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Biomedical subjects

R Dummer

Publications and source records attributed to R Dummer.

At least 199 records · Page 11Linked to original sources
PubMed1993

Tumour-infiltrating lymphocytes in primary melanoma: functional consequences of differential IL-2 receptor expression.

Tumour-infiltrating lymphocytes (TIL) have been isolated from early primary melanoma (Clark level III) and expanded in vitro using culture conditions with low concentrations of IL-2 (50 U/ml). Immediately after isolation TIL consisted of mainly CD3+ T cells, and the portion of CD56+ natural killer (NK) cells was below 20%. Fresh TIL cultures could be distinguished by CD25 expression since some contained up to 33%, others less than 5% CD25+ cells. These showed differences in subsequent development during in vitro expansion. CD25-expressing cultures remained stable in their phenotype, whereas the second TIL type showed major changes: CD3 (ca 70-30%) expression decrease, CD25 (ca 5-35%) and CD56 (ca 15-55%) expression increase. The TIL type, which remained dominated by CD3+ T cells, killed autologous tumour cells efficiently (51Cr-release greater than 30% at a E/T ratio of 20:1), which could be blocked by MoAbs against MHC class I molecules. In contrast, the other TIL type exhibited weak cytotoxicity (less than 17% 51Cr-release at an E/T ratio of 20:1) against the autologous tumour. Therefore, the expression of CD25 on freshly isolated TIL is a good marker for tumour specificity of in vitro expanded TIL.

Antigens, CD↗
PubMed1993

[Malignant melanoma of the skin].

The frequency of malignant melanoma is increasing worldwide and comprises in middle Europe about 10 per 100,000 inhabitants per year; it is fatal in each forth or fifth patient. Risk factors may be endogenous, like fair skin with high sensitivity for sun exposure and the presence of many, possibly atypical ('dysplastic') naevi, or exogenous, e.g. excessive exposure to ultraviolet light. The superficial spreading malignant melanoma is the most common form of clinical manifestation. Applying the A (asymmetry), B (border), C (color), D (diameter), E (elevation) rule is a reliable help for making the diagnosis of malignant melanoma. The differential diagnosis besides various naevi comprises a wide spectrum of pigmented new formations of the skin. Classification of malignant melanoma follows the TNM system; spread, tumor thickness and/or level of infiltration are appropriate parameters. The most important prognostic parameter is tumor thickness, which results in 10-year survival time of only 30% if it exceeds 3 mm. The therapy of malignant melanoma is performed by excision with margins between 1 and 3 cm, depending on tumor thickness. Frequency and type of investigations for follow-up controls depend on the risk for metastases, i.e. on tumor thickness. Best prevention is achieved by avoiding excessive exposure to ultraviolet light, especially during childhood, and by early diagnosis of thin melanoma.

Combined Modality Therapy↗
PubMed1993

[Malignant lymphoma of the skin].

Extranodal non-Hodgkin lymphomas preferentially involve the skin. Among them, 65% are T-cell lymphomas, 25% B-cell lymphomas and about 10% rare variants or nonclassifiable lymphomas. Mycosis fungoides is the most common form of low-grade malignant peripheral cutaneous T-cell lymphoma (CTCL): Lymphomas originating from follicular center cells are the most common types of cutaneous B-cell lymphomas (CBCL). Only 15 to 25% of cutaneous lymphomas show extracutaneous manifestations at time of diagnosis. The prognosis is relatively good, since the average survival time from diagnosis is 12 to 14 years. For making the diagnosis, clinical, histo- and cytomorphological parameters often have to be supplemented by phenotypic, genotypic and molecular biologic techniques in order to establish the correct diagnosis. An important problem still is the early diagnosis and early evaluation of prognostic parameters in CTCL. The therapeutic approach is control of the disease according to stage and prognostic parameters.

Combined Modality Therapy↗
PubMed1993

Peripheral blood mononuclear cells in patients with nonleukemic cutaneous T-cell lymphoma. Reduced proliferation and preferential secretion of a T helper-2-like cytokine pattern on stimulation.

BACKGROUND AND DESIGN: Since patients with cutaneous T-cell lymphoma (CTCL) demonstrate several immunologic abnormalities such as elevated serum immunoglobulin levels or reduced natural killer cell activity, we analyzed functional properties of the peripheral blood mononuclear cells in patients with nonleukemic CTCL and healthy donors. RESULTS: After priming with phytohemagglutinin for 3 days, a reduced proliferation in the presence of interleukin 2 and interleukin 4 was found. Limiting dilution technique revealed a diminished number of peripheral blood mononuclear cells from patients with CTCL that were capable of proliferating on interleukin 2 but not on interleukin 4 stimulation. Phytohemagglutinin induced a significantly higher release of interleukin 4 (mean +/- SD, 196 +/- 149.8 pg/mL [n = 19] vs 76.4 +/- 16.4 pg/mL [n = 248]) and a significantly lower secretion of interferon-gamma (24.9 +/- 30.7 U/mL [n = 17] vs 47.5 +/- 43.5 U/mL [n = 18]) in the peripheral blood mononuclear cells of patients with CTCL compared with the peripheral blood mononuclear cells of healthy donors (P < or = .02, U test). CONCLUSION: These functional characteristics can be explained by an imbalanced T helper-1/T helper-2 system and allow speculations concerning clinical features such as elevated immunoglobulin serum levels and reduced cytotoxic activity in patients with CTCL.

Adult↗
PubMed1992

[Current treatment methods in skin tumors].

Modern aspects of treatment for malignant melanoma, basalioma and cutaneous lymphomas are reviewed. Cytokines have been proposed as immunostimulants in adjuvant therapy (destruction of residual tumor) for malignant melanoma or at high doses for treatment of metastatic melanoma. Basalioma is the most common tumor of the skin, prone to recurrence because of its iceberg-like subclinical growth-pattern. Micrographic surgery is best adapted to this growth behaviour by following the extent of the tumor in all directions by special histopathologic techniques thus permitting radical excision. Primary lymphomas of the skin although rare (1 in 100,000 per year) prevail and cumulate because of the long course over years and decades. New treatment avenues have opened by topical use of phospholipids and cytostatic drugs i. e. carmustine (BCNU).

Administration, Topical↗
PubMed1992

The interleukin-2 receptor in lesions and serum of bullous pemphigoid.

The interleukin-2 receptor (IL-2R) is mainly expressed on activated T cells. Depending on its rate of synthesis, a portion is released from the cell surface as soluble IL-2R (sIL-2R). Since the role of mononuclear cells in the pathology of bullous pemphigoid (BP) is not well understood, we determined the sIL-2R in both blister fluid and serum of 15 BP patients with generalized disease before initiating systemic treatment. In addition, we obtained both lesional and perilesional skin biopsies and examined the mononuclear infiltrate with a panel of monoclonal antibodies. In BP blisters, sIL-2R levels were significantly increased (2070 +/- 350 U/ml), (+/- SEM) compared with serum samples taken at the time of blister puncture (1340 +/- 290 U/ml). In six patients with blisters due to second-degree burns or friction and in five suction blister volunteers, sIL-2R levels were normal in both blisters and serum. In BP, elevated serum levels decreased to normal during therapy, correlating with disease activity. The immunohistology showed that 30% of mononuclear cells in the dermal infiltrate of lesional skin expressed the IL-2R, whereas only 15% were positive in perilesional skin. IL-2R-positive cells are the most likely source of the shed receptor in BP blisters. Our results indicate the presence of activated T cells in lesions and peripheral blood of BP and thus underline the importance of cell-mediated immune mechanisms in the pathology of this disease.

Blister↗
PubMed1992

Gamma/delta receptor-expressing T-cell clones from a cutaneous T-cell lymphoma suppress hematopoiesis.

Recently we described a cutaneous T-cell lymphoma expressing the gamma/delta T-cell receptor [5]. The patient suffering from this lymphoma showed low numbers of myeloid and T cells in peripheral blood, while B and NK cells were relatively increased. In vitro culture of the patient's bone marrow (BM) cells revealed a significant suppression of myeloid/monocyte colony formation (GM-CFU) compared with normal controls. This was not due to infiltration of the BM with lymphoma cells. We speculated that a soluble factor either secreted or induced by the lymphoma cells might be responsible for the marked suppression of hematopoiesis in this patient. From a skin biopsy with infiltrating gamma/delta T-lymphoma cells we established T-cell clones bearing the gamma/delta T-cell receptor and resembling the phenotype of the lymphoma cells. The supernatant (SN) of these gamma/delta T-cell clones reduced the number of colonies in a CFU-GM assay (using normal control BM) in comparison to SN of alpha/beta T-cell clones established from the same biopsy. This suppression was seen mainly on day 7 of culture and was not neutralized by the addition of placenta-CM. The main mediator of this suppression seems to be IFN-gamma, since it was detectable in high amounts in the SN of these gamma/delta T-cell tumor clones as well as in the serum of the patient. In addition, anti-IFN-gamma antibodies can reverse the T-cell SN-mediated suppression of CFU-GM. We conclude that high serum levels of interferon-gamma, which is secreted in high amounts from gamma/delta T-cells grown from a biopsy of a cutaneous lymphoma, can suppress hematopoiesis.

Bone Marrow Cells↗
PubMed1992

Circulating intercellular adhesion molecule-1 in melanoma patients: induction by interleukin-2 therapy.

Intercellular adhesion molecule-1 (ICAM-1, CD54), a molecule bound to the cell surface membrane, mediates various cell-cell interactions in inflammation and immunosurveillance. By means of a new specific enzyme-linked immunosorbent assay (ELISA) for soluble ICAM-1, free circulating ICAM-1 was measured in serum from five healthy volunteers, 10 melanoma patients at different stages of their disease, and eight patients receiving high-dose interleukin-2 (IL-2) for metastatic melanoma. No correlation between the concentration of circulating ICAM-1 and the tumor burden could be detected. In melanoma patients receiving high-dose IL-2, we observed an increase of circulating ICAM-1 of up to 200%, compared to the concentration prior to therapy, ranging between 4 and 13 ng/ml. The increase in circulating ICAM-1 was associated with the induction of tumor necrosis factor-alpha and interferon-gamma.

Cell Adhesion Molecules↗
PubMed1992

Soluble interleukin-2 receptors inhibit interleukin 2-dependent proliferation and cytotoxicity: explanation for diminished natural killer cell activity in cutaneous T-cell lymphomas in vivo?

In patients with cutaneous T-cell lymphomas (CTCL), soluble interleukin-2 receptor serum levels (sIL-2R) were determined by ELISA technique, and natural killer cell (NK) activity, by a 4-h chromium-51 release assay. Decrease of NK activity correlated with the augmentation of serum sIL-2R. After a 4-d stimulation with interleukin 2 CTCL patients' peripheral mononuclear cells (PMC) showed an increase of cytotoxic activity similar to that in healthy donors' PMC. Normal donors' PMC demonstrated a diminished IL-2-induced cytotoxic activity in 25% CTCL serum (sIL-2R of 3000, 7330, and 10700 U/ml, respectively) compared to control serum (sIL-2R of 400, 340, and 420 U/ml, respectively). IL-2-dependent proliferation of 2-d phytohemagglutinin (PHA) blasts was lower in CTCL serum than in control serum. sIL-2R was enriched from one CTCL patient's serum by IL-2 affinity chromatography. Transfection of the Tac gene into NIH/3T3 fibroblasts resulted in the production of a recombinant sIL-2R. The presence of enriched native or recombinant sIL-2R inhibited interleukin-2-dependent generation of cytotoxic activity and PHA blast proliferation. We suggest that elevated sIL-2R levels account for diminished NK activity by neutralizing interleukin 2 in CTCL patients.

Cytotoxicity, Immunologic↗
PubMed1992

Non-MHC-restricted T-cell interaction with B cells: role of the T-cell receptor.

Non-specific antibody production usually accompanies the T-cell-regulated B-cell response. In this paper the mechanisms involved in non-MHC-restricted T-B-cell interaction were studied. As previously shown for NK cells, activated B cells induce IFN-gamma and TNF alpha production in non-MHC-restricted cytotoxic T lymphocytes (NrCTL). Using an in vitro model system, we demonstrate that direct cell-cell interactions are required to induce these cytokines in NrCTL. Receptor ligand systems involved are leucocyte function antigen-1/intercellular adhesion molecule-1 (LFA-1/ICAM-1)(CD11a, CD18/CD54), T11/LFA-3 (CD2/CD58), and the clonotypic T-cell receptor (TCR) structure NKTa of JT9/JT10 with its non-MHC-related target antigen TNKtar (4F2). Cytokine production can be induced by activating monoclonal antibodies against CD2R. Antibodies against the clonotypic TCR (NKTa) or CD3 had no cytokine-inducing effect on NrCTL cultured alone, but were able to retrieve the effect of blocking the target antigen on co-cultured B cells. We could further demonstrate that the inhibition of the TCR/target antigen interaction could be overcome by close cell-cell contact culture conditions. From these findings it is concluded that the role of the TCR in non-MHC-restricted cell-cell interaction is to facilitate LFA-1/ICAM-1-mediated effector target adhesion in a specific way rather than to mediate direct activating signals upon lymphokine production or cytotoxicity.

B-Lymphocytes↗
PubMed1992

[Shedding of soluble intercellular adhesion molecule 1 (ICAM-1) from melanoma cells and the effect on cellular cytotoxicity].

ICAM-1-mediated cell-cell adhesion is essential for various immunologic functions, including non-MHC-restricted cytotoxicity. Shedding of ICAM-1 occurred after stimulation of melanoma cells with TNF alpha and IFN gamma. Soluble forms of ICAM-1 inhibited the conjugate formation of NK clones with K562 and of LAK cells with melanoma cells. Furthermore, the non-MHC-restricted cytotoxicity mediated by NK clones or LAK cells could be abrogated by soluble ICAM-1.

Cell Adhesion↗
PubMed1991

Shedding of ICAM-1 from human melanoma cell lines induced by IFN-gamma and tumor necrosis factor-alpha. Functional consequences on cell-mediated cytotoxicity.

ICAM-1-mediated cell-cell adhesion is essential for various immunologic functions, including non-MHC-restricted cytotoxicity. The present study was designed to establish whether shedding of ICAM-1 from melanoma cells occurred and to characterize the effects of soluble ICAM-1 on some cell adhesion-dependent functions. The shed soluble ICAM-1 molecule was detected and quantified by a specific ELISA. Shedding of ICAM-1 could be induced by IFN-gamma and TNF-alpha alone, or more effectively, by a combination of the two cytokines together. The use of purified soluble ICAM-1 enabled us to test for the functional significance of the ICAM-1 shedding from tumor cells. Conjugate formation between the cloned NK cell line CNK6 and the erythromyeloid cell line K562, as well as between lymphokine-activated killer cells and the melanoma cell line M26, could be inhibited by purified soluble ICAM-1 and cell-free supernatants from melanoma cell cultures containing shed ICAM-1. Furthermore, the non-MHC-restricted cytotoxicity mediated by NK and lymphokine-activated killer cells could be abrogated either by purified soluble ICAM-1 or by melanoma cell culture supernatants containing shed ICAM-1. Thus, shedding of ICAM-1 may be one of the mechanisms by which neoplastic cells escape immunosurveillance.

Cell Adhesion↗
PubMed1991

Prognostic significance of DNA cytometry in cutaneous malignant lymphomas.

The current classification of cutaneous malignant lymphomas (ML) into low-grade and high-grade lymphomas was found to be of limited reproducibility and permitted only a rough prediction about outcome. With this in mind, the relationship between nuclear DNA content and both prognosis and histologic grading according to the Kiel classification was evaluated on Feulgen-stained imprint specimens. In all, 49 cases of malignant non-Hodgkin's lymphoma, primary of the skin or with an involvement of the skin as one of the first symptoms, were studied using a computerized high-resolution image analysis system. The 2c deviation index (2cDI), which reflects the variation of the nuclear DNA values around the normal diploid peak, was found to be the best prognostically relevant criterion. Using the 2cDI, a significant discrimination (P less than 0.001 in the U test) between low-grade and high-grade ML was achieved. The prognostic benefit of the 2cDI was well documented by a significant inverse correlation between the 2cDI and the period of time until the patients progressed at least into one higher stage or died of lymphoma (r equals -0.63, P less than 0.05). In addition, the 2cDI enabled prognosis of the course of disease. In the group with low 2cDI values (2cDI, less than 0.5), no progression of the disease was observed after 1 year. In the groups presenting with a 2cDI between 0.5 and 1.0 and higher than 1.0, a progression was found in 57% and 64% of the cases studied, respectively. In conclusion, these measurements indicate that the determination of DNA distribution patterns in imprint specimens allows a precise and objective prognostic evaluation of cutaneous ML.

Adult↗