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Biomedical subjects

U Reinhold

Publications and source records attributed to U Reinhold.

At least 55 records · Page 3Linked to original sources
PubMed2000

Interferon-alpha-associated development of bullous lesions in mycosis fungoides.

We report a 67-year-old woman with mycosis fungoides (MF) who was receiving subcutaneous injections of recombinant interferon alpha-2b (IFN-alpha). After 2 months of IFN-alpha treatment, bullous lesions appeared on her trunk and extremities. A skin biopsy specimen from the trunk revealed histopathologic features of bullous MF. Bullous lesions with specific infiltrates of MF are very rare; to the best of our knowledge, this is the first case showing specific bullous lesions of MF developed under IFN-alpha treatment.

Aged↗
PubMed1999

Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-gamma.

The expression and functionality of the Fas receptor (CD95/APO-1) play an important role for the maintenance of tissue homeostasis. Various types of tumor cells have been shown to escape immune recognition by constitutive resistance to CD95-mediated apoptosis. Furthermore, several apoptosis-related proteins have been reported to influence CD95 sensitivity. We tested an unselected panel of 11 melanoma cell lines for sensitivity to CD95 and the corresponding expression of CD95, CD95L, bcl-2, bcl-x, bcl-xS, bax and FLIP proteins. Despite detection of CD95 cell-surface expression in 9 out of the 11 cell lines tested, only 3 melanoma cell lines were sensitive to anti-CD95-MAb-induced cell death. Apoptosis-related proteins CD95L, bcl-2, bcl-x, bcl-xS and bax were found to be heterogenously expressed in different melanoma cell lines tested. The susceptibility of melanoma cells to anti-CD95-MAb-mediated apoptosis was associated with low protein expression of both bcl-2 and bcl-x. The level of CD95 cell-surface expression in melanoma cells was no indicator for CD95 sensitivity. Furthermore, FLIP protein was detectable in 7 out of the 11 cell lines, but showed no correlation to CD95 sensitivity. Certain cytokines have been described as modulating the susceptibility of tumor cells to CD95-induced cell death. Since IFN-alpha was proved to be clinically efficient in melanoma therapy, we tested whether interferons have the ability to induce sensitivity to CD95 in primarily resistant melanoma cell lines. Here we show that IFN-gamma, but not IFN-alpha, is able to increase the susceptibility of sensitive cell lines and to induce CD95 sensitivity in resistant melanoma cell lines, accompanied by up-regulation of the protein expression level of CD95 and/or bcl-xS.

Apoptosis↗
PubMed1999

Treatment of progressive pigmented purpura with oral bioflavonoids and ascorbic acid: an open pilot study in 3 patients.

BACKGROUND: Bioflavonoids and ascorbic acid have been shown to increase capillary resistance and to mediate potent antioxidative radical scavenging activities. OBJECTIVE: We evaluated the clinical effect of oral bioflavonoids and ascorbic acid in patients with chronic progressive pigmented purpura (PPP). METHODS: In an open pilot study, oral rutoside (50 mg twice a day) and ascorbic acid (500 mg twice a day) were administered to 3 patients with chronic PPP. RESULTS: At the end of the 4-week treatment period, complete clearance of the skin lesions was achieved in all 3 patients. No adverse reactions were noted. All patients remained free of lesions at the end of 3 months after treatment. CONCLUSION: Our results suggest a beneficial effect of bioflavonoids in combination with ascorbic acid on PPP. Because the disease is mostly resistant to other treatment modalities, placebo-controlled studies are necessary to determine the usefulness of this therapy in PPP.

Administration, Oral↗
PubMed1999

Specific lysis of melanoma cells by receptor grafted T cells is enhanced by anti-idiotypic monoclonal antibodies directed to the scFv domain of the receptor.

Malignant transformation of melanocytes is frequently associated with abnormalities in antigen processing and in human leukocyte antigen class I antigen expression. Here, we evaluated a human leukocyte antigen class I antigen-independent approach to target cytotoxic T lymphocytes to melanoma cells by grafting cytotoxic T lymphocytes with a chimeric receptor that consists of both a domain binding to high molecular weight-melanoma associated antigen and a cellular activation domain. The binding domain is a single-chain antibody fragment (scFv) derived from the monoclonal anti-high molecular weight-melanoma associated antigen antibody 763.74 by phage display techniques. The cellular activation domain is the signaling unit of the FcepsilonRI receptor gamma chain. Both domains constitute the chimeric receptor scFv763.74-gammaR. Cytotoxic MD45 T cells grafted with the scFv763.74-gammaR receptor bind specifically to high molecular weight-melanoma associated antigen-positive melanoma cells and lyse melanoma cells in a human leukocyte antigen class I independent fashion. Pre-incubation of receptor grafted T cells with immobilized anti-idiotypic (id) monoclonal antibody MK2-23 binding to the scFv domain of the receptor enhanced the lysis of melanoma cells indicating that the specific cytolytic activity of receptor grafted T cells can be increased by costimulation with cross-linked anti-idiotypic monoclonal antibodies that recognize the antigen binding domain of the chimeric receptor.

Amino Acid Sequence↗
PubMed1999

Grafting T cells with tumor specificity: the chimeric receptor strategy for use in immunotherapy of malignant diseases.

Appreciation of the complementary nature of T-cell- and antibody-based immunotherapy stimulated interest in developing approaches that combine their advantages and minimize their limitations. A recent strategy is based on permanent grafting of cytotoxic T cells with a recombinant chimeric receptor designed for cellular targeting with antibody-like specificity and for cellular activation after binding to antigen. The extracellular moiety of the chimeric receptor consists of an antigen-binding domain derived from an antibody, the intracellular moiety consists of a signalling domain for cellular activation, thus combining the broad specificity of antibody-based and major histocompatibility complex (MHC)-independent recognition with the potent antitumor activity of T cells. By generation of specific T cells against any antigen for which a suitable monoclonal antibody (MAb) exists, the chimeric receptor strategy has the potential to extend the adoptive immunotherapy for a variety of malignant and infectious diseases. However, little is known about the optimized design of this type of receptor. We here discuss our results in grafting T cells with chimeric receptors of various design with regard to efficient cellular activation.

Antibodies, Neoplasm↗
PubMed1999

Heterogeneity of chemosensitivity of metastatic cutaneous melanoma.

Advanced melanoma has a poor prognosis and chemotherapy provides little benefit for most patients. This may be related to heterogeneity of chemosensitivity as well as frequent constitutive resistance to individual cytotoxic drugs. We have therefore examined the heterogeneity of chemosensitivity in metastatic cutaneous melanoma specimens using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node were tested using the ATP-TCA, performed in three separate laboratories. Analysis of the data collected (based on an arbitrary sensitivity index < 300) shows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, paclitaxel, vinblastine, gemcitabine and mitoxantrone. There was also a limited direct inhibition of melanoma cell growth by interferon-alpha2b, although this agent is known to have a number of indirect biological antitumor effects. Exposure of tumor cells to combinations of drugs at the concentrations tested as single agents showed the most active combinations to be treosulfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There was considerable heterogeneity of chemosensitivity: some tumors responded well to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resistant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA could be used to select patients who might benefit from specific chemotherapeutic agents alone or in combination. This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physician's choice to determine whether assay-directed chemotherapy can improve patient response and survival.

Adenosine Triphosphate↗
PubMed1999

Successful treatment of progressive vitiligo with high-dose intravenous methylprednisolone 'pulse' therapy.

We report on the successful therapy of rapid progressive generalized vitiligo in a 24-year-old woman. After intravenous injection of 500 mg of methylprednisolone on 3 consecutive days, the disease progression was stopped and repigmentation was induced. The treatment was repeated monthly and after 6 cycles, repigmentation was achieved on vast parts of most vitiligo lesions. The treatment was well tolerated by the patient, and no side effects were noted. We conclude that high-dose glucocorticoid pulse therapy may represent a therapeutic alternative in selected patients with generalized rapid progressive vitiligo.

Adult↗
PubMed1999

CD2-mediated CD59 stimulation in keratinocytes results in secretion of IL-1alpha, IL-6, and GM-CSF: implications for the interaction of keratinocytes with intraepidermal T lymphocytes.

Normal epidermal keratinocytes are here shown to express membrane-associated complement inhibitory protein CD59 in vitro that protects keratinocytes from damage by complement because preincubation with blocking antibodies to CD59 renders the cells susceptible to complement mediated lysis. CD59 expression in keratinocytes is constitutive and not modulated by inflammatory cytokines, phorbol myristate acetate (PMA), and a number of other agents tested. Antibody mediated cross-linking of CD59, however, revealed an additional function of CD59: keratinocytes in vitro are activated to secrete the cytokines IL-1alpha, IL-6, and GM-CSF. CD59 mediated induction of these cytokines is regulated at the transcriptional level. Binding of keratinocytes to HL60 cells that express CD59 ligand CD2 induced the same pattern of secreted cytokines whereas binding to CD2-negative HL60 cells did not. Induction of cytokine secretion was completely blocked by preincubation of keratinocytes with both anti-CD58 and anti-CD59 antibodies together. The results demonstrate that CD2-mediated CD59 stimulation in human keratinocytes leads to synthesis of a particular set of cytokines implying a potential activation pathway in the interaction of keratinocytes with intraepithelial CD2+ T cells.

Antibodies, Blocking↗
PubMed1998

Predominant expression of CD44 splice variant v10 in malignant and reactive human skin lymphocytes.

The remarkable functional diversity of the cell surface receptor CD44 may be due to expression of multiple variant isoforms generated by alternative splicing of variant exons. Functional and correlative data implicate a role of CD44 variant isoforms in adhesion dependent processes such as lymphocyte recirculation and tumor progression and metastasis. We have analyzed 25 primary cutaneous lymphomas and 35 reactive lymphoid cell skin infiltrates or T cell-mediated skin diseases for the expression of CD44 variant isoforms. Irrespective of histologic typing, staging, and grading, cutaneous lymphomas as well as nonmalignant skin-infiltrating CD3+ CD4+ and CD8+ T and CD19+ B lymphocytes exhibited a strong expression of CD44v10 and a moderate expression of CD44v3 as determined by immunohistochemistry, immunofluorescence microscopy, and mRNA analysis. Expression of v5, v6, v7, and v9-containing CD44 variant isoforms was not detected. Furthermore, flow cytometry revealed expression of CD44v10 on a significant proportion of peripheral blood lymphocytes from Sézary's syndrome patients and a remarkable co-expression with cutaneous lymphocyte antigen. These results indicate a distinct CD44 variant isoform expression pattern associated with skin-homing lymphocytes different to lymphatic cells at noncutaneous sites. This differential expression pattern of CD44 variant isoforms may contribute to the development of lymphocyte skin infiltrates and/or the unique biologic behavior of cutaneous lymphomas.

Alternative Splicing↗
PubMed1998

Cytotoxic action of 2-deoxy-D-glucose tetraacetate upon human lymphocytes, fibroblasts and melanoma cells.

The tetraacetate ester of 2-deoxy-D-glucose was found to cause a concentration-related (10 microM to 1.0 mM) inhibition of activated T cell proliferation and decrease in viability of both unstimulated and anti-CD3 monoclonal antibody-stimulated peripheral blood mononuclear cells. Comparable findings were made in primary fibroblast cultures initiated from human skin explants. Likewise, 2-deoxy-D-glucose tetraacetate exerted a time-related (4-72 h) and concentration-related (0.1-1.0 mM) cytotoxic action upon human melanoma cells of the Colo 38 line. In this cell line, multiparameter flow cytometric analysis of cells stained with annexin V and propidium iodide revealed a necrotic, rather than apoptotic, form of cell death after exposure to 2-deoxy-D-glucose tetraacetate.

Cell Death↗
PubMed1997

CD4+ CD7- T cells: a separate subpopulation of memory T cells?

The CD7 molecule is apparently involved in T cell activation but is absent in a substantial subpopulation of human T cells under physiological and certain pathological conditions. The majority of CD7- T cells expresses TCR alpha/beta and is of CD4+ helper and CD45R0+CD45RA- memory phenotype. After birth, percentages and absolute numbers of circulating CD7- T cells increase significantly during aging. A number of molecules thought to be involved in organ-specific T cell homing are preferentially expressed within the subset of CD4+CD7- T cells. Specific absence of CD7 antigen expression on T cells is observed in a variety of pathologic conditions such as cutaneous T cell lymphoma, HIV infection, rheumatoid arthritis, and kidney transplantation. Current in vitro results suggest that specific downregulation of CD7 antigen expression in T cells reflects a separate and stable differentiation state occurring late in the immune response. Expansion of CD7- T cells in vivo has been found in certain diseases associated with chronically repeated T cell stimulation. The potential pathophysiological significance of this T cell subset in certain human diseases is discussed.

Animals↗
PubMed1997

Effects of diagnostic application of monoclonal antibody on survival in melanoma patients.

Follow-up data of more than 300 melanoma patients were reviewed in which an immunoscintigraphy study had been performed as part of a routine staging protocol. All patients had received a commercially available 99mTc-labeled F(ab')2 fragment specific to a high-molecular-weight melanoma-associated antigen (HMW-MAA). Survival data of patients that had received one injection (group I) were compared with those receiving two or more injections (group II). For better comparison, patients were matched according to the following risk factors: (i) age, (ii) sex, (iii) tumor level according to Clark, (iv) tumor depth according to Breslow, (v) location of primary tumor, and (vi) metastases [and if positive, (vii) location of metastases]. Twenty-eight patient pairs were established that showed no statistically significant differences comparing the above-mentioned risk factors. In addition, no significant difference was found comparing the interval between primary diagnosis of disease and first injection of monoclonal antibody (MAb) in both groups. In contrast, survival time between first diagnosis of melanoma was significantly prolonged in group II (multiple injections) as compared to group I (single injection). This was true for survival time between primary diagnosis as well as from first injection of MAb until death or closing time of study. Our data suggest, that multiple injections of melanoma-specific F(ab')2 fragment have a beneficial effect on median survival in melanoma patients.

Adult↗