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Biomedical subjects

T Ikonen

Publications and source records attributed to T Ikonen.

At least 19 recordsLinked to original sources
PubMed2000

Prevention of acute allograft rejection in nonhuman primate lung transplant recipients: induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressive activity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin.

BACKGROUND: In previous studies of cynomolgus monkey lung allograft recipients, we demonstrated significant immunosuppressive efficacy but reduced tolerability after combined treatment with high doses of microemulsion cyclosporine (CsA) and SDZ RAD (40-O-(2-hydroxyethyl)-rapamycin). The current study was designed to compare efficacy and tolerability of a combination of low-dose CsA and high-dose SDZ RAD (CTL group) to triple therapy using the chimeric anti-interleukin-2 (IL-2) receptor (CD25) monoclonal antibody (mAb) basiliximab (anti-IL-2 receptor mAb) for induction therapy (basiliximab: 5 mg intravenously on days 0 and 4) plus low-dose CsA and low-dose SDZ RAD for maintenance immunosuppression (CD25 group). CsA and anti-IL-2 receptor mAb are drugs that reduce cytokine synthesis and block IL-2-mediated lymphocyte stimulation, respectively. SDZ RAD blocks lymphocyte stimulation by other cytokines (e.g., IL-15) that are not inhibited by anti-IL-2 receptor mAb. METHODS: Twelve unilateral lung transplants were performed. Recipients were observed for 49 days by daily weight assessment, hemograms, blood chemistries, radiographs, and lung biopsies. Monkeys were euthanized before day 49 in the event of excessive weight loss (>25%) or organ failure. Target CsA trough levels were 100-200 ng/ml. Target SDZ RAD trough levels in the CTL group (no mAb) were 20-40 ng/ml, and 10-20 ng/ml in the CD25 group. RESULTS: None of the monkeys in the CD25 group needed to be euthanized early due to signs of drug toxicity. In contrast, four monkeys in the CTL group were sacrificed on days 28-35 as a result of excessive weight loss (n=3) and renal functional impairment (n=1). Three recipients in the CD25 group were euthanized on days 36, 38, and 46 as a result of persistent high fever associated with severe rejection. The median animal survival in the CTL group was 32 vs. 46 days in the CD25 group (P<0.04). The only two long-term survivors in the CTL group showed moderate rejection at day 49. The median rejection scores at day 14 (A0) and day 28 (A2) were identical in the two groups, despite the fact that the mean SDZ RAD trough level was significantly lower in the CD25 group (CTL: 38+/-3 ng/ml, CD25: 18+/-2 ng/ml, P<0.0001). After basiliximab levels fell below the minimum therapeutic level (1 mg/ml) on day 28, the median rejection score at day 49 increased to A4 in the CD25 group. CONCLUSION: This is the first study to combine an anti-IL-2 receptor mAb with a drug from the rapamycin class plus CsA. Our study shows that induction therapy with basiliximab enabled SDZ RAD blood levels to be significantly reduced, which led to improved tolerability without the penalty of increased rejection.

Animals↗
PubMed2000

Combined immunosuppression with cyclosporine (neoral) and SDZ RAD in non-human primate lung transplantation: systematic pharmacokinetic-based trials to improve efficacy and tolerability.

BACKGROUND: We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy. METHODS: Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy. RESULTS: Graft biopsies in monkeys treated with vehicle (n=4), Neoral (day 1-7: 150 mg/kg/day; day 8-28: 100 mg/kg/day; n=6; mean +/- SE trough level (MTL): 292+/-17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15+/-1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death. In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82+/-18 ng/ml). Simultaneous administration (n=6) of Neoral (150/100 mg/kg/day; MTL: 217+/-16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24+/-2 ng/ml) improved graft outcome (mild rejection). Side effects included renal failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group the MTL for cyclosporin was 143+/-13 and for RAD 38+/-3. Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea. In a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100-200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection. CONCLUSION: Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.

Animals↗
PubMed2000

Obliterative airway disease in a porcine heterotopic bronchial allograft model.

Representative animal models are needed for the study of posttransplant obliterative bronchiolitis (OB). Because human OB originates in terminal bronchi, the validity of tracheal models can be questioned. Using our hetrotopic model, we implanted pieces of a lobar bronchus subcutaneously into domestic pigs. Five groups were included: autograft implants, allograft implants, allograft implants with 2 regimens of cyclosporine (CsA)azathioprine (AZA)-methylprednisolone (MP), and allograft implants with CsA-SDZ RAD-MP. Samples were harvested at 2 weeks and at 1, 2, and 3 months. The histological findings were graded from 0 to 3. Following initial ischemic epithelial damage, autograft implants recovered, but untreated allografts and those treated with CsA-AZA-MP were totally and permanently damaged within one month. In the group treated with CsA-SDZ RAD-MP, a maximal grade 1.5 +/- 0.5 epithelial injury was seen at one month. Epithelial damage preceded and correlated with luminal obliteration. The obliterative lesions histologically resembled human OB. Differences from our previous findings with terminal bronchioles were minor. This study supports the use of larger-size airways in the study of OB.

Animals↗
PubMed2000

Major surgery increases serum levels of vascular endothelial growth factor only temporarily.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a hypoxia-induced endothelial cell-specific mitogen, which is angiogenic in vivo and up-regulated in several malignancies. VEGF can be used as a prognostic marker, but the effect of surgical trauma on serum VEGF (S-VEGF) concentrations is unknown and might reduce the value of VEGF as a serum marker. METHODS: We monitored S-VEGF levels by enzyme-linked immunosorbent assay in patients undergoing surgery. RESULTS: Eighteen patients with major surgery had slightly elevated S-VEGF compared with the preoperative level (median 9.5 pg/mL) on the first (median 35 pg/mL; P = 0.0002) and third (median 19 pg/mL; P = 0.004) postoperative day, but not in later samples. The levels measured in 8 patients after minor surgery did not differ from the preoperative levels (P = 0.14). CONCLUSIONS: Even major surgery is associated only with a slight and transient increase in S-VEGF levels, and, therefore, is unlikely to interfere markedly with the use of VEGF as a prognostic marker.

Endothelial Growth Factors↗
PubMed1999

The histology of subcutaneously implanted donor bronchial rings correlates with rejection scores of lung allografts in a primate lung transplant model.

BACKGROUND: The diagnosis of acute rejection in lung transplantation generally relies on transbronchial biopsies. This invasive procedure may be associated with bronchial bleeding or pneumothorax and may not be feasible in patients with severely compromised lung function. The hypothesis of the current study was that histopathological findings of donor bronchial segments implanted into the subcutaneous tissue of lung allograft recipients would predict lung tissue rejection scores, thus providing the clinician with an alternate source of information. METHODS: Unilateral left lung transplantation was performed in 34 cynomolgus monkeys as part of a drug efficacy study. After completion of the transplant procedure, 4 bronchial ring segments of the explanted recipient left lung and 4 bronchial ring segments of the non-transplanted right donor lung were implanted subcutaneously in the abdominal region. Lung allograft rejection was evaluated by open lung biopsies of the allograft performed on postoperative (PO) Day 14 and during sacrifice on PO Day 28. At the time of each biopsy, 2 donor and 2 recipient subcutaneous bronchial rings were explanted. Histologic evaluation of the lung tissue samples was performed according to the working formulation of the International Society for Heart and Lung Transplantation. Bronchial rings were independently evaluated by assessing the degree of airway narrowing; percentage of intact epithelial coverage as well as its specific histology (respiratory ciliated, flattened cuboidal, squamous); presence of lymphocytes, macrophages or spindle cells; and presence of peribronchial inflammation, luminal fibrosis, lymphocytic bronchitis or luminal mucous. Statistical analysis was performed by logistic regression. RESULTS: In the recipient bronchial rings, there was no evidence of airway narrowing. There was 98% epithelial coverage, 71% that were respiratory ciliated cells, and there was no inflammation. Donor bronchial rings showed no airway narrowing for monkeys with grade A0 to A2 rejection in tissue biopsies and a maximum narrowing (41.2%) with A4 rejection. Epithelial cell coverage was approximately 100% with grade A0-A2 and 44+/-11% with A4 rejection. Lymphocytic bronchitis was most severe in A4 rejection and minimal in A0 to A2 rejection. By logistic regression analysis, independent predictors of a likelihood of rejection were the degree of airway obliteration, the percentage of epithelial cell coverage, the degree of lymphocytic bronchitis and the product of respiratory and flattened cuboidal cell coverage. CONCLUSIONS: The current data show that histologic alterations of subcutaneously implanted donor bronchial rings correlate with lung tissue biopsy scores based on the ISHLT working formulation. Because subcutaneous bronchial rings can be explanted under local anesthesia, they may provide useful information for the diagnosis of acute allograft rejection in patients with impaired lung function, patients that obtaining lung tissue samples may not be feasible.

Acute Disease↗
PubMed1999

Newer immunosuppressive drugs: a review.

In recent years, many new immunosuppressive drugs have been discovered and developed for clinical use in transplantation. This review focuses on those drugs (leflunomide, mycophenolate mofetil, sirolimus, tacrolimus) that have been shown to have immunosuppressive activity in patients. Different anti-interleukin-2 receptor antibodies are also reviewed as an example of a resurgence of development in the area of monoclonal antibodies. The price for reducing the incidence of allograft rejection by improved immunosuppression was thought to be a proportional increase in the incidence of infection and malignancy. Data from Phase III clinical trials of new immunosuppressants, however, show a statistically significant reduction in the incidence of acute rejection produced by these new drugs, which has not been accompanied by increases in infection and malignancy rates. The wide array of new drugs offers the opportunity to use combinations that block different pathways of immune activation while at the same time selecting drug combinations with nonoverlapping toxicity profiles so that doses of each single drug can be reduced below toxicity levels. The immunosuppressive therapy for patients can be tailored according to their individual needs.

Animals↗
PubMed1999

Genetic parameters for the milk coagulation properties and prevalence of noncoagulating milk in Finnish dairy cows.

The genetic parameters were estimated for milk coagulation properties and milk production traits, and the prevalence of noncoagulating milk in the Finnish dairy cattle population was investigated. Data were included for 789 Finnish Ayrshire cows and 86 Finnish Friesian cows from 51 herds. The animal model used for estimation included fixed effects for parity, stage of lactation, breed, and herd. Further, effects of milk protein genotypes on phenotypic and genetic variation in the studied traits were examined. Heritability estimates for the milk coagulation properties were moderately high. The kappa-casein B allele was associated with the best phenotypic and genetic values for curd firmness, and the A and E alleles were associated with the poorest. About 24% of the additive genetic variation in the curd firmness was due to milk protein polymorphism. About 8% of the Finnish Ayrshire cows in the present study produced noncoagulating milk. Because of the occurrence of the noncoagulating milk and a possibly unfavorable genetic trend in the milk coagulation properties, it would be important to improve these traits in the Finnish Ayrshire breed. Milk coagulation properties could be improved directly by selecting for these traits or indirectly by favoring the kappa-casein B allele or by selecting against genetic markers associated with poorly coagulating or noncoagulating milk.

Alleles↗
PubMed1999

Associations between milk protein polymorphism and first lactation milk production traits in Finnish Ayrshire cows.

Genotypic effects of beta-casein (CN), kappa-CN, and beta-lactoglobulin (LG) on milk, fat, and protein production and fat and protein percentages were estimated for 18,686 Finnish Ayrshire cows in first lactation using an animal model. Casein genotype effects were estimated including individual beta-CN and kappa-CN simultaneously in a model and then as composite beta-kappa-CN. The A2 allele of beta-CN and the A allele of kappa-CN, as well as the A1 allele of beta-CN and the B or E allele of kappa-CN, appeared together more frequently than was expected. Because of linkage disequilibrium in the casein loci and, consequently, unbalanced data, some contradictory effects of casein genotypes were obtained with the two models. A well-founded way to estimate the effects of casein genotypes was to use beta-kappa-CN genotypes. Composite casein genotypes including the A2 allele of beta-CN were associated with the highest milk and protein production and the lowest fat content, those including the B allele of kappa-CN with the highest protein content, and those including the E allele of kappa-CN with the lowest protein content. The effect of the beta-kappa-CN genotypes on protein content was moderately strong, and the effect was somewhat smaller for other traits. The AA genotype of beta-LG had a favorable effect on milk and protein production, and the BB genotype had a favorable effect on fat content.

Animals↗
PubMed1998

Heterodimerization is mainly responsible for the dominant negative activity of amino-terminally truncated rat androgen receptor forms.

Rat androgen receptor (rAR) mutants devoid of the amino-terminal transactivation domain are able to behave as dominant negative regulators of wild-type rAR. To address the underlying mechanisms of the trans-dominant negative action, we have examined the roles of the DNA-binding domain (DBD) and the ligand-binding domain (LBD) in this process. Transactivation experiments in CV-1 cells complemented by electrophoretic mobility shift assays revealed that the dominant negative receptor forms repress the function of wild-type rAR mainly through heterodimer formation, rather than through competition for binding to cognate DNA elements. Heterodimerization of receptor forms containing LBDs may take place even in the absence of specific DNA binding.

Animals↗
PubMed1998

Obliterative lesions in small airways in an immunosuppressed porcine heterotopic bronchial allograft model.

We have recently developed a heterotopic large-animal model for research into obliterative lesions in small airways caused by allograft rejection. In this model, the small airways of subcutaneously implanted allografts gradually obliterate, whereas autografts remain patient. Twenty lung fragments and 20 segments of bronchi were implanted in domestic pigs weighing 20 kg from non-related donors. The histology of five animals receiving daily cyclosporine A (CsA) (10 mg/kg), azathioprine (2 mg/kg) and methylprednisolone (20 mg), Group C, was compared with that of six animals without immunosuppression, Group A. Four animals received monotherapy with CsA (10 mg/kg) or methylprednisolone (3 mg/kg). The histological findings were graded from 0 to 3 on the basis of implants harvested repeatedly over 3 months. Epithelial destruction and bronchial obliteration was rapid and permanent in all the allografts. Inflammation and fibrosis of the bronchial wall was less prominent in Group C than in Group A and the onset of fibrosis was delayed. Cartilage degeneration and pericartilagineous inflammation were significantly less severe in Group C (P < 0.05). Monotherapy was less potent than triple therapy. This large-animal model is useful for studying the effects of immunosuppressive drugs on obliterative airway disease.

Animals↗
PubMed1998

Raised endothelin content in bronchoalveolar lavage fluid during lung allograft rejection in pigs.

Various pathophysiologic mechanisms are implicated in the rejection of transplanted lungs, for example production of vasoactive substances such as endothelin. In this study the measured endothelin content of bronchoalveolar lavage (BAL) fluid was correlated to the grade of lung allograft rejection. Left lung allotransplantation was performed in seven piglets (weight 16-24 kg). Triple-drug immunosuppression (cyclosporin, azathioprine, methylprednisolone) was given, and episodes of acute rejection were induced by withdrawing the medication. The development of acute rejection was monitored with computed tomography and bronchoscopy with BAL and transbronchial biopsy. In 46 BAL samples the endothelin content was radioimmunologically assayed. Transbronchial biopsies taken simultaneously showed grade 0 rejection in 17 tissue samples, grade 1 in 21 and grade 2 in eight. The endothelin content of BAL (pg/ml) increased from 34.3 +/- 6.1 in grade 0 rejection to 54.6 +/- 6.8 in grade 1 and to 98.5 +/- 35.6 in grade 2. The increase from grade 0 was statistically significant to grade 1 (p < 0.05) and to grade 2 (p < 0.02). The increased endothelin content of BAL may have harmful effects on the lung, as endothelin is a potent vaso- and bronchoconstrictive peptide with mitogenic properties.

Animals↗
PubMed1998

Small airway obliteration in a new swine heterotopic lung and bronchial allograft model.

BACKGROUND: We studied a heterotopic large-animal model with obliterative airway lesions caused by allograft rejection. METHODS: Lung fragments (1 cm3) with airways (LB), and 1 to 2 mm diameter bronchi alone (B) were implanted subcutaneously in 11 domestic piglets weighing 20 kg. Six animals each received 40 implants from nonrelated donors without immunosuppression (group A). Another 5 animals had autograft implants (group U). The implants were harvested consecutively for histologic analysis over 3 months in group A and 6 months in group U. RESULTS: In group U, the initial ischemia caused mild to moderate epithelial damage with moderate metaplasia but with a return to normal ciliary epithelium within 1 month. Transient mild luminal obliteration with granulation tissue and mononuclear cells was observed during the first weeks, but after 4 weeks the lumen was patent and filled with mucus. In the bronchial wall, moderate fibrosis developed in LB implants, whereas mild fibrosis was seen in B implants. In group A, the epithelium was totally absent by 2 weeks, and mild inflammation, fibrosis, and destruction of the cartilage with pericartilaginous mononuclear accumulation were observed in the bronchial wall. Small airways were gradually obliterated between days 7 and 21, initially by granulation tissue and mononuclear cells and later by progressive fibrosis. CONCLUSIONS: In this model, autografted airway implants stayed patent for at least 6 months, whereas total luminal obliteration histologically resembling obliterative bronchiolitis developed in allografts within 21 days. Because small airways, including bronchioli, can be transplanted with the use of this model, it may be useful for research into the causes of airway obliteration, which may be relevant to the pathogenesis of obliterative bronchiolitis in lung recipients.

Animals↗
PubMed1997

Interaction between the amino- and carboxyl-terminal regions of the rat androgen receptor modulates transcriptional activity and is influenced by nuclear receptor coactivators.

Identical N-terminal deletions in the wild-type rat androgen receptor (rAR) and a constitutively active rAR (ARDelta641-902) devoid of the ligand-binding domain (LBD) resulted in dissimilar consequences in transcriptional activation: deletion of residues 149-295 abolished wild-type AR activity, but did not influence that of ARDelta641-902. The activity of the N-terminal transactivation domain is thus controlled by the hormone-occupied LBD, suggesting that the N- and C-terminal regions of rAR communicate. Consistent with this idea, a strong androgen-dependent interaction between the N-terminal region and LBD was demonstrated in a mammalian two-hybrid system using GAL4 and VP16 fusion proteins. This interaction can be direct or indirect. Several nuclear receptor coactivators (CBP, F-SRC-1, SRC-1, and RIP140) that interact with other steroid receptors were tested as potential mediators of the N- and C-terminal interaction of rAR using the mammalian two-hybrid system. CBP or F-SRC-1 not only enhanced AR-mediated transactivation, but also facilitated the androgen-dependent interaction between the N- and C-terminal domains, implying that part of the coactivator-dependent transcriptional activation occurs via this mechanism. In contrast, SRC-1, a coactivator for the progesterone receptor, inhibited both AR-mediated transactivation and interaction between the N and C termini. Recruitment of coregulators may involve AR domains other than the LBD, as F-SRC-1 and CBP enhanced, but SRC-1 repressed, the transcriptional activity of ARDelta641-902. Collectively, interplay between the N-terminal region and LBD of rAR results in the formation of a transactivation complex that includes coregulators and that is mandatory for optimal activation of androgen-induced promoters.

Animals↗
PubMed1997

The presence of a transcription activation function in the hormone-binding domain of androgen receptor is revealed by studies in yeast cells.

To assess the importance of various regions of the androgen receptor (AR) in transcriptional regulation, we have compared its activation functions (AFs) in yeast and mammalian cells. The receptor's amino-terminal region contains a major transcriptional activator (AF-1) in both cell types, whereas AF-2 in the ligand-binding domain (LBD) is very weak in mammalian cells but clearly functional in the yeast. Hormone-binding ability of LBD is mandatory for AF-2 to operate, as illustrated by mutated LBD constructs. The activity of AF-2 in yeast is severely attenuated when the hinge region is attached to LBD, suggesting that the former region modulates AF-2 in vivo, probably by presenting an interface for interacting proteins.

Androgens↗