Soluble interleukin-2 receptors and cutaneous T-cell lymphoma.
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Humans↗
Biomedical subjects
R Dummer
Publications and source records attributed to R Dummer.
UVA suppresses shedding of ICAM-1 from interferon-gamma (IFN-gamma)-pretreated transformed keratinocytes.
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Cell Adhesion Molecules↗
Topical administration of hexadecylphosphocholine in patients with cutaneous lymphomas: results of a phase I/II study.
BACKGROUND: Hexadecylphosphocholine is a new antineoplastic drug that inhibits tumor cell growth directly and, in addition, might have immunoregulatory properties. OBJECTIVES: We investigated the topical application of this phospholipid in patients with cutaneous lymphoma. METHODS: Twenty-four patients with histologically documented cutaneous lymphoma were treated for 8 weeks. Lesions that responded to treatment were biopsied and evaluated histologically. RESULTS: Of 15 patients with cutaneous T-cell lymphomas, 12 were evaluable. Two complete remissions, four partial remissions, and one minor remission were observed. Of seven patients with B-cell lymphomas, six were evaluable. One complete remission, three partial remissions, one case of stable disease, and one case of progressive disease were seen. However, histologic monitoring demonstrated only a partial clearing of infiltrating lymphocytes in lesions that showed a partial or complete response clinically. Both patients with lymphomatoid papulosis had complete clearing of the lesions clinically. An objective response rate (partial and complete response) of 56% (10/18) was achieved in the patients with cutaneous lymphoma who were treated in this study. CONCLUSION: Hexadecylphosphocholine appears to be effective topically in the treatment of some cases of cutaneous lymphomas.
Administration, Cutaneous↗
Lesion-specific activation of cloned human tumor-infiltrating lymphocytes by autologous tumor cells: induction of proliferation and cytokine production.
To investigate the mechanisms by which tumor-infiltrating lymphocytes exert their antitumor effects, tumor-specific tumor-infiltrating lymphocyte clones, as well as autologous tumor cell lines from primary and secondary tumors of two patients during the course of melanoma progression were established. Enrichment for tumor-infiltrating lymphocytes expressing CD25, as well as low concentrations of interleukin-2 (30 IU/ml) in the culture medium, led to a preferential outgrowth of cells that express the high-affinity interleukin-2 receptor. All of these expressed CD2, CD3, CD11, and CD25. Coculture of tumor-infiltrating lymphocyte clones with irradiated, autologous tumor cells induced an up to 480% greater proliferative responses than recombinant interleukin-2 alone. Approximately 60% of the tumor-infiltrating lymphocyte clones showed cytotoxicity against the relevant tumor in a 4-h 51Cr-release assay. When tested in an 18-h 51Cr-release assay, the number of tumor-infiltrating lymphocyte clones exhibiting cytotoxicity against the relevant tumor increased to over 85%. In response to autologous tumor cells, nine of 15 clones secreted interferon-gamma, tumor necrosis factor-alpha, or both. Cytokine production was not restricted to either CD4+ or CD8+ T cells because both CD4+ and CD8+ tumor-infiltrating lymphocyte clones secreted cytokines. Tumor-infiltrating lymphocyte tumor interaction appears to be lesion specific because induction of proliferation and cytokine production, as well as susceptibility to cytolysis, was found not only restricted to the autologous system, but also to the specific lesion. The pattern of tumor-infiltrating lymphocyte tumor interaction specificity indicates a possible loss of antigens expressed on the tumor during disease progression.
Cell Division↗
T cells migrate to tumour sites after extracorporeal interleukin 2 stimulation and reinfusion in a patient with metastatic melanoma.
Peripheral blood mononuclear cells (PBMC) were taken by leukapheresis from a patient with melanoma skin metastases and stimulated in vitro using 1000 IU recombinant interleukin 2 (IL-2)/ml to generate lymphokine-activated killer cells (LAK cells). Two-colour immunofluorescence analysis demonstrated an IL-2-induced up-regulation of CD25 on natural killer cells (CD56+) as well as on T lymphocytes (CD3+). After radiolabelling with indium-111, the cells were reinfused. Gamma-camera imaging revealed an enrichment at the tumour sites. Immunostaining of tumour tissue taken before and after scintigraphy demonstrated CD25+ T lymphocytes (CD2+, CD3+), but no natural killer cells (CD16+, CD56+) infiltrating the metastases. LAK cell enrichment at melanoma metastases in vivo did not involve natural killer cells, but was characterized by increased numbers of activated T lymphocytes in this patient.
Cell Movement↗
Evidence for cell-mediated immune mechanisms in the pathology of pemphigus.
Pemphigus is an autoimmune blistering disease in which autoantibodies have clearly been shown to be pathogenic. Because autoantibodies are also found in uninvolved skin, further mechanisms may be important in the development of pemphigus lesions. In addition to granulocytes, mononuclear cells are commonly found in pemphigus lesions. To elucidate the role of mononuclear cells in the pathology of this disease, we determined the levels of soluble interleukin-2 receptor in blister fluid and serum samples from pemphigus patients prior to treatment. The interleukin-2 receptor (IL-2R) is expressed on activated mononuclear cells. Depending on its rate of synthesis, a portion is released from the cell surface in a soluble form (sIL-2R). In blister fluid, sIL-2R levels were 2186 +/- 288 U/ml (+/- SD), which was significantly higher than levels in concurrently obtained serum samples (1299 +/- 165 U/ml; P < 0.001). In suction blisters in volunteers, and in patients with second-degree burns or friction-induced bullae, sIL-2R levels were normal in both blister fluid and serum. In pemphigus patients, sIL-2R serum levels continuously declined during systemic therapy, correlating with disease activity. Immunohistological studies demonstrated a marked increase in IL-2R+ cells in both the epidermis and dermis of lesional skin compared with perilesional skin. In the dermis, CD3+ T cells predominated, whereas monocytes/macrophages were most frequent in the epidermis. In pemphigus vulgaris, monocytes/macrophages were restricted to the basal keratinocytes, whereas in pemphigus foliaceus, they were found throughout the lesional epidermis. Our data indicate that activated mononuclear cells are present in lesional skin of pemphigus patients, and may contribute to the pathology of this disease.
Aged↗
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↗
[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↗
[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↗
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↗
[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↗
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↗
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↗
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↗
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↗
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↗
Serum levels of soluble interleukin-2 receptor in systemic and circumscribed scleroderma.
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Adult↗
Topical application of hexadecylphosphocholine in patients with cutaneous lymphomas.
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Administration, Cutaneous↗