Signaling through a novel domain of gp130 mediates cell proliferation and activation of Hck and Erk kinases.

Interleukin-6 (IL-6) induces the activation of the Src family kinase Hck, which is associated with the IL-6 receptor beta-chain, gp130. Here we describe the identification of an "acidic" domain comprising amino acids 771 to 811 of gp130 as a binding region for Hck, which mediates proliferative signaling. The deletion of this region of gp130 (i.

Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells.

Gene therapy vectors based on adeno-associated virus-2 (AAV2) offer considerable promise for human gene therapy. Applications for AAV vectors are limited to tissues efficiently transduced by the vector due to its natural tropism, which is predominantly skeletal muscle, neurons, and hepatocytes. Tropism modification to elevate efficiency and/or selectivity to individual cell types would enhance the scope of AAV for disease therapies.

Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d.

Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL).

Standard heparin, low molecular weight heparin, low molecular weight heparinoid, and recombinant hirudin differ in their ability to inhibit transduction by recombinant adeno-associated virus type 2 vectors.

Recombinant adeno-associated virus type 2 (rAAV) is a promising vector for in vivo gene therapy. Transduction by rAAV requires binding to heparan sulfate proteoglycan on the cell surface, and heparin can block this binding. Because heparin is administered to most patients undergoing cardiovascular gene transfer in order to prevent thrombotic events, it is important to identify anticoagulants which do not interfere with rAAV transduction.

New aspects on the pathogenesis, diagnostic procedures, and therapeutic management of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia of the B-cell type (B-CLL) is the most frequently occurring leukemia in the Western hemisphere. Until 10 years ago, the basic medical approach to this disease was expectative and palliative. Chemotherapy with alkylating agents such as chlorambucil used to be the main therapeutic option, and only patients at advanced stages of B-CLL were treated.

Recombinant adeno-associated virus (rAAV) vector-mediated cotransduction of CD70 and CD80 into human malignant melanoma cells results in an additive T-cell response.

Genetic modification of malignant melanoma cells by transduction of cDNA encoding costimulatory molecules, cytokines or tumor-associated antigens has been shown to induce antitumor immunity. An important step in this scenario is the activation of T cells. CD80 is a pivotal costimulatory molecule for T-cell activation.

IDEC-C2B8 (Rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group.

Purpose: The current study was initiated to assess the clinical efficacy and side effects of rituximab in patients with relapsed advanced stage follicular lymphoma.

Patients And Methods: The study was performed as an open-label non-randomized multicenter phase-II trial and included patients older than 18 years of age with relapsed advanced-stage follicular lymphomas (FL) grades I and II, according to the REAL classification, or with centroblastic/centrocytic (CB/CC lymphomas according to the Kiel classification. Four weekly doses of 375 mg/m2 rituximab were applied.

Monoclonal antibodies against the adeno-associated virus type 2 (AAV-2) capsid: epitope mapping and identification of capsid domains involved in AAV-2-cell interaction and neutralization of AAV-2 infection.

The previously characterized monoclonal antibodies (MAbs) A1, A69, B1, and A20 are directed against assembled or nonassembled adeno-associated virus type 2 (AAV-2) capsid proteins (A. Wistuba, A. Kern, S.

Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines.

Chronic myeloid leukemia (CML) is a malignant stem cell disease characterized by an expansion of myeloid progenitor cells expressing the constitutively activated Bcr-Abl kinase. This oncogenic event causes a deregulation of apoptosis and cell cycle progression. Although the molecular mechanisms protecting from apoptosis in CML cells are well characterized, the cell cycle regulatory event is poorly understood.

The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X.

CGP 57148 is a potent inhibitor of the ABL protein tyrosine kinase and a promising new compound for the treatment of a variety of BCR-ABL-positive leukemias. We used this enzyme inhibitor to characterize the biological effects of BCR-ABL in primary cells and two growth factor-dependent BCR-ABL-transfected cell lines. The effect of CGP 57148 on primary cells is dependent on the stage of differentiation.

The activation of intracellular tyrosine kinases by interferon-alpha (IFNalpha) correlates with its antiproliferative activity in B-lymphoid cell lines, but not in B-cell chronic lymphocytic leukemia patients.

The response to interferon-alpha (IFNalpha) treatment in leukemias of the B-cell lineage shows a marked heterogeneity. A distinct subset of patients with B-CLL responds to treatment with IFNalpha, while the drug has no therapeutic effect in the majority of patients. The mechanism of this phenomenon is poorly understood.

Reconstitution of the cellular immune response after autologous peripheral blood stem cell transplantation in patients with non-Hodgkin's lymphoma.

Peripheral blood stem cell (PBSC) transplants may be depleted of lymphoid progenitors, thereby disabling the cellular immune response against viral pathogens after autologous PBSC transplantation (PBSCT). To monitor the cellular immune reconstitution after autologous PBSCT, we investigated the cytolytic activity (CLA) of peripheral blood T lymphocytes against Epstein-Barr virus (EBV) in 13 patients with non-Hodgkin's lymphoma or multiple myeloma. The individual EBV-directed CLA (EBV-CLA) was determined by calculating the number of cytolytic effector cells in 106 T cells needed to lyse 25% of autologous EBV-transformed B-lymphoblastoid cells, expressed as lytic units (LU25).

Eosinophilia during fludarabine treatment of chronic lymphocytic leukemia.

Although eosinophilia has been reported as a side effect of purine analogues, there is no report on fludarabine-induced eosinophilia in chronic lymphocytic leukemia (CLL). During chemotherapy with fludarabine and cyclophosphamide, we observed two cases of significant eosinophilia. A 67-year-old patient with CLL developed bone marrow and peripheral blood eosinophilia up to 7.

Induction of tumor immunity by autologous B lymphoma cells expressing a genetically engineered idiotype.

A fusion protein containing a B cell lymphoma idiotype (Id) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent stimulator of tumor immunity. In three different tumor models we show that immunization with autologous lymphoma cells that have been engineered to express the Id in the context of GM-CSF is much more effective than immunization with an equivalent dose of the purified protein. The lymphoma Id could be modified by introducing the GM-CSF gene into the immunoglobulin (Ig) heavy chain locus via gene targeting.

Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2.

The human parvovirus adeno-associated virus type 2 (AAV2) has many features that make it attractive as a vector for gene therapy. However, the broad host range of AAV2 might represent a limitation for some applications in vivo, because recombinant AAV vector (rAAV)-mediated gene transfer would not be specific for the tissue of interest. This host range is determined by the binding of the AAV2 capsid to specific cellular receptors and/or co-receptors.

Involvement of the CD27-CD70 co-stimulatory pathway in allogeneic T-cell response to follicular lymphoma cells.

Non-activated follicular lymphoma (FL) cells do not function as effective antigen-presenting cells in vivo. CD40 activation of FL cells up-regulates critical adhesion and co-stimulatory molecules, thereby inducing lymphoma-specific cytotoxic T cells in vitro. However, other evidence suggests that CD70 is another important co-stimulatory molecule involved in antigen dependent T-cell activation.

Efficient gene transfer into human keratinocytes with recombinant adeno-associated virus vectors.

Gene transfer into the skin is a promising approach to treat inherited or acquired dermatological diseases and systemic monogenic deficiencies. For this purpose, the efficient and sustained gene delivery into keratinocytes is of critical importance. Recombinant adeno-associated virus (rAAV) vectors hold the potential to achieve a long-term gene transfer into various human organs.