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Biomedical subjects

G Riethmüller

Publications and source records attributed to G Riethmüller.

260 records · Page 15Linked to original sources
PubMedDate not supplied

Differential expression of MHC class II subregion products on bile duct epithelial cells and hepatocytes in patients with primary biliary cirrhosis.

To study the expression of MHC Class II subregion gene products on biliary epithelial cells in primary biliary cirrhosis, frozen sections from liver biopsies of 15 patients with primary biliary cirrhosis were studied immunohistochemically using HLA-D subregion specific monoclonal antibodies L243 (HLA-DR), Leu10 (HLA-DQ) and B7/21 (HLA-DP). Patients with early stages of primary biliary cirrhosis showed expression of HLA-DP, HLA-DR and HLA-DQ subregion gene products on bile duct epithelial cells. In advanced stages of disease, no MHC Class II antigens or only HLA-DR and HLA-DP were expressed on bile duct cells. While normal hepatocytes did not express detectable amounts of MHC Class II antigens, hepatocytes from liver biopsies of four patients with primary biliary cirrhosis showed a distinct staining exclusively with monoclonal antibodies specific for HLA-DR. The expression of MHC Class II antigens on parenchymal cells was independent of a lymphocytic infiltration into the tissue. This study demonstrates that bile ductular cells, but not hepatocytes, express a full set of MHC Class II molecules at least during the early stages of primary biliary cirrhosis. We propose, therefore, that the expression of both HLA-DR and HLA-DQ subregion products on bile duct epithelial cells may be a necessary, although not sufficient, condition for the initiation of an autoimmune process leading to the destruction of intrahepatic bile ducts in primary biliary cirrhosis.

Antibodies, Monoclonal↗
PubMedDate not supplied

Construction and biological activity of a recombinant bispecific single-chain antibody designed for therapy of minimal residual colorectal cancer.

Unlike monoclonal antibodies, clinical application of bispecific antibodies has so far lagged behind because of difficult, low-yield production techniques as well as considerable toxicity attributed to bispecific antibody preparations containing immunoglobulin-Fc parts and anti-CD3 homodimers. These difficulties were overcome by recombinant generation of a bispecific single-chain antibody (bscAb) joining two single-chain Fv fragments via a five-amino-acid glycine-serine linker. The anti-CD3 specificity directed against human T cells was combined with another specificity against the epithelial 17-1A antigen. The following domain arrangement was critical in this individual case to obtain a fully functional bscAb: VL17-1A-VH17-1A-VHCD3-VLCD3. The bscAb was expressed in chinese hamster ovary cells with a yield of 15 mg/l culture supernatant whereas numerous attempts to obtain a functional protein expression in Escherichia coli failed. The low-molecular-mass bispecific construct (60 kDa) could easily be purified by its C-terminal histidine tail. The antigen-binding properties are indistinguishable from those of the corresponding univalent single-chain Fv fragments as shown by enzyme immunoassay and flow cytometry. We could show that the bscAb, which lacks Fc parts and anti-CD3 homodimers is highly cytotoxic for 17-1A positive tumor cells in nanomolar concentrations and in the presence of human T cells. Most remarkable, it does not stimulate T lymphocyte proliferation in the absence of tumor cells and, moreover, does not induce CD25 up-regulation and the secretion of potentially toxic lymphokines such as tumor necrosis factor alpha, interleukin-6 and interferon gamma. Maximal cytotoxicity (51Cr release) was achieved without notable costimulation and was not further enhanced by adding costimulatory signals such as those delivered by anti-CD28 antibodies. CD8+ as well as CD4+ T cell subpopulations were recruited to exert cytotoxicity against tumor cells with different kinetics. CD8+ cells induced high 51Cr release within 4 h while CD4+ cells required a 20-h incubation. The systemic application of the 17-1A/CD3-bscAb could be a major improvement in therapy against disseminated micrometastatic tumor cells. A prospective, randomized clinical trial showing that an anti-17-1A monoclonal antibody could prolong survival of colorectal cancer patients after 5 and 7 years, warrants an assessment of the clinical efficacy of this bscAb exhibiting a 1000-fold higher specific cytotoxicity against tumor cells in vitro.

Animals↗
PubMedDate not supplied

Characteristics of a monoclonal beta-endorphin antibody recognizing the N-terminus of opioid peptides.

The properties of a mouse monoclonal antibody to beta-endorphin secreted by a clone of hybrid myelomas (3-E7) are described. The antibody displays virtually complete cross-reactivity to met-enkephalin and leu-enkephalin, but no cross-reactivity to beta-lipotropin, alpha-N-acetyl-beta-endorphin and des-Tyr1-beta-endorphin. Substantial cross-reactivity is seen with some other naturally occurring opioid peptides bearing the enkephalin sequence, such as dynorphin, alpha-neo-endorphin and BAM 22, but cross-reactivity is lacking in the case of certain synthetic enkephalin derivatives possessing a D-amino acid in position 2. The data indicate that for the binding of an antigen to the antibody the N-terminal tyrosine moiety is essential. The antibody recognizes, thus, a site which is of functional significance for the interaction of many naturally occurring opioid peptides with the opiate receptor.

Amino Acid Sequence↗
PubMedDate not supplied

Expression of the CD6 T lymphocyte differentiation antigen in normal human brain.

Antigens shared by the immune and central nervous systems (CNS) have been described repeatedly. The present study reports the expression of the CD6 lymphocyte differentiation antigen in normal human brain evidenced by immunohistochemistry and Northern blot analysis. A panel of various anti-CD6 monoclonal antibodies (mabs) tested on serial cryostat sections identified CD6-positive cells randomly scattered in parenchyma of all examined brain areas. Northern blot analysis with a highly sensitive cRNA probe revealed a 3.1 kb CD6-specific mRNA in various brain regions, especially in basal ganglia and cortex cerebellum. Staining with mabs raised against different hematopoietic cell types, as well as hybridization with probes specific for the beta- and gamma-T cell receptor (TCR) chains support the notion that CD6 is expressed by original brain cells. The nature of the CD6-positive cell type and possible functions of shared antigens in immune and nervous systems are discussed.

Antibodies, Monoclonal↗
PubMedDate not supplied

Prevention of manifest metastasis with monoclonal antibodies: a novel approach to immunotherapy of solid tumours.

Until now, surgery, chemotherapy and radiotherapy have remained the mainstay of current cancer therapy. The major limitation of chemo- and radiotherapy is their narrow therapeutic index between cancer and normal cells. In the search for less toxic and more specific therapies, various modalities of immunotherapy have been tried. It is now increasingly recognised that patients presenting with minimal cancer burden or micrometastatic disease will experience the greatest benefit from treatment with monoclonal antibodies (mAbs). The first proof of efficacy of a monoclonal antibody in minimal residual disease has recently been published, with mAb 17-1A in patients with colorectal cancer stage III after complete resection of the primary tumour. After a median follow-up of 5 years, antibody therapy reduced the overall death rate by 30% and decreased the recurrence rate by 27%. This result is similar to the benefit obtained in (radio)chemotherapy trials, however, with notably lesser toxicity. It is clear from past experience that all currently available treatment modalities for cancer are far from perfect. However, because the mechanism of action or target cells of different treatment modalities may be complementary in the control of tumour growth, the next logical step is to rationally design clinical trials that combine conventional chemo-, hormonal or radiation therapy with immuno- or biotherapy.

Antibodies, Monoclonal↗
PubMedDate not supplied

Treatment of non-hodgkin's lymphoma of low-grade malignancy with human fibroblast interferon.

10 patients with advanced non-Hodgkin's lymphoma of low malignancy were treated with partially purified HulFN-beta. They received daily i.v. infusions of 4.5 X 10(6) IU for 4 weeks, followed by 9 X 10(6) IU daily for 2 weeks. Patients with stable disease during this period received consolidation therapy with 4.5 X 10(6) IU three times per week for a maximum of 20 weeks. Six out of 10 patients had progressive disease after the initial 6 week treatment and 4 had stable disease. Two of the latter developed progressive disease during consolidation therapy, one had a complete remission of minimal bone marrow involvement, and one was in partial remission with a loss of bone marrow infiltration but unchanged lymph node enlargement.

Adult↗