PubMed Health⌕ Search

Biomedical subjects

H K Muller

Publications and source records attributed to H K Muller.

At least 55 records · Page 3Linked to original sources
PubMed1995

Tobacco smoke condensate cutaneous carcinogenesis: changes in Langerhans' cells and tumour regression.

Tobacco smoke condensate was painted on the skin of BALB/c mice. It increased the density and changed the morphology of Langerhans' cells (LC). LC number in epidermal sheets of treated mice was significantly higher (1793 LC/mm2) than in controls (946 LC/mm2) (P < 0.0001) and remained elevated for 35 weeks. LC became less dendritic, or even rounded in shape, and smaller in size. The function of the morphologically altered LC was impaired when assessed by the contact hypersensitivity response. These changes were associated with skin tumour development in all treated mice. Ten weeks after stopping the TSC treatment, LC number in skin tumours and in skin around these lesions had not decreased, but significantly increased (P < 0.0001). During this period tumour regression occurred in 23% of tumours; the remaining tumours showed a 50% reduction in size. At 45 weeks, the LC number in epidermal sheets around skin papillomas was 2274 +/- 14.14/mm2 and in invasive squamous cell carcinomas was 2088 +/- 183/m2. This was associated with reversible changes in LC morphology, where cells became fully dendritic. This also correlated with lymphocytic infiltration into tumours, tumour necrosis, reduction in tumour size and/or tumour regression. It is concluded that the influx of normal LC into the skin tumours allowed the development of an immune response with tumour regression.

Animals↗
PubMed1994

Ultraviolet irradiation of murine skin alters cluster formation between lymph node dendritic cells and specific T lymphocytes.

Exposure of murine skin to suberythemal doses of ultraviolet-B (UVB) radiation before contact sensitization alters the activity of antigen-presenting cells (APC) in the draining lymph nodes (DLN), decreases the contact hypersensitivity (CHS) response, and induces hapten-specific Ts cells. We determined whether in vivo UVB irradiation alters the ability of hapten-bearing APC from the DLN to form clusters with hapten-specific T lymphocytes. When APC from UV-irradiated, fluorescein isothiocyanate (FITC)-sensitized mice were mixed with a FITC-specific T-cell line, significantly fewer clusters formed compared with FITC+ APC from unirradiated mice. A higher percentage of clusters formed with APC from UV-irradiated mice were Mac-1+ and bound both CD4+ and CD8+ T cells, whereas FITC+ APC from nonirradiated mice bound CD4+ cells. These results suggest that UVB irradiation interferes with the induction of CHS by altering the functional interaction between APC and T cells, perhaps by altering the population of APC in the skin.

Animals↗
PubMed1994

The migration of Langerhans' cells into and out of lymph nodes draining normal, carcinogen and antigen-treated sheep skin.

Epidermal Langerhans' cell (LC) migration to the regional lymph node and beyond into central lymph was examined in sheep following topical application of the complete chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) or the contact sensitizing antigen 2,4,6-trinitrochlorobenzene (TNCB). This was facilitated by cannulating previously constructed pseudoafferent lymphatic vessels draining the skin treated with these agents or alternatively, the efferent lymphatic vessel of the regional lymph node. Application of DMBA resulted in a biphasic increase in LC migration. There was an initial increase in LC migration at 25 h with the maximum response (3.6 x 10(7) LC/h) occurring approximately 5 days after DMBA treatment. In contrast, the contact sensitizing antigen TNCB caused enhanced LC migration within minutes of the application of antigen (3.3 x 10(6) LC/h) and peak migration at 8-12 h. Examination of efferent lymph cells from the regional lymph node after DMBA treatment showed uncharacteristically large numbers of LC traversing the lymph node. These LC migration patterns suggest different mechanisms may trigger the migration of LC from skin after the application of DMBA to those associated with the normal processes of antigen presentation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1994

Langerhans cell migration patterns from sheep skin following topical application of carcinogens.

Application of tumour promoters or complete chemical carcinogens to skin alters the density and/or morphology of epidermal Langerhans cells (LC). To examine the hypothesis that these chemical carcinogens alter LC migration kinetics from the epidermis, pseudoafferent lymphatic vessels draining defined areas of carcinogen treated sheep skin were cannulated and the number of LC migrating enumerated using indirect immunofluorescence and flow cytometry. The complete carcinogen benzo[a]pyrene (BP) and the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) caused an immediate two to four-fold increase in the rate of LC migration, while the tumour initiator urethane did not alter LC migration. The antigenicity of the carcinogens utilized was assessed in contact hypersensitivity experiments in mice. BP and TPA were mildly antigenic whereas urethane failed to initiate a contact hypersensitivity response in sensitized mice. It is concluded that the initial increase in LC migration from skin following the application of the tumour promoter TPA and the complete carcinogen BP is partly due to LC recognizing these carcinogens as antigens.

Acetone↗
PubMed1993

Cell-mediated immunity in combat veterans with post-traumatic stress disorder.

OBJECTIVE: To explore immune function in patients with chronic post-traumatic stress disorder (PTSD). DESIGN: A case-control study using the standardised Cell-mediated Immunity (CMI) Multitest. PARTICIPANTS: Cases were 25 Vietnam combat veterans undergoing treatment for clinically diagnosed PTSD. Controls had no diagnosed psychiatric disorders: 28 were civilians and 20 were servicemen who had had South-east Asian postings but no combat experience. MAIN OUTCOME MEASURES: The sum score, the number of reactions and the compound scores from the CMI Multitest were assessed as a measure of immune function. RESULTS: Psychometric tests distinguished between cases and controls at a highly significant level (P < 0.001). Veterans with PTSD had enhanced cell-mediated immunity compared with civilians (P = 0.008) and servicemen (P = 0.02). CONCLUSION: PTSD in combat veterans is associated with enhanced cell-mediated immune responsiveness. This could have wide implications for psychiatry and general medicine.

Adult↗
PubMed1993

Carcinogen-treated skin allografts rejected by T lymphocytes specific for class I but not class II MHC antigens.

Treatment of skin with the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), which reduces the density of epidermal class II MHC-expressing Langerhans cells (LC), enhances its survival when transplanted onto histoincompatible hosts. We have examined the ability of T lymphocytes which reject DMBA-treated skin to lyse P388D1 cells expressing either only class I or class I and II antigens. Lymphocytes isolated from solvent-treated grafts showed greater cytotoxicity for the targets expressing both antigens, indicating that some of these lymphocytes were specific for class II MHC antigens. In contrast, lymphocytes isolated from carcinogen-treated grafts lysed both targets similarly and hence did not contain any cells specific for class II MHC antigens. Anti-class I MHC antibody blocked cytotoxicity by both leukocyte populations to similar extents, but anti-class II MHC antibodies preferentially blocked T cells isolated from the solvent-treated grafts. There was no difference in the phenotype of the cytotoxic cells isolated from solvent- and carcinogen-treated grafts. Thus, whereas solvent-treated skin grafts are rejected by T cells specific for class I and II MHC antigens, DMBA-treated skin grafts are only rejected by class I MHC-specific T cells which may account for the enhanced survival of the carcinogen-treated grafts.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival.

Antigen presenting S100 positive dendritic cells have been quantified in normal trachea, lung, bronchial lymph nodes, 130 lung tumors and in 100 lymph nodes regional to tumor. Dendritic cells are rarely seen as intraepithelial components of the normal bronchial mucosa, but are more commonly observed in the perivascular lymphoid tissue of the submucosa and in the alveolar septae of normal lung parenchyma (6 +/- 4.85 cells/HPF). The density of these dendritic cells is marked in histologically normal bronchial lymph nodes. Bronchioalveolar (Alveolar II), well and moderately differentiated squamous cell carcinomas contain the highest density of S100 positive dendritic cells, while small cell lung cancer and poorly differentiated squamous cell carcinoma show the lowest density. Regional lymph nodes to lung tumors with lymphocytic predominance and active germinal centres show the highest density of dendritic cells, while unstimulated lymph nodes contain the lowest number of S100 positive dendritic cells. Tumor infiltrating lymphocytes are marked in and around lung tumors with the higher density of dendritic cells. Survival of patients whose tumors contain high density of S100 positive dendritic cells is more favourable compared to tumors with low density of these cells. It is concluded that the density of the antigen presenting S100 dendritic cells in lung tumors is related to subtype, and tumor differentiation. A high dendritic cell density is associated with enhanced patient survival.

Bronchi↗
PubMed1992

Migration of Langerhans cells from carcinogen-treated sheep skin.

To define the mechanism(s) of carcinogen depletion of Langerhans cells (LC) from skin, the migration of LC from the skin to the regional lymph node was examined in carcinogen-treated, antigen-treated, and control sheep. This was assessed by cannulation of afferent lymphatic vessels that drain the treated areas of skin or the efferent lymphatic draining the regional lymph node. Cells draining from test or control skin were continuously collected and enumerated by indirect immunofluorescence and flow cytometry using specific anti-CD1 monoclonal antibodies. There was a marked increase in the rate of LC migration in the 8 h following the application of the contact sensitizing antigen trinitrochlorobenzene (TNCB). The chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) triggered a tenfold-greater migration of LC compared with TNCB--with the peak response at 5 d. After DMBA treatment LC were also detected in the efferent lymph of the regional lymph node. It is concluded that the depletion of LC from carcinogen-treated skin is due to the increased LC migration and not carcinogen-induced cell death.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Acceptance of class II major histocompatibility complex disparate skin grafts associated with suppressor cells and elevated Langerhans cell numbers.

Class II major histocompatibility complex (MHC) molecules are only present on Langerhans cells (LC) in normal murine epidermis. Depletion of this antigen with the chemical carcinogen dimethylbenzanthracene (DMBA) causes I-E disparate B10.A(2R) congenic tail skin to be accepted permanently when grafted onto B10.A(4R) recipients. Adoptive transfer of spleen cells from these recipients into naive syngeneic hosts inhibited the ability of the host mice to reject untreated B10.A(2R) tail skin grafts. Hence DMBA-treated LC depleted I-E disparate skin grafts activate suppressor cells which did not inhibit BALB/c mice from rejecting a B10.A(2R) tail skin graft. In contrast, the tobacco derived carcinogen benzo(a)pyrene (BP) increased the number of epidermal LC but had no effect on either class I or class II MHC disparate skin graft survival time. This confirms that the number of class II MHC-positive LC is critical for the initiation of skin graft rejection; when the threshold level is attained graft rejection proceeds at a maximal rate that cannot be enhanced by raising the number of LC. The tolerant skin grafts had increased numbers of LC; this was not observed in syngeneic grafts and therefore may be related to the active suppression of immunity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Antigen presentation in the skin: modulation by u.v. radiation and chemical carcinogens.

The skin provides an excellent model to investigate antigen presenting cells (APC) particularly using contact hypersensitivity responses. The skin has its own distinct APC of which Langerhans cells (LC) are the best characterized. Fluorescein isothiocyanate (FITC) has proved a useful reagent with which to follow antigen-labeled APC to draining lymph nodes, where they bind to T lymphocytes. Cluster formation appears to be a necessary component of the APC-T cell interaction. Both u.v. radiation and chemical carcinogens are able to alter LC in the skin, resulting in immunological tolerance when antigen is presented through such treated sites. The changes in APC function are linked mainly to the tumor promoting action of carcinogens. The nature of the APC that trigger suppressor circuits and the potential chemical mediators involved are discussed. These studies have important implications for the immunobiology of the skin and for cutaneous carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Indomethacin inhibits the chemical carcinogen benzo(a)pyrene but not dimethylbenz(a)anthracene from altering Langerhans cell distribution and morphology.

Treatment of murine skin with the polyaromatic hydrocarbon carcinogens benzo(a)pyrene (BP) or dimethylbenz(a)anthracene (DMBA) for 3 weeks resulted in an increase and a decrease in epidermal Langerhans cell (LC) numbers, respectively, compared with solvent-treated skin. Implantation of subcutaneous indomethacin pellets prior to carcinogen treatment prevented the changes in LC numbers and morphology in BP, but not DMBA-treated skin. Indomethacin treatment was also found to reduce elevated prostaglandin E2 (PGE)2 levels in the skin of BP-treated mice, whereas PGE2 levels were not significantly raised in DMBA-treated mice. There thus appears to be a link between altered prostaglandin levels and LC numbers in murine skin treated with BP, but not DMBA. In the latter, LC numbers were reduced by mechanisms not reversed by indomethacin. It is concluded that increased prostaglandin levels may contribute to the impairment of cutaneous immunity previously observed in BP-treated mice by altering LC density and morphology within the epidermis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

A role for prostaglandins in the suppression of cutaneous cellular immunity and tumour development in benzo(a)pyrene- but not dimethylbenz(a)anthracene-treated mice.

Prostaglandins have been implicated in the immune suppression associated with the development of some tumours. Application of the prostaglandin synthetase inhibitor indomethacin, to murine skin prior to treatment with the chemical carcinogens benzo(a)pyrene (BP) or 7,12 dimethylbenz(a)anthracene (DMBA), restored contact sensitivity responses to 2,4-dinitrofluorobenzene in BP- but not DMBA-treated mice. However, indomethacin failed to restore antibody responses in either group of mice. Prolonged treatment with BP or DMBA led to cutaneous tumour formation. Indomethacin was found to delay the onset and reduce the size of tumours in BP- but not DMBA-treated mice. It is proposed that prostaglandin-induced suppression of cellular cutaneous immunity may play a role in BP- but not DMBA-induced cutaneous carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Langerhans cell depletion in gliotoxin-treated murine epidermis.

Langerhans cells (LC) are dendritic antigen presenting cells of bone marrow origin which reside in the suprabasal layer of the epidermis. They express high concentrations of Class II MHC glycoproteins on their plasma membrane and transport cutaneous antigen to local lymph nodes for presentation to helper T cells. They are thus essential for the induction of cutaneous immunity. Gliotoxin is a member of the epipolythiodioxopiperazine (ETP) group of fungal metabolites, derived from the human pathogen Aspergillus fumigatus. It has been shown to have immunomodulating properties in vivo and in vitro, and has been proposed as a potential immunosuppressant for transplantation therapy. Epicutaneous application of gliotoxin reduced the numbers of epidermal LC by 30-35 per cent with an associated morphological change from highly dendritic to a more rounded form. Electron microscopic studies showed selective damage to LC at very low (nM) concentrations of gliotoxin, with no obvious effect on adjacent keratinocytes. LC numbers remained depleted for 13 weeks after initial treatment, suggesting that systemic suppression or prolonged retention of gliotoxin within the skin may play a role in its mechanism of action.

Animals↗
PubMed1990

Immunophenotypic and cell cycle analysis of lymph node cells from dimethylbenzanthracene-treated mice.

The chemical carcinogen 7, 12-dimethylbenz-(a)anthracene (DMBA) depletes Langerhans cells from murine epidermis. Application of contact sensitizers to DMBA-treated skin induces specific immunological tolerance due to a DMBA-resistant epidermal antigen presenting cell (APC) migrating to local lymph nodes where it presents antigen in a way which activates suppressor cells. As alterations in local lymph node lymphocytes may enhance the ability of the DMBA-resistant APC to activate suppressor cells, these cells were examined in DMBA-treated mice. Lymph nodes in DMBA-treated mice had normal morphology but were larger and contained increased numbers of lymphocytes. Cell cycle analysis revealed that these lymphocytes did not arise from division within the lymph node, suggesting alterations in homing properties of lymphocytes. Contact sensitizer applied to DMBA-treated skin did not increase lymphocyte division, possibly due to suppressor cell inhibition of the development of effector lymphocytes. DMBA treatment had no effect on B cells or Ia expression, but decreased levels of the T lymphocyte cell surface molecule Thy-1, and increased L3T4 and Lyt-2 as quantitated by flow cytofluorimetry. These changes could influence the development of immune responses as these T cell molecules are receptors involved in lymphocyte interactions.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Effects of gliotoxin on Langerhans' cell function: contact hypersensitivity responses and skin graft survival.

Dendritic Langerhans' cells (LC), which are essential for the induction of cutaneous immunity, express high concentrations of class II major histocompatibility (MHC) glycoproteins (Ia in the mouse) on their plasma membrane. Application of gliotoxin, a member of the epipolythiodoxopiperazine (ETP) group of fungal metabolites, reduces epidermal LC density and alters their morphology from highly dendritic to a more rounded form. Here we demonstrate that gliotoxin also alters LC function, reducing contact hypersensitivity (CHS) responses due to the development of suppressor cells, and enhancing C57BL tail skin graft survival on BALB/c recipients. The reduction in LC density following gliotoxin application was shown to enhance skin graft survival, by reducing the concentration of Ia antigens within the graft, by using congenic mouse strains: B10.A(2R) x B10.A, differing only at H-2D, and B10.A(2R) x B10.A(4R), differing only at H-2 I-E. Treatment of B10.A(2R) tail skin with gliotoxin for 1 week did not affect its survival when grafted onto H-2D-disparate B10.A mice, whereas, when grafted onto H-2 I-E-disparate B10.A(4R) hosts, the grafts were not only accepted permanently, but induced specific unresponsiveness. It is concluded that gliotoxin has a marked effect on LC function, inhibiting CHS responses by the induction of suppressor cells and prolonging graft survival between H-2-disparate and congenic mouse strains.

Animals↗
PubMed1990

Presentation of antigen to suppressor cells by a dimethylbenz (a) anthracene-resistant, Ia-positive, Thy-1-negative, I-J-restricted epidermal cell.

The epidermal layer of the skin contains class II major histocompatibility (MHC)-positive antigen-presenting cells (APC), the most well characterized population being Langerhans' cells (LC). The chemical carcinogen 7,12 dimethylbenz (a) anthracene (DMBA) depletes about two-thirds of these cells from murine epidermis, and contact sensitizers applied to DMBA-treated skin induce specific immunological tolerance. This tolerance results from epidermal cells migrating to local lymph nodes within 3-6 hr after contact with antigen where they present the antigen to suppressor cells. Here we demonstrate that this epidermal cell which activates suppressor cells is a class II MHC-positive. Thy-1-negative, I-J-restricted APC. Hence at least two types of class II MHC-positive epidermal cells migrate to local lymph nodes and present antigen to lymphocytes; LC, which are sensitive to the effects of DMBA and activate helper lymphocytes, and another, which is resistant to DMBA and activates suppressor cells in an I-J-restricted manner. During the early stages of carcinogenesis any antigen present in the epidermis would be presented only by the cells which activate suppressor lymphocytes, resulting in tolerance induction. This may enable neoplastic cells to avoid the initiation of anti-tumour immunity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Differential effects of benzo[a]pyrene and dimethylbenz[a]-anthracene on Langerhans cell distribution and contact sensitization in murine epidermis.

The exposure of murine skin to potent chemical carcinogens induced distinctive effects on the distribution of epidermal Langerhans cells (LC). Our previous finding that weekly applications of 7,12-dimethylbenz[a]anthracene deplete the numbers of adenosine triphosphatase (ATPase)-positive LC was extended to show that LC are also depleted on Ia and beta-glucuronidase staining. In contrast, application of the tobacco-derived carcinogen, benzo[a]pyrene (BP), caused a significant increase in Ia-positive LC density within 2 weeks and elevated levels were maintained for up to 6 months with continuous treatment. The tobacco-derived cocarcinogenic agent, catechol, also enhanced the numbers of epidermal LC. The LC in carcinogen treated epidermis were morphologically abnormal; after BP and catechol treatment LC appeared smaller with shorter dendrites, whereas in DMBA treated epidermis LC were enlarged with elongated dendrites. Application of the contact sensitizing agent, dinitrofluorobenzene, to skin treated with BP induced hyporesponsiveness rather than contact sensitivity upon subsequent antigen challenge. Hence, the function of the large number of morphologically altered LC in BP treated skin was impaired. We conclude that carcinogen-induced alterations of LC are associated with impaired immunocompetence, although different carcinogens probably operate via different mechanisms to induce such phenomena.

9,10-Dimethyl-1,2-benzanthracene↗