Biomedical subjects

J Kuhlmann

Publications and source records attributed to J Kuhlmann.

At least 19 recordsLinked to original sources

PubMed1996

Defective interactions between TCR chains and CD3 heterodimers prevent membrane expression of TCR-alpha beta in human T cells.

The human TCR complex is composed of two clonotypic polypeptide chains, TCR-alpha and TCR-beta (or TCR-gamma and TCR-delta) associated with CD3 gamma-, delta-, and epsilon-chains and zeta 2 homodimers. All six polypeptide chains are indispensable for TCR membrane expression and signaling function. In the present paper is described the analysis of a new TCR membrane-negative Jurkat T cell variant: E6.R3. The defect in this variant bears on the interaction between TCR and CD3 chains. E6.R3 cells have deleted three nucleotides in the TCR-alpha transmembrane (TM) region, which consequently lacks a leucine. This defect causes 1) lack of association between TCR alpha-chains and CD delta epsilon heterodimers; 2) lack of formation of disulphide-linked, fully glycosylated TCR-alpha beta heterodimers; and 3) lack of interaction between TCR-alpha beta/CD3 complexes and zeta-chains. Despite these defective interactions, TCR alpha-chains appear to become fully glycosylated, i.e., they are not retained in the endoplasmic reticulum but are further processed in the Golgi apparatus without such interactions. The defect may be due to the observation that in the E6.R3 TCR alpha- chains TM region, the two charged amino acids are situated on the same side of the alpha-helix; these two amino acids are exposed on opposite faces of the TM alpha-helix in normal TCR alpha-chains, possibly allowing TCR alpha-chains to interact with both CD3 delta- and CD3 epsilon-chains. Further possible consequences of the leucine deletion in the E6.R3 TCR-alpha TM region are discussed.

Amino Acid Sequence↗

PubMed1996

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.

The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a two-compartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V2), volume of the peripheral compartment (V3), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL = 8.8 + 0.396. WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V2 and V3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V2 and V3, respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

Administration, Oral↗

PubMed1996

The influence of age on the pharmacokinetics of nimodipine.

Single and multiple dose pharmacokinetics and absolute bioavailability of the calcium antagonist nimodipine (Nimotop) were investigated in 24 young (age: 22 - 40 years) and 24 elderly (age: 59 - 79 years) healthy subjects. There were no significant changes in blood pressure, heart rate, and ECG-parameters in both age groups, and no increase in frequency of adverse events was observed in the elderly. Following a single intravenous infusion of 15 micrograms/kg for 1 hour, there were no significant differences in nimodipine pharmacokinetics between young and elderly volunteers. Oral administration (single dose of 30 mg, 30 mg t.i.d. for 6 days), however, resulted in pronounced differences in AUC and Cmax between elderly and young subjects when the same doses were given. Under steady-state conditions the elderly reached significantly higher Cmax (g.mean/SD: 23.3/1.62 micrograms/l) and AUC-values (47.5/1.62 micrograms*h/l) than the young volunteers (13.5/2.03 micrograms/l, and 25.7/1.73 micrograms*h/l, respectively). The absolute bioavailability was 10.6/1.60% in the elderly and 5.4/2.11% in young subjects. The observed pharmacokinetic differences in the study most likely reflect the reduced metabolic clearance of nimodipine in the elderly.

Adult↗

PubMed1995

Nimodipine. Potential for drug-drug interactions in the elderly.

Nimodipine is indicated for a variety of conditions in elderly patients. Elderly patients often have multiple morbidity and receive treatment with a variety of drugs. Therefore, it is important to investigate the possible pharmacokinetic and pharmacodynamic interactions of nimodipine with various drugs commonly prescribed for elderly patients. There were no clinically relevant interactions of nimodipine with any of the following specific agents studied: the antiarrhythmics mexiletine, propafenone, disopyramide or quinidine, digoxin, the beta-adrenoceptor antagonists propranolol or atenolol, nifedipine, warfarin, diazepam, indomethacin, ranitidine or glibenclamide (glyburide). However, there were some notable interactions. In epileptic patients taking the anticonvulsants carbamazepine, phenobarbital (phenobarbitone) and/or phenytoin, there was a 7-fold decrease in the area under the plasma concentration versus time curve (AUC) and an 8- to 10-fold decrease in the maximum plasma concentration of nimodipine. These effects were to be expected, considering the hepatic enzyme-inducing properties of these anticonvulsant drugs. Therefore concomitant use of these agents with oral nimodipine is not recommended. In contrast, epileptic patients treated with nimodipine and valproic acid (sodium valproate) showed an increase in both the AUC (approximately 50%) and maximum plasma concentrations (approximately 30%) of nimodipine, which may be explained by valproic acid inhibiting the presystemic oxidative metabolism of nimodipine. Concomitant administration of cimetidine produced an approximate doubling of the bioavailability of nimodipine. This again was to be expected, considering the known inhibitory effect of cimetidine on cytochrome P450. However, no changes in haemodynamics, clinical or laboratory status or tolerability were observed, and dose adjustment did not appear to be clinically necessary.

Aged↗

PubMed1995

Pharmacokinetic development of quinolone antibiotics.

A prerequisite for the pharmacokinetic development of quinolone antibiotics is a sensitive and accurate method for the quantification of the drug in biological fluids. Both, a drug specific (e.g. HPLC) and a drug non-specific but effect related assay (e.g. bioassay) should be used during early clinical development to detect major active metabolites. The basic pharmacokinetic behavior of the drug is investigated as part of the early phase I program, where single and multiple ascending dose studies are performed to characterize the safety and tolerability of the quinolone in healthy volunteers. Further pharmacokinetic studies are performed to describe the absolute bioavailability, dose proportionality, pharmacokinetics in young and elderly, male and female volunteers. The suitability of the clinical dosage from must be evaluated in comparison to an oral solution and by quantification of the effect of food on bioavailability. The characterization of the absorption in different parts of the gastrointestinal tract may be valuable for dosage form optimization. In order to start phase IIb clinical trials, the potential of possible drug-drug interactions with antacids, cimetidine, theophylline and warfarin has to be evaluated. This can be done by in vitro and in vivo preclinical experiments, before formal clinical-pharmacology studies are performed. Further pharmacokinetic characterization (e.g. studies in special subpopulation, extended interaction studies, total recovery using 14C-labelled compound, blister fluid penetration) will be done parallel to the phase II/III development program. During these efficacy and safety trials blood samples should be obtained and PK-parameters can be calculated using sparse data analysis methods like non-linear mixed effect modeling (NONMEM) or Bayesian methods to characterize the pharmacokinetics in the target population.

4-Quinolones↗

PubMed1995

Chronic administration of nimodipine and propranolol in elderly normotensive subjects--an interaction study.

Nimodipine (30 mg t.i.d.) and propranolol (40 mg t.i.d.) were given orally to 24 healthy elderly subjects in a randomized, un-blinded, threefold crossover study. Each of the study periods lasted 8 days with a 5-day treatment phase separated by 2-week washout phases. Mean peak nimodipine plasma concentration was decreased after combined administration of the two drugs (16.1 +/- 8.1 micrograms/l vs. 12.4 +/- 9.5 micrograms/l). Nimodipine AUCss slightly decreased under propranolol co-medication from 44.9 +/- 15.1 micrograms x l/l to 38.8 +/- 22.5 micrograms x h/l, resulting in an AUC ratio of 88.8 +/- 44.5%. The relative bioavailability of propranolol was 104.1 +/- 38.3% after the combined propranolol and nimodipine medication, all other pharmacokinetic parameters remained unchanged. The pharmacological effects on the cardiovascular system were negligible after nimodipine alone. The reductions in blood pressure and pulse rate and the prolongations of typical ECG times observed after propranolol monotherapy and after the combination therapy were of similar size and were almost solely attributed to the action of the beta-blocker. The findings of this study indicate that chronic treatment with nimodipine together with propranolol should not be associated with a clinically relevant interaction.

Aged↗

PubMed1995

The influence of nimodipine on hemodynamic parameters and peak and trough plasma concentrations of nifedipine chronically administered to elderly hypertensive patients.

Possible drug interactions between the two calcium channel blockers nimodipine and nifedipine were investigated in 12 elderly patients with stable mild to moderate hypertension. Their individually adjusted nifedipine treatment had been unchanged for at least 5 weeks. There was no evidence of significant changes in nifedipine efficacy as seen from blood pressure and heart rate after a 7-day comedication of 30 mg nimodipine t.i.d. as compared with the findings after combined administration of nifedipine and placebo. Nifedipine steady-state trough and peak concentrations were not significantly altered by concomitant nimodipine administration. On the other hand, nifedipine did not affect nimodipine trough and peak concentrations when compared with published data. Differences in clinical chemistry or tolerance between both treatment regimens did not occur or were marginal, respectively. In conclusion, a clinically relevant drug interaction between nifedipine and nimodipine which might be potentially harmful for patients with hypertension was not observed in this study.

Aged↗

PubMed1995

Rat adjuvant arthritis: imaging with technetium-99m-anti-CD4 Fab' fragments.

UNLABELLED: The abundance of CD4 molecules on inflammatory cells in the synovial membrane renders anti-CD4 monoclonal antibodies (MAbs) or their fragments very promising for specific imaging of arthritic joints. METHODS: Joint uptake and body distribution of a 99mTc-labeled Fab', derived from the anti-rat CD4 MAb W3/25 (IgG1), were investigated following intravenous injection in normal and adjuvant arthritic rats. An isotype-matched Fab' (anti-human nonspecific crossreacting antigen-90) was used as control. RESULTS: A 14-hr sequential pinhole scan of the ankle joints revealed that both the anti-CD4 and the control Fab' accumulated to a higher degree in arthritic than in normal ankle joints; however, accumulation of the anti-CD4 Fab' in arthritic joints exceeded that of the control Fab' (approximate to 1.6 fold). Preferential joint accumulation of anti-CD4 Fab' was confirmed by whole-body scans at 14 hr and by direct well counter measurements of tissue samples at 16 hr following injection. Unlike the control Fab', the anti-CD4 Fab' preferentially accumulated in the liver and lymph nodes, organs rich in CD4-positive cells, as observed by direct tissue measurements. CONCLUSION: Despite its monovalency, the anti-CD4 Fab' retains the in vivo selectivity for CD4-positive cell-rich tissues, previously reported for the complete anti-CD4 MAb, and improves imaging of inflamed joints in experimental adjuvant arthritis.

Animals↗

PubMed1995

Pharmacokinetics, safety and tolerability of the orally administered receptor antagonist of cysteinyl-leukotrienes BAY x 7195 in single-dose escalation studies.

BAY x 7195 is a novel receptor antagonist of cysteinyl-leukotrienes currently under development for the treatment of asthma. It is effective in antagonizing the leukotriene-D4 induced bronchoconstriction in healthy volunteers following oral administration. The pharmacokinetics, safety and tolerability of the drug were investigated in six partially placebo-controlled studies in healthy volunteers with single oral administration of a 50, 100, 250, 500 and 1000 mg dose as a tablet. The drug was well tolerated. The only remarkable adverse event was diarrhea in one volunteer receiving the highest dose of 1000 mg. There were no additional clinically relevant changes in any safety parameter including laboratory values. Concentrations of BAY x 7195 were determined in plasma and urine by high performance liquid chromatography with fluorescence detection and plasma-concentrations were further evaluated by compartmental and non-compartmental methods. The concentration vs time profiles of the drug were biphasic with a dominant t1/2 of 0.5-2 h and a terminal t1/2 of 5-10 h. Pharmacokinetics were linear in the investigated range of doses. In spite of substantial inter-subject variability intra-individual variability in AUC and Cmax was reasonable. In general, the concentration vs time profiles could be described with a 2-compartment body model. However, in some cases the occurrence of second and third concentration maxima necessitated the use of a multiple segment absorption model to accomplish a good fit to the data. Enterohepatic recirculation following glucuronidation of the drug is the likely reason for the multiple peaks. Urinary excretion of BAY x 7195 and its glucuronide metabolite was negligible the amount excreted into urine from 0 to 48 h being < 0.1% of the dose. The low renal clearance of BAY x 7195 (< or = 0.07 ml/min) is suggestive of significant reabsorption in the renal tubuli taking into account that the expected renal clearance for a drug with 99.5% protein binding is about 0.6 ml/min.

Administration, Oral↗

PubMed1994

Structure of the T cell receptor in a Ti alpha V beta 2, alpha V beta 8-positive T cell line.

The T cell receptor (TcR) is composed of at least six different polypeptide chains consisting of the clonotypic Ti heterodimer (Ti alpha beta or Ti gamma delta) and the noncovalently associated CD3 chains (CD3 gamma delta epsilon zeta). The exact number of subunits constituting the TcR is still not known; however, it has been suggested that each TcR contains two Ti dimers. To gain insight into the structure of the TcR we constructed a Ti alpha V beta 2, alpha V beta 8-positive T cell line which expressed the endogenous human TiV beta 8 and the transfected mouse TiV beta 2 both in association with the endogenous Ti alpha and CD3 chains at the cell surface. Preclearing experiments with radioiodinated cell lysate prepared with digitonin lysis buffer demonstrated that depleting the lysate of Ti alpha V beta 8 by immunoprecipitation with anti V beta 8 monoclonal antibody (mAb) did not reduce the amount of Ti alpha V beta 2 in the lysate, and likewise, depleting the lysate of Ti alpha V beta with anti-V beta 2 mAb did not reduce the amount of Ti alpha V beta 8. Comodulation experiments showed that V beta 8 and V beta 2 did not comodulate with each other. Furthermore, functional tests demonstrated that TcR containing V beta 8 and TcR containing V beta 2 mediated transmembrane activation signals independently of each other. These data demonstrate that mouse V beta 2 and human V beta 8 were not expressed in the same TcR in agreement with a TcR model where each TcR contains only one Ti dimer.

Animals↗

PubMed1994

Effect of BAY x 7195, an oral receptor antagonist of cysteinyl-leukotrienes, on leukotriene D4-induced bronchoconstriction in normal volunteers.

Leukotrienes (LT) have been proposed to play an important role in the pathogenesis of asthma. This paper reports the results of two studies investigating the effect of BAY x 7195, a new oral receptor antagonist of cysteinyl-leukotrienes, on LTD4-induced bronchoconstriction in healthy male volunteers. Using a double-blind, placebo-controlled, crossover design, volunteers received 250 mg (n = 6; study 1) and 100 and 500 mg (n = 6; study 2) of BAY x 7195. Bronchoprovocation with nebulized LTD4 was performed 2 (250 mg) and 2 and 8 (100 and 500 mg) h p.a. The specific airway's conductance (SGaw) was used to assess the airway's response. Blood samples to determine plasma concentrations of BAY x 7195 were taken at the end of bronchoprovocation. BAY x 7195 showed no effect on baseline lung function. Compared to placebo, the different doses of BAY x 7195 increased the concentration of LTD4 needed to produce a 35% decrease in SGaw 2 h p.a. between 1- and 23-fold. Eight hours p.a., 100 and 500 mg caused shifts in the concentration-response curve of between 1- and 13-fold. There was no predictive relationship between plasma concentrations of BAY x 7195 and the response to LTD4 challenge. However, there was a relationship between dose and effect. No relevant adverse effects were reported. In conclusion, the present results suggest that BAY x 7195 is an effective LTD4-receptor antagonist in man.

Administration, Inhalation↗

PubMed1994

Lack of interaction between diazepam and nimodipine during chronic oral administration to healthy elderly subjects.

1. Nimodipine (30 mg three times daily) and diazepam (10 mg once daily), were given orally to 24 elderly healthy subjects in a randomized, non-blinded, threefold-crossover study. Each of the three treatment periods lasted 5 days separated by 2 week washout phases. 2. Plasma concentrations of nimodipine and diazepam were not affected by the combined treatment. 3. No clinically relevant changes in haemodynamics, ECG recordings, clinical chemistry or haematology were observed after all of the three treatments. The overall frequency of side effects was lowest during monotherapy with nimodipine and highest during diazepam monotherapy. 4. In the test of subjective rating of tiredness (VAS) and the Pauli calculation test, diazepam, alone and with nimodipine co-medication, produced an increase in tiredness and a clear reduction in performance and endurance. After nimodipine monotherapy an improvement was observed only in the Pauli test. Using the critical flicker fusion frequency test (CFF) significant decrements in performance were found after diazepam monotherapy only. 5. In summary, there was no evidence that either nimodipine or diazepam affected the pharmacokinetics, safety and tolerance of each other. However, the CNS-effects of diazepam were compensated partially by nimodipine.

Administration, Oral↗

PubMed1994

Bicarbonate-based dialysis solution preserves granulocyte functions.

OBJECTIVE: Intraperitoneal phagocytes play an important role in local defense in preventing continuous ambulatory peritoneal dialysis (CAPD) peritonitis. This study therefore investigates the effect of the conventional lactate-based dialysis solution-pH 5.2 (LBDS-pH 5.2) and a bicarbonate-based dialysis solution (BBDS) on various cell functions. DESIGN: We studied C5a-induced actin polymerization (AP) as a measure of the cytoskeletal alteration, phagocytosis of zymosan particles, and chemotaxis in neutrophils incubated in either LBDS-pH 5.2, LBDS-pH 7.4, or BBDS-pH 7.4, comparing the data with cells treated with phosphate-buffered saline-pH 7.4 (PBS-pH 7.4) as a control. SUBJECTS: Polymorphonuclear neutrophils (PMNs) were isolated from the blood of healthy donors and incubated with dialysis solution prior to the experiment. RESULTS: C5a-induced AP was dramatically inhibited in PMNs incubated in LBDS-pH 5.2, paralleled by a complete inhibition of phagocytosis and C5a-induced chemotaxis. In comparison, BBDS improved AP to values above the control and also nearly normalized phagocytosis. Chemotaxis markedly improved in cells treated with the low glucose-containing BBDS (Bic 20), containing high glucose concentrations (Bic 30). CONCLUSION: In comparison with conventional lactate-based dialysis solution-pH 5.2, bicarbonate-based dialysis solution at low osmolality better preserves neutrophil functions that involve the cytoskeleton.

Actins↗

PubMed1994

Drug interaction studies during drug development: which, when, how?

Drug-drug interaction studies have become an important aspect of the development process of new drugs. Since formal studies of all possible interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated during the development phase is indicated. Priorities should be based on the likelihood of certain combinations to occur in clinical practice as well as on risks associated with them. In the main, clinical drug interaction studies are performed during late phase II and phase III of clinical drug development. In some exceptional cases clinical interaction studies are necessary at an earlier stage of development. This counts especially for drugs with a small therapeutic range and a steep course of the dose-response curve and especially for drug interactions which may effect vital processes. For all other drugs often administered together an initial screen for pharmacokinetic and/or pharmacodynamic interactions with plasma level measurements and examinations of a possible concentration-effect relationship might be sufficient. Taking these criteria into account an interaction program for new drugs under development with different indications like cardiovascular diseases, respiratory diseases, diseases of the central nervous system as well as rheumatic diseases, metabolic diseases and infectious diseases was developed.

Dose-Response Relationship, Drug↗

PubMed1993

Characterization of T cell receptor assembly and expression in a Ti gamma delta-positive cell line.

T cell antigen receptor (TcR) heterodimers of both the Ti-alpha beta and Ti-gamma delta types are expressed at the surface of T cells noncovalently associated with the CD3 complex composed of the monomorphic chains gamma, delta, epsilon and zeta. The structural relationship and assembly of the various components of this multimeric protein complex is still not fully understood. In this report, the human leukemic T cell line Lyon which expresses a Ti-gamma delta/CD3 complex, was characterized and compared to another human leukemic T cell line Jurkat (Ti-alpha beta/CD3). Membrane TCR-/CD3- variants of the T cell Lyon were induced and found to produce all of the Ti/CD3 components, with the exception of Ti-delta. Biochemical analysis indicated that: (1) Ti-gamma/CD3 gamma, delta, epsilon complexes were formed in the endoplasmic reticulum in the absence of Ti-delta; (2) the CD3-zeta chain did not associate with the Ti-gamma/CD3 gamma delta epsilon complex and (3) the Ti-delta chain was required for cell surface expression of the Ti-gamma delta/CD3 complex. Introduction of Jurkat wild-type Ti-alpha cDNA into Lyon T cells resulted in Ti-alpha beta/CD3 expression and abrogated Ti-gamma delta/CD3 expression. In contrast, the expression of the Ti-gamma delta/CD3 complex was not affected by transfection of a mutated Ti-alpha cDNA into Lyon cells. The mutated Ti-alpha chain formed complexes with Ti-beta and CD3 gamma delta epsilon, but the CD3-zeta chain did not associate with these complexes. Taken together analysis of Lyon cells transfected with either wild-type or mutated Ti-alpha suggested that the CD3-zeta chain may have higher affinity for Ti-alpha beta/CD3 complexes than for Ti-gamma delta/CD3 complexes.

Biological Transport↗

PubMed1993

Effect of food on the pharmacokinetics of the active metabolite of the prodrug repirinast.

The effect of food on the pharmacokinetics of the active metabolite of the new antiasthmatic drug repirinast was investigated in two different studies after oral administration of 300 mg of repirinast. In each study, 12 healthy volunteers received the repirinast dose under fasting or fed conditions in a crossover manner. In one study, a high-fat meal (American breakfast) was used and in another study, a low-fat, high-carbohydrate meal (continental breakfast) was used. Concentrations of the active metabolite in plasma and urine were determined by reversed-phase high-performance liquid chromatography with UV detection. After administration of repirinast with a low-fat and a high-fat meal, the relative bioavailability of the active metabolite increased by factors of 1.9 and 2.4, respectively, as expressed by area under the curve of concentration versus time from 0 to 12 h. The amount excreted into urine doubled after drug administration with both types of food and accounted for approximately 8% of the dose under fasting conditions and approximately 16% of the dose under fed conditions. Maximum concentrations in plasma were different between the two studies: mean maximum concentrations in plasma increased by factors of 1.7 and 3.2 after administration of drug with a low-fat (drug intake immediately after breakfast) and a high-fat breakfast (drug intake just before breakfast), respectively, compared with fasting conditions.

Adult↗

PubMed1993

Structure of the T-cell receptor in a Ti alpha beta, Ti gamma delta double positive T-cell line.

The multichain T-cell receptor is composed of at least six different polypeptide chains. The clonotypic Ti heterodimer (Ti alpha beta or Ti gamma delta) is non-covalently associated with the CD3 chains (CD3 gamma delta epsilon zeta). The exact number of subunits constituting the T-cell receptor is still not known. It has been suggested that each T-cell receptor contains two Ti dimers. To gain insight into the structure of the T-cell receptor we constructed a Ti alpha beta, Ti gamma delta double positive T-cell line which contained four functional Ti chains (Ti alpha, beta, gamma, and delta). The data demonstrated an absence of Ti dimers containing mixtures of chains other than the typical Ti alpha beta and Ti gamma delta combinations. Furthermore, by co-modulation experiments we demonstrated that the Ti alpha beta and the Ti gamma delta dimers were not expressed in the same T-cell receptor. Our data indicate that the T-cell receptor does not contain two Ti dimers.

Antibodies, Monoclonal↗

PubMed1993

The IE allogeneic response of T cells from C57Bl/6 mice is associated with genes in the TCRa locus.

It has been demonstrated that induction of immune responses, infectious diseases and autoimmune manifestations can be associated with at least four gene loci: the major histocompatibility complex (MHC) locus; the immunoglobulin (Ig) heavy chain (Hc) locus; and the T-cell receptor (TCR) TCR-alpha or TCR-beta chain loci. In the present study, we have analysed whether T-cell responses of IE-negative C57Bl/6 (B6) mice to IE alloantigen (IE alpha transgenic B6 mice = B6.E alpha 16) or to trinitrophenylated (TNP) syngeneic spleen cells were influenced by changes in the Ig-Hc locus or the TCRa locus. Whereas the fine specificity of T-cell responses to IE alloantigen was the same in B6 mice and in Ig-Hc congenic B6.26a or TCRa congenic B6.10TCa mice, the latter strain of mice demonstrated much higher IE-specific T-cell responses against B6.E alpha 16 spleen cells than B6 or B6.26a mice. This high responsiveness was a dominant feature and associated with the TCRa locus. In addition, the TCRV alpha or V beta repertoire of the congenic strains of mice was polyclonal and very similar. The TNP-specific T-cell responses of B6 and B6.10TCa mice showed the same restricted TCRV alpha and V beta repertoire. It is concluded that in both an oligoclonal T-cell response (anti-TNP) and a polyclonal T-cell response (anti-IE), exchange of Ig-Hc or TCRa loci does not significantly influence the TCRV alpha or V beta repertoire in IE-negative C57Bl/6 mice.

Animals↗