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Biomedical subjects

F Schaper

Publications and source records attributed to F Schaper.

At least 37 records · Page 2Linked to original sources
PubMed2000

Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD Study. Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes.

AIMS: Only scarce information exists on the distribution and atherosclerosis risk in different types of hyperglycaemia at diabetes detection. This study aimed to analyse the occurrence of isolated fasting (IFH), isolated post-challenge (IPH) and combined hyperglycaemia (FH/PH) among subjects detected to have diabetes and the association of these types of hyperglycaemia with cardiovascular risk factors and carotid intima-media thickness (IMT). METHODS: A total of 785 middle-aged subjects of the Risk Factors in Impaired Glucose Tolerance (IGT) for Atherosclerosis and Diabetes (RIAD) study underwent a 75-g oral glucose tolerance test and examination of various atherosclerosis risk factors. IMT was measured by B-mode ultrasound. RESULTS: One hundred and nineteen (15.2%) asymptomatic diabetic subjects were detected: of these, 35.3% with IFH, 26% with IPH and 38.7% with FH/PH. The level of risk factors was higher in diabetic vs. non-diabetic subjects. HbA1c and cardiovascular risk factors were in the same range for IFH and IPH except for active plasminogen activator inhibitor (PAI)-1 which was significantly higher in IFH. A higher risk burden was found in the FH/PH group vs. both IFH and IPH. IMT was as follows: non-diabetic subjects 0.85 +/- 0.18 mm, IFH 0.91 +/- 0.20 mm, IPH 0.94 +/- 0.18 mm, FH/PH 0.98 +/- 0.17 mm (P < 0.05 vs. non-diabetes). 2 h post-challenge glucose (2hPG) correlated more closely (r = 0.23, P < 0.001) to IMT than fasting plasma glucose (FPG) (r = 0.14, P = 0.004). The importance of 2hPG was confirmed by the direct comparison of FPG and 2hPG in a three dimensional analysis. A significant increase of IMT was only observed in the subgroups with abnormal post-challenge hyperglycaemia for both combinations with normal FPG and IFG. FPG category did not significantly add to IMT in either group of post-challenge hyperglycaemia. Regression analysis in the whole sample revealed 2hPG but not FPG as a significant determinant of IMT. Further significant risk factors were age, male sex, total cholesterol, HDL-cholesterol and hypertension. CONCLUSIONS: The RIAD study population at high risk for Type 2 diabetes mellitus, post-challenge hyperglycaemia was found to relate more strongly than fasting hyperglycaemia with carotid IMT.

Adult↗
PubMed2000

Prevalence and atherosclerosis risk in different types of non-diabetic hyperglycemia. Is mild hyperglycemia an underestimated evil?

So far little is known about the importance of different types of non-diabetic hyperglycemia for the development of macrovascular disease. The aim of this work was to examine the intima-media thickness (IMT) of the common carotid artery (CCA), a well-accepted marker of atherosclerosis, as well as various risk factors for atherosclerosis in non-diabetic subjects with isolated fasting (IFH; n=67), isolated postchallenge (IPH; n=82) and combined hyperglycemia (CH; n=88) in comparison to normoglycemic (NG; n=265) controls. Subjects were participants of the RIAD study (Risk Factors in IGT for Atherosclerosis and Diabetes). IMT in the IPH (IMTmean: 0.89+/-0.02 mm; IMTmax: 1.01+/-0.02 mm; mean+/-SEM) and CH group (IMTmean: 0.91+/-0.02 mm; IMTmax: 1.03+/-0.02 mm) was significantly increased vs. the NG (IMTmean: 0.82+/-0.01 mm; IMTmax: 0.94+/-0.01 mm) and IFH group (IMTmean: 0.81+/-0.02 mm; IMTmax: 0.90+/-0.03 mm). IMT of the IFH group was similar to the normoglycemic controls. Subjects in the first and second tertile for postchallenge plasma glucose have similar carotid IMT irrespective of the level of fasting plasma glucose. The individuals of the third tertile for 2 h plasma glucose, whether in the first, second or third tertile of fasting plasma glucose, showed the same carotid IMT, which was significantly higher than all other groups, except for the one with lowest tertile for fasting and postchallenge plasma glucose. Except for total cholesterol and von Willebrand factor the levels of all other risk parameters were significantly higher in the hyperglycemic groups in comparison to the normoglycemic controls. Among the hyperglycemic subjects the CH group was at the highest risk for atherosclerosis with significantly increased levels of plasma triglycerides, fibrinogen, PAI-1, albuminuria, HDL-triglycerides, free fatty acids, insulin and proinsulin, and significantly reduced HDL-cholesterol in comparison to the normoglycemic controls. In summary, postchallenge hyperglycemia within the non-diabetic range is associated with atherosclerosis, as measured by the increased intima-media thickness of the common carotid artery. Furthermore, cardiovascular risk factors are significantly raised in all types of non-diabetic hyperglycemia.

Albuminuria↗
PubMed1999

LPS and TNFalpha induce SOCS3 mRNA and inhibit IL-6-induced activation of STAT3 in macrophages.

Recent findings indicate that cytokine signaling can be modulated by other mediators of simultaneously activated signal transduction pathways. In this study we show that LPS and TNFalpha are potent inhibitors of IL-6-mediated STAT3 activation in human monocyte derived macrophages, rat liver macrophages and RAW 264.7 mouse macrophages but not in human hepatoma cells (HepG2) or in rat hepatocytes. Accordingly, LPS and TNFalpha were found to induce the expression of SOCS3 mRNA in each of the investigated type of macrophages but not in HepG2 cells. Using a specific inhibitor, evidence is presented that the p38 MAP kinase might be involved, especially for the inhibitory effect of TNFalpha.

Animals↗
PubMed1999

Different protein turnover of interleukin-6-type cytokine signalling components.

Interleukin (IL)-6 and IL-6-type cytokines signal through the gp130/Jak/STAT signal transduction pathway. The key components involved are the signal transducing receptor subunit gp130, the Janus kinases Jak1, Jak2 and Tyk2, STAT1 and STAT3 of the family of signal transducers and activators of transcription, the protein tyrosine phosphatase SHP2 and the suppressors of cytokine signalling SOCS1, SOCS2 and SOCS3. Whereas considerable information has been accumulated concerning the time-course of activation for the individual signalling molecules, data on the availability of the proteins involved in IL-6-type cytokine signal transduction are scarce. Nevertheless, availability of these molecules, determined by the balance of protein synthesis and degradation, also influences IL-6-type cytokine signal transduction. Here, we present a comprehensive set of data on the half-lives of the key molecules involved in the IL-6 signal transduction pathway. The turnover rates for the various proteins differ substantially. Three groups of signalling proteins can be discriminated: whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3 and SHP2 have an extremely slow turnover rate. Interestingly, the half-life of STAT3beta, a splice variant of STAT3alpha, is reduced to almost 50% of the half-life of STAT3alpha. The Janus kinases Jak1, Jak2, Tyk2 and gp130 show intermediate half-lives. Our data imply that signalling components activated by post-translational modifications are long-lived whereas the activity of very short-lived proteins is regulated mainly at the transcriptional level.

Antigens, CD↗
PubMed1999

[Prevalence of newly diagnosed type 2 diabetes, impaired glucose tolerance and abnormal fasting glucose in a high risk population. Data from the RIAD study using new diagnostic criteria for diabetes].

BACKGROUND AND OBJECTIVE: In 1997 the American Diabetes Association (ADA) introduced new criteria for the diagnosis of type 2 diabetes mellitus, reducing the upper limit of normal fasting blood sugar from 140 to 126 mg/dl. A level of between 110 and 126 < mg/dl (6.1-7.0 mmol/l) was added as a new category, "impaired fasting glucose" (IFG) as an at-risk factor. It was the aim of this study to determine what effect these new criteria will have on the prevalence of type 2 diabetes and other glucose tolerance stages in the German population. PATIENTS AND METHODS: The analysis was based on data collected in the "Risk-factors in IGT for atherosclerosis and diabetes" (RIAD) study. 1139 persons of an at-risk population group (aged 40-70 years) were investigated. Most of them were relatives of diabetics and/or themselves had obesity and/or dyslipidaemia. All known diabetics were excluded. All subjects underwent an oral glucose test with 75 g glucose, and plasma glucose values were used for classifying them into different glucose tolerance stages. RESULTS: According to the new ADA criteria, confirmed by WHO in 1998, the prevalence of type 2 diabetes mellitus was shifted from 11% to 15.1%, that of IGT from 28.8% to 26.2%. An impaired fasting glucose was found in 27.1% of the population cohort, 9.2% of whom had 2-hour plasma glucose levels corresponding to the diabetes criteria. Men in the first age decade (40-49 years) had a 14% prevalence of previously undetected type 2 diabetes, double that in women. Hyperlipidaemia, hypertension and obesity were significantly more common in diabetics and persons with IGT than in normoglycaemic persons. CONCLUSIONS: The prevalence of previously unknown type 2 diabetes is very high in this at-risk part of the population. Using the criteria for impaired fasting glucose, 9.2% diabetics would remain undetected. We, therefore, support the recommendation that an oral glucose tolerance test be performed in those of the population aged over 45 years and in younger at-risk persons so that any indicated treatment can be initiated at the earliest. Measurement of fasting glucose is adequate in the population aged under 45 years not at special risk.

Adult↗
PubMed1999

Identification of a Leu-lle internalization motif within the cytoplasmic domain of the leukaemia inhibitory factor receptor.

Leukaemia inhibitory factor (LIF) signals via a heterodimeric receptor complex comprised of the LIF receptor (LIFR) and the interleukin (IL)-6 signal transducer gp130. Upon binding to its cognate receptor LIF is internalized. In this study, we show that the LIFR is endocytosed independently of gp130. By using a heterochimaeric receptor system we identified a dileucine-based internalization motif within the cytoplasmic domain of the LIFR. Our findings suggest that a heterodimeric LIFR/gp130 complex and homodimeric gp130/gp130 complex are endocytosed via distinct internalization signals.

Animals↗
PubMed1999

Characterization and binding specificity of the monomeric STAT3-SH2 domain.

Signal transducers and activators of transcription (STATs) are important mediators of cytokine signal transduction. STAT factors are recruited to phosphotyrosine-containing motifs of activated receptor chains via their SH2 domains. The subsequent tyrosine phosphorylation of the STATs leads to their dissociation from the receptor, dimerization, and translocation to the nucleus. Here we describe the expression, purification, and refolding of the STAT3-SH2 domain. Proper folding of the isolated protein was proven by circular dichroism and fluorescence spectroscopy. The STAT3-SH2 domain undergoes a conformational change upon dimerization. Using an enzyme-linked immunosorbent assay we demonstrate that the monomeric domain binds to specific phosphotyrosine peptides. The specificity of binding to phosphotyrosine peptides was assayed with the tyrosine motif encompassing Tyr705 of STAT3 and with all tyrosine motifs present in the cytoplasmic tail of the signal transducer gp130.

Binding Sites↗
PubMed1999

Diminished susceptibility to in vitro oxidation of low-density lipoproteins in hypercholesterolemia: key role of alpha-tocopherol content.

Oxidizability of low-density lipoproteins (LDL) in hypercholesterolemia is of clinical relevance, but previous studies revealed diverging results. Therefore, we studied ex vivo oxidation of LDL in plasma samples of 57 hypercholesterolemic and 20 normocholesterolemic volunteers. LDL were isolated by ultracentrifugation and analyzed for lipids and alpha-tocopherol. The formation of conjugated dienes, lipoperoxides and malondialdehyde was measured at 0.1 micromol/l LDL, 3.2 micromol/l CuSO4. We found prolongation of the lagtime (53.6/65.8/71.4 min) with tertiles (< or = 3.17/3.89/14.2 mmol/l) of LDL-cholesterol (LDL-C). Regression analysis revealed that the lagtime increased with the apparent concentrations of cholesterol (P = 0.003) and alpha-tocopherol (P = 0.001) in the oxidation assay. A multiple regression model with the apparent concentrations of alpha-tocopherol, triglycerides and cholesterol explained 40% of the variation in lagtime. The close relationship between plasma concentrations of LDL-C and LDL-alpha-tocopherol (P = 0.002) indicated that LDL contained more of this antioxidant in hypercholesterolemia. This might provide an explanation for the positive relationship between lagtime and LDL-C. The latter was independent of whether LDL-C or LDL-protein was chosen for standardization of the oxidation assay. The formation of conjugated dienes (P = 0.000), lipoperoxides (P = 0.038) and malondialdehyde (P = 0.001) increased with the cholesterol level in the assay. This may be due to the increased load of LDL with cholesterol esters as a substrate for oxidation in hypercholesterolemia. Our data do not support the opinion that hypercholesterolemia is characterized by increased susceptibility of LDL to oxidation.

Adult↗
PubMed1999

Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals.

Postprandial (pp) hyperglycemia--frequently associated with an increase in cardiovascular risk factors--may be damaging for the endothelium. So far, little information exists how glucose, insulin and lipids may affect atherosclerosis in the pp state. Therefore, we evaluated the relationship of pp hyperglycemia, insulin secretion and coronary risk factors to intima-media thickness (IMT) in a non-diabetic risk population. In 403 subjects (147 males, 256 females), aged 40-70 years, in the majority relatives of index cases with type 2 diabetes--a 75 g oral glucose tolerance test was performed together with measurement of insulin fractions, various risk factors and IMT of the common carotid artery. We found a continuous rise of 2h pp insulin fractions along the quintiles of 2h pp plasma glucose. A significant increase of body mass index, waist to hip ratio, triglycerides and decrease of HDL-cholesterol was observed in the top quintile of 2h pp plasma glucose (8.24 > or = pp plasma glucose < 11.1 mmol/l). Albuminuria was significantly enhanced in the 5th quintile. In parallel, IMT was significantly increased in the 5th quintile versus the bottom quintile of 2 h and maximal glucose (range 11.7-15.3 mmol/l) postprandially. After age and sex adjustment pp glucose and C-peptide, total cholesterol, triglycerides and HDL-cholesterol but not fasting plasma glucose were significantly correlated to IMT. In multivariate analysis age, male sex, pp plasma glucose, total and HDL-cholesterol were found to be independent risk factors for increased IMT. In conclusion, our data in a non-diabetic European risk population show that the two top quintiles of pp plasma glucose are associated with a clustering of standard risk factors. Corresponding to this clustering of risk factors IMT was significantly increased in the top quintile of 2 h and maximal pp plasma glucose. These data show that pp hyperglycemia may exert a noxious impact on the arterial wall together with a cluster of anomalies typical for the metabolic syndrome.

Adult↗
PubMed1999

Impaired fasting glucose is not a risk factor for atherosclerosis.

AIM: To determine a new category of dysfunctional glucose homeostasis - impaired fasting glucose (IFG) - introduced by the American Diabetes Association (ADA) and the World Health Organization (WHO) defining those with abnormal but nondiabetic fasting glucose values and with a possible risk for developing diabetes. It is not known whether IFG is a risk factor for atherosclerosis, as is impaired glucose tolerance (IGT). METHODS: In this case-control cross-sectional study in which the oral glucose tolerance (75-g OGTT) and the carotid intima-media thickness (IMT) with B mode ultrasound, as a marker of atherosclerosis, were measured, together with HbA1c, lipids, plasminogen activator (PAI), insulin and proinsulin concentrations in blood plasma. Out of 788 subjects of the risk factors in IGT for Atherosclerosis and Diabetes (RIAD) study we found 104 IFG cases that were compared to 104 controls with fasting plasma glucose (FPG)<6.1 mmol/l, matched for age, sex and body mass index. Subjects with 2h postprandial (pp) plasma glucose > or = 11.1 mmol/l were excluded. The rest were subdivided into those with 2h plasma glucose < 7.8 mmol/l (63 pairs, NGT) and those with plasma glucose > 7.8 mmol/l and < 11.1 mmol/l (41 pairs, IGT). RESULTS: The case and control groups showed no significant differences in the major risk factors except for waist-to-hip ratio (WHR) which was higher in the IFG with NGT. IFG with NGT exhibited significantly higher levels of HbA1c, true insulin and proinsulin. In IFG with IGT, only HbA1c and proinsulin were significantly increased vs. controls. IMT was in the same range for cases and controls in both subgroups. However, IMT mean and IMTmax were significantly increased in IFG with IGT vs. IFG with NGT (0.95 mm vs. 0.80 mm and 1.10 mm vs. 0.90 mm). Cumulative distribution analysis of IMT illustrates that IMT in IFG with IGT is more shifted to higher artery wall thickness than in IFG with NGT. CONCLUSIONS: In our case-control study IFG alone was not related to increased IMT. Only IFG in a combination with IGT exhibited atherosclerotic changes of the carotid arteries. IFG is not analogous to IGT as a risk factor for atherosclerosis.

Arteriosclerosis↗
PubMed1999

Increased intimal-medial thickness in newly detected type 2 diabetes: risk factors.

OBJECTIVE: To examine carotid intimal-medial thickness (IMT) and its determinants in newly detected type 2 diabetic subjects, classified according to the new criteria of the American Diabetes Association, in comparison with age- and sex-matched control subjects with normal glucose tolerance. RESEARCH DESIGN AND METHODS: This study was case-controlled, with matched pairs for 71 newly diagnosed type 2 diabetic individuals. Subjects aged 40-70 years were recruited from a risk population for diabetes seen in the Risk Factors in IGT for Atherosclerosis and Diabetes (RIAD) Study. Standard risk factors, 75-g oral glucose tolerance test with real insulin, proinsulin, and C-peptide, and ultrasound measurement of the IMT of the common carotid artery were performed. RESULTS: The diabetic subjects, both men and women, displayed carotid intimal-medial thickening, even in the subgroup with fasting plasma glucose between 7.0 and 7.8 mmol/l. HbA1c was significantly increased in the diabetic patients (6.33 vs. 5.48%). Insulin, proinsulin, and C-peptide were also significantly higher. Among the coronary risk factors, triglycerides and plasminogen activator inhibitor were significantly increased. After age and sex adjustment. IMT in the diabetic group was correlated to triglycerides and the total-to-HDL cholesterol ratio. In the total group, IMT was significantly correlated to blood pressure, 2-h glucose in oral glucose tolerance testing, triglycerides, albuminuria, and the total-to-HDL cholesterol ratio, and inversely correlated to HDL cholesterol. No independent determinant of IMT was found in the diabetic group by multivariate analysis. CONCLUSIONS: Newly detected type 2 diabetic patients exhibit a higher degree of early atherosclerosis than normal glucose-tolerant subjects matched for age and sex. Our data suggest that hyperglycemia, together with a clustering of risk factors, and in particular dyslipidemia, may cause intimal-medial thickening in the early phases of diabetes.

Adult↗
PubMed1998

Constitutive internalization and association with adaptor protein-2 of the interleukin-6 signal transducer gp130.

The transmembrane protein gp130 is the common signalling receptor subunit for the interleukin-6 (IL-6)-type cytokines. It has recently been shown that the cytoplasmic domain of gp130 contains a dileucine internalization motif and that endocytosis of gp130 occurs signal-independent. Here, we have studied whether gp130 itself undergoes constitutive internalization or whether its endocytosis is stimulated by formation of the IL-6/IL-6R/gp130 complex. Using two different assays, we found that gp130 is internalized independent from IL-6/IL-6R stimulation. In addition, we show that gp130 is constitutively associated with the cell surface adaptor complex AP-2. Our findings strongly suggest endocytosis of gp130 to be constitutive.

Adaptor Protein Complex alpha Subunits↗
PubMed1998

Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression.

Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor-glycoprotein 130 (IL-6R-gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6-soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759-->Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.

Antigens, CD↗
PubMed1998

Functional domains of interferon regulatory factor I (IRF-1).

Interferon (IFN) regulatory factors (IRFs) are a family of transcription factors among which are IRF-1, IRF-2, and IFN consensus sequence binding protein (ICSBP). These factors share sequence homology in the N-terminal DNA-binding domain. IRF-1 and IRF-2 are further related and have additional homologous sequences within their C-termini. Whereas IRF-2 and ICSBP are identified as transcriptional repressors, IRF-1 is an activator. In the present work, the identification of functional domains in murine IRF-1 with regard to DNA-binding, nuclear translocation, heterodimerization with ICSBP and transcriptional activation are demonstrated. The minimal DNA-binding domain requires the N-terminal 124 amino acids plus an arbitrary C-terminal extension. By using mutants of IRF-1 fusion proteins with green fluorescent protein and monitoring their distribution in living cells, a nuclear location signal (NLS) was identified and found to be sufficient for nuclear translocation. Heterodimerization was confirmed by a two-hybrid system adapted to mammalian cells. The heterodimerization domain in IRF-1 was defined by studies in vitro and was shown to be homologous with a sequence in IRF-2, suggesting that IRF-2 also heterodimerizes with ICSBP through this sequence. An acidic domain in IRF-1 was found to be required and to be sufficient for transactivation. Epitope mapping of IRF-1 showed that regions within the NLS, the heterodimerization domain and the transcriptional activation domain are exposed for possible contacts with interacting proteins.

Amino Acid Sequence↗
PubMed1998

Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway.

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.

Animals↗