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Biomedical subjects

M Hertl

Publications and source records attributed to M Hertl.

At least 73 records · Page 4Linked to original sources
PubMed1995

Lymphocyte activation in cutaneous drug reactions.

Peripheral blood lymphocytes from both drug-induced immediate and delayed cutaneous hypersensitivity reactions frequently can be stimulated in vitro with the particular culprit drug. Immunohistochemical analysis has identified CD8+ T cells as the predominant epidermal T-cell subset in drug-induced maculopapular and bullous eruptions and in patch-test reactions to beta-lactam antibiotics. Beta-lactam-specific peripheral and epidermal T lymphocytes from bullous exanthems were predominantly T-cell receptor alpha/beta+, CD8+, CD4-. Three CD8+ epidermal T-cell clones from penicillin-induced bullous exanthems displayed a TH1-like cytokine pattern and proliferated in an antigen- and major histocompatibility complex-specific manner. These epidermal T-cell clones were cytotoxic against autologous B cells upon stimulation through the T-cell receptor and against epidermal keratinocytes in lectin-induced cytotoxicity assays. In contrast, peripheral T-cell lines from patients with penicillin-induced urticarial exanthems were predominantly T-cell receptor alpha/beta+, CD4+, CD8- and displayed a Th2-like cytokine pattern. CD8+ dermal T cells from a sulfamethoxazole-induced bullous exanthem proliferated in vitro in response to sulfamethoxazole. This T-cell proliferation was significantly increased in the presence of microsomes, which suggests that microsomal enzymes, such as cytochrome P450 enzymes, generate highly reactive metabolites which are the nominal antigens for T-cell activation. In summary, drugs may be processed and presented in different ways, which is reflected by the observation that Th1-like CD8+ T cells are primarily activated in delayed cutaneous hypersensitivity reactions, whereas Th2-like T-cell responses are present in patients with drug-induced urticarial exanthems.

Antigens↗
PubMed1995

Inhibition of interferon-gamma-induced intercellular adhesion molecule-1 expression on human keratinocytes by phosphorothioate antisense oligodeoxynucleotides is the consequence of antisense-specific and antisense-non-specific effects.

Expression of intercellular adhesion molecule-1 (ICAM-1) by keratinocytes is an important event in the pathogenesis of T-cell-mediated inflammatory skin diseases. To determine if ICAM-1 expression could be selectively modulated, two antisense phosphorothioate oligonucleotides (S-ODN) targeting the translation initiation and 3' untranslated regions of ICAM-1 mRNA were added as lipid complexes to cultures of keratinocytes. Interferon-gamma was added after 24 h to induce ICAM-1 expression, which was quantitated by flow cytometry after 48 h. The S-ODN targeting the translation initiation site did not inhibit ICAM-1 expression at 0.2-20.0 microM. In contrast, 0.2-1.0 microM of the S-ODN targeting a site in the 3' untranslated region abrogated ICAM-1 expression in up to 75% of the keratinocytes; this inhibition was reversible when complementary sense S-ODN was added. Phosphodiester ODN (PD-ODN) targeting the same sites did not inhibit ICAM-1 expression on keratinocytes, most likely as a consequence of rapid degradation. Inhibition of ICAM-1 by the antisense S-ODN was selective; expression of beta 2-microglobulin, alpha 3-integrin, and beta 1-integrin remained largely unaffected and interferon-gamma-induced HLA-DR expression was inhibited to a much lesser extent than ICAM-1. Antisense-non-specific inhibition was also noted in that two scrambled S-ODN with an identical nucleotide (14 of 20 cytosines) composition inhibited ICAM-1 expression in up to 44% of the keratinocytes, whereas a degenerate S-ODN did not. The data demonstrate the complex effects exerted by antisense S-ODN in that ICAM-1 expression was inhibited via antisense-non-specific mechanisms probably due to the intrinsic properties of the S-ODN as well as via the anticipated sequence-specific mechanisms.

Base Sequence↗
PubMed1995

CD8+ dermal T cells from a sulphamethoxazole-induced bullous exanthem proliferate in response to drug-modified liver microsomes.

There is evidence that T lymphocytes play a critical role in the pathogenesis of drug-induced bullous exanthems. Sulphonamides are known to be among the most frequent aetiological agents in these severe drug-induced cutaneous hypersensitivity reactions. Several studies indicate that cytochrome P450-dependent metabolites of sulphonamides act as the nominal allergens. A 70-year-old woman with a severe blistering exanthem caused by cotrimoxazole (sulphamethoxazole and trimethoprim) was studied. We employed an in vitro approach to determine whether cytochrome P450-dependent enzymes activated drug-specific T lymphocytes from this patient. Immunohistochemical analysis of involved skin revealed a majority of epidermal CD8+ T lymphocytes, whereas the dermal infiltrate was composed of both CD4+ and CD8+ T cells. Dermal T lymphocytes isolated from lesional skin proliferated in response to sulphamethoxazole, but not to trimethoprim, in the presence of autologous mononuclear cells used as antigen-presenting cells. The antigen-specific response of sulphamethoxazole-specific T cells was significantly augmented in the presence of murine liver microsomes with P450-dependent catalytic activities. Our observations suggest that some cutaneous hypersensitivity reactions to sulphamethoxazole are due to drug-specific T lymphocytes. Cytochrome P450-dependent enzymes may play a critical role in the formation of the nominal antigen, which is recognized by antigen-specific T cells.

Aged↗
PubMed1995

Evidence of preservation injury to bile ducts by bile salts in the pig and its prevention by infusions of hydrophilic bile salts.

Preservation injury to bile ducts is a serious problem in liver transplantation, especially when preservation exceeds 12 hours. The authors hypothesized that the injury was caused by contact of bile ducts with bile salts during cold preservation and might be preventable by infusion of more hydrophilic bile salts. Swine livers were harvested after intraportal infusions of saline (control), of the hydrophobic bile salt taurodeoxycholate, or of the hydrophilic bile salts tauroursodeoxycholate or dehydrocholate. The effect of infusing a combination of hydrophilic and hydrophobic bile acids was also studied. Bile samples were taken before and during the infusions. Then livers were perfused with UW solution, ducts were flushed retrograde with UW, and livers were stored at 0 to 1 degree C for 20 hours. Bile ducts were harvested after preservation, and coded microscopic slides of the specimens were examined by light microscopy. There was large variability in baseline bile salt concentration. Injury after preservation consisted of sloughing and pyknosis of surface and glandular epithelium. The histologic injury score determined after preservation was directly related to bile salt concentration in bile ducts at the time of flushing. During bile salt infusions, the infused bile salt replaced most or all of the other bile salts present in bile. Severe postpreservation injury of intrahepatic ducts occurred after taurodeoxycholate infusions, but injury was minimal when either of the two hydrophilic bile salts was infused. The mixture of bile acids produced intermediate results. Retrograde flushing with UW does not prevent injury to intrahepatic ducts. The authors conclude that the injury is caused by contact with bile salts, is dependent on bile salt concentration and composition, and is preventable.

Adenosine↗
PubMed1994

Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation.

Initial poor function and primary nonfunction are important problems in clinical transplantation. The incidence of primary nonfunction is about 6% and that of initial poor function is about 15%. Grafts with initial poor function have a higher graft failure rate in the first 3 mo after transplantation. Severe steatosis and cold preservation in University of Wisconsin solution for over 30 hr will alone cause primary nonfunction. However, primary nonfunction is probably most often caused by the presence of multiple relative risk factors. The major donor-relative risk factors are moderate steatosis, cold preservation over 12 hr and donor age over 50 yr, whereas retransplantation, high (United Network of Organ Sharing class 4) medical status and kidney failure are recipient relative risk factors. The most important perioperative risk factor is warm ischemia time. Rates of primary nonfunction and initial poor function might be reduced by avoidance of combinations of risk factors. Several tests have been developed to predict primary nonfunction and initial poor function, but none is yet clinically efficient.

Adult↗
PubMed1994

The effects of hepatic preservation at 0 degrees C compared to 5 degrees C: influence of antiproteases and periodic flushing.

The optimal preservation temperature for liver allografts is unknown. We evaluated the effect of small differences in preservation temperature, 5 degrees C vs 0 degrees C, on outcome of prolonged preservation. Livers of Wistar rats were preserved at these temperatures in UW solution for 40 h. Function was studied during reperfusion on the isolated perfused rat liver system at 37 degrees C. To compare the effects of a small reduction in temperature with known beneficial strategies, the effects of including antiproteases and periodic flushing of the graft with UW solution during cold preservation at 5 degrees C were also studied. Aspartate transaminase (AST) and alanine transaminase release after 4 h of reperfusion were much higher in the livers stored at 5 than at 0 degrees C (P < 0.0005). Addition of antiproteases to the preservation solution or periodic flushing reduced AST release but neither treatment at 5 degrees C was as good as simple storage at 0 degrees C. Cumulative bile production after 4 h of reperfusion was significantly greater in the 0 degrees C preserved group than in liver at 5 degrees C or 5 degrees C with periodic flushing. The addition of antiproteases resulted in slightly increased bile production (not significant). Platelets and WBCs in the perfusate decreased during reperfusion. This effect was more pronounced in the 5 degrees C preserved livers than in those stored at 0 degrees C. Antiproteases in the preservation solution appeared to inhibit platelet and WBC loss. Perfusate flow was significantly higher in the 0 degrees C group. We conclude that small differences in preservation temperature even at these low temperatures are important in postreperfusion liver function.

Adenosine↗
PubMed1994

[Simultaneous occurrence of extra-abdominal fibromatosis and post-traumatic keloid].

The report deals with the clinical features of a 26-year-old man with the extraabdominal form of deep fibromatosis, which became manifest at the age of 18 years as acute ileus caused by diffuse intraabdominal fibromatous tumours. In the later course of the disease extensive fibromatous lesions developed, mainly at the skin. In addition, multiple keloids occurred after excision or after negligible traumas. The pathogenetic events of the clinical picture described may be linked to the activation of mesenchymal cells leading to the generation of either fibromatous tumours or posttraumatic keloids.

Adult↗
PubMed1993

Predominance of epidermal CD8+ T lymphocytes in bullous cutaneous reactions caused by beta-lactam antibiotics.

The phenotype and functional characteristics of skin-infiltrating lymphocytes in beta-lactam antibiotic-induced vesiculobullous exanthemas were studied in vivo and in vitro. Immunohistochemical analysis demonstrated that CD8+ T lymphocytes were the predominant epidermal T-cell subset in these reactions. Epidermal T lymphocytes were isolated and expanded for in vitro studies. Fluorescence-activated cell sorter analysis showed the majority of epidermal T cells to be CD3+, T-cell receptor alpha/beta+, CD4-, CD8+, and HLA-DR+, which correlated with the predominance of epidermal CD8+ T lymphocytes found in situ. Three CD8+ epidermal T-cell clones derived from cutaneous lesions proliferated in response to penicillin-pulsed autologous antigen-presenting cells but not allogeneic antigen-presenting cells, indicating that those clones were antigen and major histocompatibility complex specific. All T-cell clones produced significant amounts of interleukin-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Additionally, the T-cell clones displayed cytotoxicity against epidermal cells in lectin-mediated cytotoxicity and against B-cell lines in T-cell receptor-triggered cytotoxicity. These data demonstrate the presence of epidermal drug-specific CD8+ T cells in bullous drug reactions. Because these CD8+ T cells have a cytotoxic potential, they may contribute to the necrosis of keratinocytes associated with drug-induced blister formation.

Anti-Bacterial Agents↗
PubMed1993

Selective generation of CD8+ T-cell clones from the peripheral blood of patients with cutaneous reactions to beta-lactam antibiotics.

The presence, phenotype, and functional characteristics of peripheral blood penicillin-specific T lymphocytes in individuals with cutaneous allergic reactions to penicillin were investigated using in vitro long-term culture techniques. Peripheral blood mononuclear cells from two penicillin-allergic patients were stimulated in vitro with penicillin, and T-cell blasts were clonally expanded by limiting dilution. Seven T-cell clones were derived, all of which were CD3+ CD4- CD8+ HLA-DR+, and produced IL-2 and IFN-gamma upon stimulation. T-cell proliferation required the presence of antigen and autologous, but not allogeneic, antigen-presenting cells. In addition to the parent compound, the T-cell clones also developed a proliferative response to penicilloyl, the major metabolite of penicillin. The cloned T-cell lines were found to exhibit marked suppressor activity for Con A mitogenesis. The observed suppressor activity required cell-to-cell contact, as supernatants from these T-cell clones had no comparable inhibitory effect. These findings indicate that there is a predominance of penicillin-specific CD8+ T cells in the peripheral blood of individuals sensitized to beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed1991

The accessory function of B lymphocytes is resistant to the adverse effects of UV radiation.

The effect of UV radiation on the accessory activities of B lymphoblastoid cell lines (B-LCL) was investigated in three types of in vitro T lymphocyte proliferation assay, each of which differed in its accessory requirements. In contrast to monocytes whose accessory function was universally sensitive to UV radiation, B-LCL were resistant to UV in oxidative mitogenesis and staphylococcal enterotoxin B assays, in which stimulus processing was not a requirement. Expression of membrane interleukin (IL) 1 and HLA-DR antigens by B-LCL and monocytes was not affected by UV, nor was surface membrane expression of intercellular adhesion molecule-1 (ICAM-1) on B-LCL. These results were in marked contrast to monocytes in which there was a greater than 65% reduction in ICAM-1 expression. When UV-irradiated B-LCL were employed as antigen-presenting cells for tetanus toxoid-dependent T cell stimulation, a reduction in antigen-presenting function was observed. However, pulsing of B-LCL with tetanus toxoid prior to UV irradiation preserved their antigen-presenting capacity in this system also. These findings indicate that there is differential UV sensitivity among accessory cells which may be explained by different effects of UV radiation on antigen processing and adhesion molecule expression.

B-Lymphocytes↗