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Manfred Wehrmann

Publications and source records attributed to Manfred Wehrmann.

25 records · Page 2Linked to original sources
PubMed2004

Organ-specific T cell receptor repertoire in target organs of murine graft-versus-host after transplantation across minor histocompatibility antigen barriers.

BACKGROUND: Minor histocompatibility antigens (miHags) are recognized by alloreactive cytotoxic donor T lymphocytes and trigger potent immune reactions such as graft-versus-host disease (GvHD) after major histocompatibility complex-matched transplantation. Our study focuses on tissue-specific T-cell responses to miHag-encoded peptides in GvHD target organs during the first 30 days in a murine transplant model. METHODS: Complementarity determining region (CDR)3-size spectratyping was used to study T cell receptor (TCR) repertoires in recipient skin, liver, ileum, colon, spleen, and heart. RESULTS: GvHD occurred as early as day 14 and was proven by histology in skin, liver, ileum, and colon. The heart was histologically not affected by GvHD but showed endomyocardial "quilty lesions." Two distinct patterns of TCR diversities could be identified. In skin, a restricted V beta usage in combination with all J beta segments contrasted with a complete V beta repertoire in intestinal organs combined with a restricted J beta usage. Interestingly, TCR repertoire in the heart was almost identical with intestinal CDR3-size patterns. Persisting clones were found in skin from day 9 to 30. In intestine and heart, identical sequences were obtained from several organs on day 14 and 21, but no persistence of CDR3 sequences could be observed. CONCLUSIONS: These results suggest that in the skin a limited number of persisting T cell clones maintains GvHD, whereas in the intestine, temporary expansions of different clones may fuel the process of GvHD. Strategies that eliminate tissue-specific T cells on the basis of their activational status rather than their V beta expression but at the same time preserve a broad, overall TCR repertoire will help to increase the efficacy and safety of allogeneic stem cell transplantation.

Amino Acid Sequence↗
PubMed2003

[18F]FLT PET for diagnosis and staging of thoracic tumours.

The nucleoside analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been introduced for imaging of tumour cell proliferation by positron emission tomography (PET). This study evaluated the use of FLT in patients with thoracic tumours prior to treatment. Whole-body FLT PET was performed in 16 patients with 18 tumours [17 thoracic tumours (nine non-small cell lung cancers, five oesophageal carcinomas, two sarcomas, one Hodgkin's lymphoma) and one renal carcinoma] before treatment. Fluorine-18 fluorodeoxyglucose (FDG) PET was performed for comparison except in those patients with oesophageal carcinoma. For semi-quantitative analysis, the average and maximum standardised uptake values (avgSUV and maxSUV, respectively) (FLT, 114+/-20 min p.i.; FDG, 87+/-8 min p.i.; 50% isocontour region of interest) was calculated. All 17 thoracic tumours and 19/20 metastases revealed significant FLT accumulation, resulting in easy delineation from surrounding tissue. The additional small grade 1 renal carcinoma was not detected with either FLT or FDG. In most lung tumours (avgSUV 1.5-8.2) and metastases, FLT showed intense uptake. However, one of two spinal bone metastases was missed owing to the high physiological FLT uptake in the surrounding bone marrow. Oesophageal carcinoma primaries (avgSUV 2.7-10.0) and occasional metastases showed particularly favourable tumour/non-tumour contrast. Compared with FDG, tumour uptake of FLT was lower (avgSUV, P=0.0006; maxSUV, P=0.0001), with a significant linear correlation (avgSUV, r2=0.45; maxSUV, r2=0.49) between FLT and FDG. It is concluded that FLT PET accurately visualises thoracic tumour lesions. In the liver and the bone marrow, high physiological FLT uptake hampers detection of metastases. On the other hand, FLT may be favourable for imaging of brain metastases owing to the low physiological uptake.

Adult↗
PubMed2003

Experimental thermoradiotherapy in malignant hepatocellular carcinoma.

PURPOSE: The human liver is known to be a relatively radiosensitive organ that develops clinically relevant late radiation hepatitis subsequent to whole liver treatment with total doses above 30 Gy in conventional fractionation. Experimental data, as well as clinical series, have demonstrated that hyperthermia of solid tumors in addition to radiotherapy enhances tumor growth inhibition and tumor control probability. We therefore developed an experimental model for combined radiotherapy and hyperthermia of the liver in transplantable rat Morris hepatoma 3924A. METHODS AND MATERIALS: A cube of approximately 8 mm(3) was implanted subcapsularly into the middle liver lobe of 59 male syngenic ACI rats weighing approximately 180-200 g. On Day 16 after tumor implantation, irradiation of the tumor-bearing liver with either 0 Gy/25 Gy/35 Gy/45 Gy total dose in 10 fractions +/- hyperthermia (target temperature 40-42 degrees C) twice a week was initiated. Energy deposition was monitored by temperature probes in the liver and esophagus of the rats. Determination of tumor volume with magnetic resonance imaging was performed 2 to 5 weeks after the end of therapy. The tumor growth rates could be estimated for 44 rats. If the growth rate was positive (37 rats), the inverse of the growth rate was interpreted as the time to 10-fold tumor volume. Otherwise the maximum observation time was considered as a censored value in a parametric survival analysis. RESULTS: Intrahepatic temperature probes showed a temperature plateau of greater than 40 degrees C after 5 to 8 min subsequent to initiation of hyperthermia. The target temperatures could be maintained for at least 22 min > or =40 degrees C and 10 min > or =41 degrees C, respectively. Median plateau temperature in liver, esophagus, and epicutaneously was 41.2 degrees C (standard deviation [SD] 0.7 degrees C; range 38.2 to 43.3 degrees C), 40.4 degrees C (SD 1.08 degrees C; range 38.9 to 41.8 degrees C), and 40.8 degrees C (SD 0.8 degrees C; range 38.2 to 42.7 degrees C), respectively. Elevation of the temperature in the esophagus correlated with intrahepatic temperatures in the range of 39-42 degrees C, r = 0.957. The increase in time to 10-fold tumor volume for each step of irradiation dosage was by 34% (95% confidence interval [CI] 20% to 49%) without hyperthermia and by 60% (95% CI 47% to 80%) with hyperthermia (p < 0.0001). CONCLUSION: Treatment outcome after experimental percutaneous thermoradiotherapy in intrahepatically implanted Morris hepatoma 3924A was related to total dose of irradiation and concurrently administered regional hyperthermia. An increased radiosensitivity due to hyperthermia (<42 degrees C) has to be assumed.

Animals↗
PubMed2002

Renal dysplasia in children with posterior urethral valves: a primary or secondary malformation?

Routine prenatal ultrasound examination of the urogenital tract is of importance in patients with posterior urethral valves (PUV), because the renal function and long-term prognosis of these patients depend on early diagnosis and subsequent therapy. Opinion is divided as to whether the often-observed association of PUV with renal dysplasia represents a primary malformation or a secondary pathology caused by recurrent infections. These aspects should have an influence on therapeutic consequences and optimal timing of therapy in order to preserve long-term renal function. The histology of kidney specimens from 13 children with PUV who underwent nephrectomy was reviewed to attempt to differentiate between primary dysplastic malformations and secondary pathologies. Clinical data were analyzed and compared with the histologic findings. The average age at nephrectomy was 29 months (range 3-158 months). Approximately 80% of the specimens showed primary dysplastic malformations (mesenchymal or fetal cartilage tissue or dysplastic glomeruli and tubuli) in the presence of well-developed renal parenchyma. All specimens showed secondary pathologies such as renal-cortical atrophy, interstitial fibrosis, and interstitial-nephritis atrophy. The histologic evidence of well-differentiated renal parenchyma in concurrence with dysplastic parenchyma makes infravesical obstruction as the only cause of renal alterations in patients with PUV questionable. This coincides with the fact that organogenesis of the kidney is terminated at the 12th gestational week and secondary renal damage is irreversible at the 20th gestational week, but prenatal urinary diversion of the upper urinary tract is feasible in the 20th gestational week at the earliest. These facts must be taken into account when considering intrauterine urinary diversion.

Humans↗
PubMed2002

Differential renal response to Nomega-nitro-L-arginine methyl ester and L-arginine in rats with hypertensive or diabetic nephropathy.

The present experiments were designed to assess the renal functional response to alterations in nitric oxide formation in animals with different forms of nephropathy. To address this issue, the effects of Nomega-nitro-L-arginine methyl ester (L-NAME) or L-arginine were assessed in animal models exhibiting arterial hypertension due to chronic nitric oxide inhibition (L-NAME, 50 mg/l in drinking water for 12 weeks) or diabetes mellitus (streptozotocin, 60 mg/kg IP). Vehicle-treated, age-matched animals served as controls. Following 12 weeks of pretreatment, mean arterial pressure (MAP), renal hemodynamics, urinary albumin, and electrolyte excretion were determined in standard clearance experiments prior to and following infusion of L-NAME (50 microg/kg/min), l-arginine (5 mg/kg/min), or saline vehicle. In control animals, L-NAME resulted in an increase in MAP and renal vascular resistance and a decline in glomerular filtration rate and renal plasma flow, as expected. L-arginine had no effect on renal hemodynamics. In nitric oxide-depleted hypertensive animals, L-NAME had no additional effect on MAP or renal hemodynamics. Infusion of L-arginine reduced elevated MAP but did not reverse changes in renal hemodynamics. Diabetic rats demonstrated glomerular hyperfiltration and proteinuria. No significant changes in MAP or renal hemodynamics were observed following infusion of L-NAME or L-arginine, respectively. However, L-NAME increased urinary albumin excretion in the absence of hemodynamic changes. The effects of nitric oxide on vascular tone were shown to be dependent on the vascular bed and the underlying disease. Variations in local nitric oxide formation and susceptibility may account for the differential response of the systemic and renal vasculature and contribute to the degree of renal functional impairment observed in different systemic diseases.

Animals↗
PubMedDate not supplied

Reliability of differentiating human coronary plaque morphology using contrast-enhanced multislice spiral computed tomography: a comparison with histology.

BACKGROUND: Initial clinical results indicate that multislice spiral computed tomography (MDCT) might be useful for the noninvasive characterization of human coronary plaque morphology by determining tissue density within the lesions. This seems to be of clinical relevance, because coronary artery disease might be detected at an early stage before calcifications occur and noncalcified plaques that may be more likely to rupture could also be visualized noninvasively. The aim of the present study was to evaluate the reliability of contrast-enhanced MDCT in differentiating human atherosclerotic coronary plaque morphology by comparing it with the histopathologic gold standard. METHODS AND RESULTS: Twelve human hearts were scanned postmortem using an MDCT (Somatom Volume Zoom; Siemens, Forchheim, Germany) high-resolution computed tomography scanner to detect atherosclerotic coronary plaques. Density measurements were performed within detected plaque areas. The exact location of each plaque was marked at the surface of the heart to assure accurate histopathologic sectioning of these lesions. The plaques were classified according to a modified Stary classification. Seventeen plaques were identified by MDCT. Six plaques were histopathologically classified as lipid rich (Stary III/IV), 6 plaques as intermediate (Stary V), and 5 plaques as calcific (Stary VII). Lipid-rich plaques had a mean density on MDCT of 42 +/- 22 Hounsfield units (HU), intermediate plaques had a mean density of 70 +/- 21 HU, and calcific plaques had a mean density of 715 +/- 328 HU. ANOVA analysis revealed a significant difference in plaque density between the 3 groups (P < 0.0001). CONCLUSIONS: The comparison with histopathology confirms that tissue density as determined by contrast-enhanced MDCT might be used to differentiate atherosclerotic plaque morphology.

Analysis of Variance↗