The extent of changes were comparable to those of surgical splenectomy. At later intervals (20 and 50 days after EP injection) some animals showed partial regeneration of the sequestration ability of the spleen; in some other animals the splenic damage was permanent. Changes induced by small doses of EP were less pronounced and of transient character.

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Abbreviations EP ethyl palmitate - S.D. standard deviation     

Differences of cellular composition and adhesion molecule expression in “leukemic” as compared with “normal” human long-term bone marrow cultures

Summary Human long-term bone marrow cultures (HLTBMCs) were established with bone marrow samples collected from 15 patients with acute myeloid leukemia (AML) and compared with HLTBMCs from eight healthy volunteers. During 6 weeks of culture, the cellular composition of HLTBMCs was quantitatively studied. The cells of the HLTBMCs were divided into three main categories: fibroblasts, macrophages, and other cells (endothelial cells, hematopoietic cells and undefined cells). HLTBMCs derived from healthy volunteers demonstrated a very consistent development. The number of fibroblasts increased during culture and the number of macrophages decreased, resulting in a steady state after 3 weeks of culture. In contrast, HLTBMCs derived from patients with AML showed a strikingly different pattern of irregular development and a steady state was not reached under our conditions. The APAAP technique was used to demonstrate expression of adhesion molecules. VLA2, VLA5, VLA6, LFA1, Mac1, p150/95, ₂-chain, HCAM, ICAM1, NCAM, and VCAM1 were more expressed on normal as compared with leukemic bone marrow stromal cells, although this reached significance only for ₂-chain and NCAM. VLA1, 3, and 4 were expressed in a higher percentage on leukemic stroma (not significant). More expression was seen on normal as opposed to leukemic macrophages for the adhesion molecules tested, except for VLA5. The differences reached significance for the majority of molecules tested. It is concluded that striking differences exist in cellular composition and adhesion molecule expression between HLTBMCs from healthy individuals and those from patients with AML. This may have an impact on the pathogenesis of AML.     

Radiologic appearance of gallstones and its relationship with biliary symptoms and awareness of having gallstones

In the course of two cross-sectional epidemiological surveys carried out by the Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO), cholecystography was performed in 82 of 126 subjects identified by means of ultrasonography as having gallstones. In four subjects gallstones were not detected by cholecystography. The x-ray characteristics of the gallbladder and gallstones of the remaining 78 subjects were related to age, sex, presence of biliary symptoms in the five years prior to the study, and awareness of having gallstones. Twenty-three of the 78 gallstone subjects (29.5%) showed a nonvisualized gallbladder. Among the 55 subjects with visualized gallbladder, 16 (29.1%) and 28 (50.9%) showed radiopaque and solitary stones, respectively. The mean diameter of the largest stone was 19.7 mm±11.2 (sd). Age was related inversely to the number of stones. X-ray characteristics of gallstones did not differ between men and women. Presence of biliary symptoms in the five years prior to the study or awareness of having gallstones were not related to any radiologic feature, either in univariate or multivariate statistical analysis which included age, sex, weight, and height as possible confounding variables. Nineteen (24.3%) of the 78 subjects showed gallstones which would have been suitable for medical therapy with bile acids (ie, radiolucent, with a diameter of less than 20 mm, and in a visualized gallbladder).Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO) (For the composition of GREPCO, see appendix).This study was supported by a grant from Ministero della Sanità, No. CS/30/245/3458.     

Triplication (/ααα<Superscript>Anti3.7</Superscript>) or deletion (-α<Superscript>3.7</Superscript>/) association in Argentinian β-thalassemic carriers

Prevalence of alpha gene triplication or deletion in -thalassemia carriers was studied in 109 unrelated individuals in Rosario, Argentina. In different populations -^3.7 allele presents a higher prevalence than ^anti3.7; thus, -thalassemia associated with -thalassemia is more frequently observed. Nevertheless, this event was detected in only one case (0.9%), while the association with alpha triplication was present in two subjects (1.8%).     

The prognostic significance of cytological,histological and cytogenetic findings in refractory anaemia (RA) and RA with sideroblasts

Summary Two independent observers performed a double review of cytological and histological bone marrow material obtained at diagnosis and during follow up in 34 patients with the myelodysplastic syndrome (MDS), subtypes refractory anaemia (RA) and RA with ringed sideroblasts (RA-S) (26 and 8 patients, respectively). Average values were used for the analyses. Data obtained at diagnosis confirmed earlier observations that a worse prognosis was indicated by high blast cell counts (P<0.01), presence of blast foci and clonal cytogenetic abnormalities (P=0.08). Data obtained during follow up, in addition, showed that an increased probability of progression to FAB-subtype RA with an excess of blasts was related to both the occurrence of blast foci (P<0.05) and the occurrence of new or additional clonal abnormalities (karyotype shift) (P<0.01). The relationship between parameters investigated at diagnosis, during follow up, and in the pooled material, points to RA-S being a separate entity having a better prognosis than RA, and further substantiates an earlier observed relationship between blast cell accumulation and the frequency of cytogenetically abnormal metaphases.This work was supported by Grant no. 003/83 from The Danish Cancer Society     

Pancreatic polypeptide — A postulated new hormone: Identification of its cellular storage site by light and electron microscopic immunocytochemistry

Summary A peptide, referred to as pancreatic polypeptide (PP), has recently been isolated from the pancreas of chicken and of several mammals. PP is thought to be a pancreatic hormone. By the use of specific antisera we have demonstrated PP immunoreactivity in the pancreas of a number of mammals. The immunoreactivity was localized to a population of endocrine cells, distinct from the A, B and D cells. In most species the PP cells occurred in islets as well as in exocrine parenchyma; they often predominated in the pancreatic portion adjacent to the duodenum. In opossum and dog, PP cells were found also in the gastric mucosa. In opossum, the PP cells displayed formaldehyde-induced fluorescence typical of dopamine, whereas no formaldehyde-induced fluorescence was detected in the PP cells of mouse, rat and guinea-pig. Also in these latter species, however, PP cells appear to possess amine-handling properties, a feature common to many peptide hormone-producing cells. The ultrastructure of the PP cells was defined by combining immunohistochemistry of semi-thin plastic sections with electron microscopy of adjacent ultrathin sections. PP cells show the ultrastructural features of peptide hormone-secreting cells. The PP cells of cat and dog contain fairly large, rather electron-lucent granules, and are probably identical with the previously described F cells. The PP cells of rat, guinea-pig, chinchilla and man contain small, fairly electron-dense granules. In these latter species no F cells are found. By immunoperoxidase staining of ultrathin sections, the PP immunoreactivity was found to be localized to the cytoplasmic granules. These observations provide support for the view that PP is a true pancreatic hormone.Presented in part at the 11th Annual Meeting of the European Association for the Study of Diabetes, Munich 4–6 Sept., 1975.     

Lazy leukocyte syndrome

Summary A-35-year-old woman with a long-lasting history of neutropenia and recurrent infections was found to have defective neutrophil chemotaxis, random motility, and in vivo migration. Although the bone marrow granulocyte reserve was normal, the patient failed to release an appropriate amount of granulocytes after injection of etiocholanolone. These features are characteristic of the so-called Lazy leukocyte syndrome. The clinical presentation of the five cases of this syndrome so far reported and its pathophysiological aspects are discussed.     

γ/δ Receptor-expressing T-cell clones from a cutaneous T-cell lymphoma suppress hematopoiesis

Summary Recently we described a cutaneous T-cell lymphoma expressing the / T-cell receptor [5]. The patient suffering from this lymphoma showed low numbers of myeloid and T cells in peripheral blood, while B and NK cells were relatively increased. In vitro culture of the patient's bone marrow (BM) cells revealed a significant suppression of myeloid/monocyte colony formation (GM-CFU) compared with normal controls. This was not due to infiltration of the BM with lymphoma cells. We speculated that a soluble factor either secreted or induced by the lymphoma cells might be responsible for the marked suppression of hematopoiesis in this patient. From a skin biopsy with infiltrating / T-lymphoma cells we established T-cell clones bearing the / T-cell receptor and resembling the phenotype of the lymphoma cells. The supernatant (SN) of these / T-cell clones reduced the number of colonies in a CFU-GM assay (using normal control BM) in comparison to SN of / T-cell clones established from the same biopsy. This suppression was seen mainly on day 7 of culture and was not neutralized by the addition of placenta-CM. The main mediator of this suppression seems to be IFN-,since it was detectable in high amounts in the SN of these / T-cell tumor clones as well as in the serum of the patient. In addition, anti-IFN- antibodies can reverse the T-cell SN-mediated suppression of CFU-GM. We conclude that high serum levels of interferon-, which is secreted in high amounts from / T-cells grown from a biopsy of a cutaneous lymphoma, can suppress hematopoiesis.Abbreviations TCR T-cell receptor - IFN- interferon- - SN supernatant - placenta CM placenta conditioned medium - BM bone marrow - CFU-GM myeloid/monocyte colony formation - NK cells natural killer cells - Ab antibody M. Wilhelm was supported by theDeutsche Forschungsgemeinschaft (DFG Wi 728-2)     

Acute hematologic effects of interferon alpha,interferon gamma,tumor necrosis factor alpha and Interleukin 2

Summary This study was designed to investigate acute effects of various doses of the cytokines IFN-alpha, IFN-gamma Interleukin 2 and tumor necrosis factor alpha on white blood cell differential counts. Before initiation of phase II trials, a dose-determination phase was performed, where three different dose levels of each cytokine were applied as a single dose. White blood cell differential counts were assessed immediately before and 2, 12, 24, 48 and 168 h after injection. Patients enrolled suffered from metastatic cancer or chronic active hepatitis. In addition, IFN-alpha was administered to five healthy volunteers. Results indicate that cytokines cause rapid and transient changes in the numbers of leukocyte subsets. Hematologic changes were cell-type- and cytokine-specific: transient lymphopenia was observed after administration of all four cytokines, reaching a nadir 12 to 24 h after subcutaneous injection. Administration of TNF-alpha and IFN-gamma also caused transient monocytopenia. Neutrophilia developed after administration of Interleukin 2, IFN-alpha and TNF-alpha. We conclude that cytokines play a key role in the regulation of peripheral blood cell traffic by their capacity to influence homing patterns of peripheral blood leukocytes.     

Short-term inhibition of peroxisome proliferator-activated receptor-γ coactivator-1α expression reverses diet-induced diabetes mellitus and hepatic steatosis in mice

Aims/hypothesis The coactivator of nuclear receptors, peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) has been implicated in a series of events that contribute to the control of glucose metabolism. We have recently reported the use of a PGC-1 antisense oligonucleotide (PGC-1AS) that inhibits up to 60% of PGC-1 expression in pancreatic islets, leading to increased insulin secretion. This oligonucleotide was used in this study to try to ameliorate diet-induced type 2 diabetes in a genetically predisposed mouse strain (Swiss mice).Materials and methods Glucose and insulin tolerance tests, euglycaemic–hyperinsulinaemic clamp, immunoprecipitation assays, immunoblotting assays and immunohistochemistry were used in this investigation.Results Swiss mice became obese and overtly diabetic after 8 weeks of feeding with chow containing 24% saturated fat. One daily dose (1.0 nmol) of PGC-1AS significantly reduced glucose and increased insulin blood levels without affecting food intake and body weight. These effects were accompanied by a reduced area under the glucose curve during an intraperitoneal glucose tolerance test, an increased constant of glucose decay (K_itt) during an insulin tolerance test, and an increased glucose consumption rate during a euglycaemic–hyperinsulinaemic clamp. Moreover, mice treated with PGC-1AS presented an outstanding reduction of macroscopic and microscopic features of hepatic steatosis. These effects were accompanied by reduced expression or function of a series of proteins involved in lipogenesis.Conclusions/interpretation PGC-1 is an attractive target for pharmacological therapeutics in type 2 diabetes mellitus and diet-induced hepatic steatosis.     

A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM

Summary To assess the role of fasting plasma non-esterified fatty acids (NEFA) in the development of non-insulin-dependent diabetes mellitus (NIDDM), data were analysed from annual examinations of 190 non-diabetic Pima Indians. Glucose tolerance was measured by a 75-g oral glucose tolerance test, insulin action by a euglycaemic hyperinsulinaemic (40 mU · m^–2 · min^–1) clamp and in vitro lipolysis using isolated abdominal fat cells. After a mean follow-up period of 4.0±2.4 years (mean ± SD), 47 subjects developed NIDDM. Risk factors for NIDDM were estimated by proportional-hazards analysis and risk ratios (RR) with 95% confidence intervals (95% CI) calculated at the 90th and 10th percentile of the predictor variables. A large average fat-cell volume was predictive of NIDDM (RR=2.4; 95% CI=1.2–4.8) independent of age, sex, percent body fat and body fat distribution. A high fasting plasma NEFA concentration was also a risk factor for NIDDM (RR=2.3; 95% CI=1.1–4.7) independent of sex, percent body fat, waist/thigh ratio, insulin-mediated glucose uptake and fasting triglyceride concentration. We conclude that large fat cells and the resulting increased plasma NEFA concentrations are risk factors for the development of NIDDM.Abbreviations NEFA Non-esterified fatty acids - NIDDM non-insulin-dependent diabetes mellitus - CI confidence interval - RR risk ratio     

Hyperplasia of “pancreatic polypeptide”-cells in the pancreas of juvenile diabetics

Summary The cellular composition of the pancreatic islets of juvenile diabetics was studied, using recently developed immunocytochemical methods. B-cells were identified only in juvenile diabetics with a disease of short duration. In chronic juvenile diabetics, the islets which are classically viewed as atrophic, were shown to be composed of glucagon- and of somatostatin-cells. Another type of islets which commonly occurs in the pancreas of juvenile diabetics, i. e. the ribbon-like type first described by Cecil in 1911, appeared to be composed almost exclusively of pancreatic polypeptide (HPP)-cells. It is suggested that hyperplasia of the HPP-cells in the pancreas of juvenile diabetics results from an atypical type of islet regeneration induced by a severe and prolonged injury to the pancreatic endocrine tissue.     

Effect of recombinant human transforming growth factor beta and tumor necrosis factor alpha on bone marrow progenitor cells of HIV-infected persons

Summary With progressive disease, the majority of patients with human immunodeficiency virus (HIV) infection develop bone marrow failure with anemia, leukopenia, and thrombocytopenia, the cause of which has not yet been clarified. Besides direct infection of bone marrow progenitor cells and immune-mediated cytolysis, the action of inhibitory cytokines, like transforming growth factor beta (TGF-) and tumor necrosis factor alpha (TNF-), has to be discussed with regard to their pathophysiological role in HIV-induced bone marrow failure. Therefore, the influence of recombinant human TGF- and TNF- on colony growth of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells from the bone marrow of HIV-1-infected persons and normal controls was assessed in methylcellulose cultures. Both cytokines inhibited the colony formation of hematopoietic progenitor cells from HIV-positive persons. When added to unseparated bone marrow cells from HIV-infected persons and normal controls, the 50% inhibition (ID₅₀) of BFU-E by TGF- occurred at 1.3 ng/ml and 3.7 ng/ml, respectively, while the ID₅₀ of CFU-GM occurred at 15.5 ng/ml and 142.7 ng/ml. Concentrations of TNF-, causing 50% inhibition of colony formation by bone marrow cells from HIV-infected or noninfected individuals were 6.3 U/ml and 17.0 U/ml for BFU-E, and 24.4 U/ml and >3,000 U/ml for CFU-GM, respectively. The ID₅₀ of the CFU-GEMM growth was below the lowest concentration of both cytokines tested. The suppressive effects were specifically abolished by antibodies against TGF- and TNF-, thus confirming that the inhibitory activities were due to the cytokine preparation used.The study was supported by a grant from theBundesgesundheitsamt     

Effects of Cytokines on the Binding of Leukocytes to Cultured Rat Hepatocytes and on the Expression of ICAM-1 by Hepatocytes

Adhesions of leukocytes to hepatocytes andsinusoidal endothelial cells mediates the induction andprogression of hepatic injury. However, in contrast toendothelial cells, information regarding the regulation of interactions between leukocytes andhepatocytes is limited. In the present study, weinvestigated the effect of inflammatory mediatorsincluding lipopolysaccharide (LPS), staphylococcalenterotoxin B (SEB), interferon- (IFN-), tumornecrosis factor- (TNF-), andinterleukin-1 (IL-1) on the adhesion ofpolymorphonuclear leukocytes or lymphocytes to primarycultured rat hepatocytes, and on the expression of intercellular adhesionmolecule-1 (ICAM-1) gene in hepatocytes. Bothpolymorphonuclear leukocyte and lymphocyte adhesion tohepatocytes were enhanced after exposure of hepatocytes to IFN- and TNF-, but not afterexposure to LPS, SEB or IL-1. The adhesion inducedby either IFN- or TNF- was inhibited bymonoclonal antibodies against ICAM-1 or lymphocytefunction-associated antigen-1 (LFA-1). Nonstimulated hepatocytesexpressed faintly ICAM-1 mRNA, which increased slightlyduring the culture period. ICAM-1 mRNA expression wasup-regulated to a greater extent by incubating hepatocytes with IFN- or TNF-,and peaked after 12 hr of incubation with TNF-and after 24 hr with IFN-. These results indicatethat IFN- and TNF- induce the expressionof ICAM-1 on parenchymal hepatocytes and that theLFA-1-ICAM-1 pathway plays an important role in theinteraction between hepatocytes and neutrophils orlymphocytes.     

Impairment of monocyte “lectin-like” receptor activity in Type 1 (insulin-dependent) diabetic patients

Summary In order to investigate whether the ability of peripheral blood monocytes to bind bacteria is impaired in diabetes, we studied carbohydrate-binding (lectin-like) receptors and the receptor for the Fc portion of immunoglobulin on monocytes from 25 male Type 1 (insulin-dependent) diabetic patients and 10 age-matched healthy control subjects. Peripheral blood monocytes from the diabetic patients expressed lower levels of lectin-like receptors compared to the control subjects, whereas the expression of the receptor for the Fc portion of immunoglobulin was similar in both populations. There was no correlation between the degree of lectin-like binding activity and plasma glucose concentration or glycaemic control. Recognition of unopsonized bacteria by the lectin-like receptor is impaired in Type 1 diabetes; this may affect the efficient elimination of potential pathogens.     

On the pathogenesis of preleukemic myelodysplastic syndromes

Summary After a single pulse dose of DMBA, rats develop bone-marrow hypoplasia, which is almost compensated for by regeneration after 16 weeks. Subsequently, dysplastic signs of hemopoiesis appear in all experimental animals as massive extrusion of normoblasts into the peripheral blood, red-cell anisoand poikilocytosis, nuclear deformities, atypical mitoses, and PAS-positivity, as well as megaloblastoid maturation dissociation of erythroblasts and nuclear and granulation anomalies of neutrophilic granulocytes and monocytes, comparable to human pseudo-Pelger cells and paraneutrophils. At the time of death (112-497 days after DMBA pulse) experimental animals showed hyperplastic bone marrow with increased granulopoietic/erythropoietic ratios and an augmented, mainly erythropoietic, hemopoiesis in the spleen, with splenomegaly in six rats. Splenic hemopoiesis is accompanied by white pulp atrophia. The cause of death was septicopyemia in three rats, anemia in three, and bleeding in one rat. None of the animals developed a leukemic blast phase. Myelodysplastic changes in this experiment are the same as have been shown to precede leukemia in rats treated with five DMBA pulses (Fohlmeister et al. 1981). Possible relations of myelodysplasia and leukemia are discussed.Supported by Deutsche Forschungsgemeinschaft (DFG)     

Diagnosis of metastatic lesions to the stomach by salvage cytology

Summary Secondary neoplasms of the stomach are rare and are often clinical and diagnostic problems. Three patients with bleeding volcano-like ulcers were diagnosed by combined endoscopic salvage cytology and surgical biopsy as having metastatic submucosal lesions from hematologic spread. The combination of endoscopic appearance, clinical findings, and tissue and cytologic examination can lead to the correct diagnosis. The results from these cases support the utility of this cytologic technique in combination with biopsy in this clinical setting.     

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

Aims/hypothesis Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival.Methods A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis.Results Exposure of RINm5F cells to IL-1 or to a cytokine mixture (IL-1, TNF-, IFN-) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-B, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1 or the cytokine mixture. In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA (MAMA) and transport-associated protein (TAP1/MTP), whereas the plasma membrane calcium ATPase (PMCA) 2 and PMCA 3 genes were down-regulated by cytokines.Conclusions/interpretation Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.Electronic Supplementary Material Electronic supplementary material is available in the online version of this article at Abbreviations CAIN calcineurin inhibitor - EP extension-protected adaptor - Hsp70 heat shock protein 70 - iNOS inducible nitric oxide synthase - MAMA murine adherent macrophage protein - MnSOD manganese superoxide dismutase - NF-B nuclear factor kappa B - NO nitric oxide - PMCA plasma membrane calcium ATPase - Rab3 rab3 GDP/GTP exchange protein - RFDD-PCR restriction fragment differential display PCR - SD standard adaptor - Syt synaptotagmin V - TAP1 transport-associated protein 1