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At least 37 records · Page 2Linked to original sources
PubMed2000

Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids.

Reports of spontaneous regressions of metastases and the demonstration of tumor-reactive cytotoxic T lymphocytes indicate the importance of the host's immune system in controlling the devastating course of metastatic renal cell carcinoma. Recent research indicates that immunization with hybrids of tumor and antigen presenting cells results in protective immunity and rejection of established tumors in various rodent models. Here, we present a hybrid cell vaccination study of 17 patients. Using electrofusion techniques, we generated hybrids of autologous tumor and allogeneic dendritic cells that presented antigens expressed by the tumor in concert with the co-stimulating capabilities of dendritic cells. After vaccination, and with a mean follow-up time of 13 months, four patients completely rejected all metastatic tumor lesions, one presented a 'mixed response', and two had a tumor mass reduction of greater 50%. We also demonstrate induction of HLA-A2-restricted cytotoxic T cells reactive with the Muc1 tumor-associated antigen and recruitment of CD8+ lymphocytes into tumor challenge sites. Our data indicate that hybrid cell vaccination is a safe and effective therapy for renal cell carcinoma and may provide a broadly applicable strategy for other malignancies with unknown antigens.

Aged↗
PubMed2004

Phase I/II trial of melanoma patient-specific vaccine of proliferating autologous tumor cells, dendritic cells, and GM-CSF: planned interim analysis.

AIM: The aim of this study was to investigate the feasibility, safety, and clinical efficacy of patient-specific dendritic cell vaccines in patients with metastatic melanoma. A planned interim analysis was conducted on the first 20 patients. METHODS: Tumor cell lines were established from metastatic tumor, expanded to 200 million cells, and then incubated with interferon-gamma for patients who were candidates for therapy. Cells were irradiated and cryopreserved. Patients underwent leukapheresis to obtain mononuclear cells that were cultured in the presence of IL-4 and GM-CSF to produce dendritic cells, which were incubated with cryopreserved, irradiated tumor cells, and then stored in aliquots of about 20 million cells for subcutaneous (s.c.) injections with GM-CSF once a week for 3 weeks, then once a month for 5 months. RESULTS: The first 20 eligible patients included 10 men and 10 women, with a median age of 48 years (range, 16-79 years). Three (3) patients had brain metastases, and 13 patients had experienced disease progression after biochemotherapy. At the time of vaccine treatment, 6 patients had evaluable metastatic disease, while 14 patients lacked measurable disease. Vaccine therapy was well tolerated, except for what appeared to be GM-CSF-related allergic reactions in 2 patients. Delayed-type hypersensitivity (DTH) tests to irradiated tumor cells were positive in 0 of 20 patients tested at baseline, but converted to positive in 8 patients (40%). At a median follow-up of 13.8 months, there is a 95% overall survival and a 48% progression-free survival. Four (4) patients have already survived more than 3.0 years since starting the vaccine. CONCLUSION: Based on tolerability, rate of tumor DTH conversion, and encouraging survival, the trial will continue accrual to at least 19 patients with measurable disease and 40 patients who lack measurable disease at the time of treatment.

Adolescent↗
PubMedDate not supplied

Langerhans cells - dendritic cells of the epidermis.

Langerhans cells (LC) are dendritic cells of the epidermis. They are highly specialized leukocytes that serve immunogenic and tolerogenic purposes. Here, we review some aspects of LC biology, emphasizing those areas where LC are or may turn out to be special.

Animals↗
PubMed2002

Dynamic imaging of T cell-dendritic cell interactions in lymph nodes.

T cell immune responses begin within organized lymphoid tissues. The pace, topology, and outcomes of the cellular interactions that underlie these responses have, so far, been inferred from static imaging of sectioned tissue or from studies of cultured cells. Here we report dynamic visualization of antigen-specific T cells interacting with dendritic cells within intact explanted lymph nodes. We observed immunological synapse formation and prolonged interactions between these two cell types, followed by the activation, dissociation, and rapid migration of T cells away from the antigenic stimulus. This high-resolution spatiotemporal analysis provides insight into the nature of cell interactions critical to early immune responses within lymphoid structures.

Animals↗
PubMed2003

T cell-dendritic cell interaction in vivo: random encounters favor development of long-lasting ties.

Understanding the complexity of the functional communication between cells composing the immune system is central to improving our capacity to manipulate it and conceive better strategies to combat microbial pathogens. So far, these studies have been based on immunohistochemistry of fixed tissues and in vitro attempts to reproduce functional connections between cells. The application of two-photon laser microscopy to the observation of viable immune cells in their natural environment where foreign antigens are carried to trigger an immune response opens a new era for these studies. They reveal exceptional properties of the locomotion of T cells that facilitate encounters with dendritic cells and the receipt of information that promotes T cell survival, death, or initiation of immune responses. These studies also complement in vitro observations addressing the importance of time of stimulation in determining T cell fates.

Cell Communication↗
PubMed2006

Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction.

CD8+ T cells have a crucial role in resistance to pathogens and can kill malignant cells; however, some critical functions of these lymphocytes depend on helper activity provided by a distinct population of CD4+ T cells. Cooperation between these lymphocyte subsets involves recognition of antigens co-presented by the same dendritic cell, but the frequencies of such antigen-bearing cells early in an infection and of the relevant naive T cells are both low. This suggests that an active mechanism facilitates the necessary cell-cell associations. Here we demonstrate that after immunization but before antigen recognition, naive CD8+ T cells in immunogen-draining lymph nodes upregulate the chemokine receptor CCR5, permitting these cells to be attracted to sites of antigen-specific dendritic cell-CD4+ T cell interaction where the cognate chemokines CCL3 and CCL4 (also known as MIP-1alpha and MIP-1beta) are produced. Interference with this actively guided recruitment markedly reduces the ability of CD4+ T cells to promote memory CD8+ T-cell generation, indicating that an orchestrated series of differentiation events drives nonrandom cell-cell interactions within lymph nodes, optimizing CD8+ T-cell immune responses involving the few antigen-specific precursors present in the naive repertoire.

Animals↗
PubMed2005

Allogeneic gastric cancer cell-dendritic cell hybrids induce tumor antigen (carcinoembryonic antigen) specific CD8(+) T cells.

The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research of their potential use in immunotherapy. Accumulating results show the efficacy of this treatment on melanomas which are highly immunogenic. However, its efficacy remains unclear in other tumors. In this study, allogeneic gastric cancer cell-DC hybrids were used to determine the efficacy of this type of immunotherapy in gastric cancer. Fusion cells of DC and allogeneic gastric cancer cells were generated by polyethylene glycol (PEG) and electrofusion. These hybrids were used to induce tumor associated antigen (TAA) specific cytotoxic T lymphocytes (CTLs). The DCs were successfully fused with the allogeneic gastric cancer cells resulting in hybrid cells. These hybrid cells were functional as antigen-presenting cell because they induced allogeneic CD4(+) T cells proliferation. CD8(+) T cells stimulated by the MKN-45-DC hybrid cells were able to kill MKN-45 when used for immunization. The CTLs killed another gastric cancer cell line, MKN-1, as well as a melanoma cell line, 888mel, suggesting the recognition of a shared tumor antigen. MKN-45 specific CTLs can recognize carcinoembryonic antigen (CEA), indicating that the killing is due to tumor antigens as well as alloantigens. This approach suggests the possible use of allogeneic gastric cancer cell-DC hybrids in DC based immunotherapy for gastric cancer treatment.

CD4-Positive T-Lymphocytes↗
PubMed2005

Natural killer cell-dendritic cell crosstalk in the initiation of immune responses.

Dendritic cells (DCs) and natural killer (NK) cells play a critical role in early defences against cancer and infections. They specialise in complementary functions, including IL-12 or IFN-alpha/beta secretion and antigen presentation for the former, and IFN-gamma secretion and killing of infected or tumour cells for the latter. Both DCs and NK cells are also sensors of the immune system that have developed different, but partially overlapping, systems to identify pathology associated danger signals. Evidence of NK-DC interaction has accumulated recently. This interaction may lead to NK cell activation, DC activation, or apoptosis depending on the activation status of both cell types. Thus, the outcome of NK-DC crosstalk is likely to influence both innate and adaptive immune responses. This review addresses the molecular mechanisms under-lying the different NK-DC interactions, and their in vivo significance in anti-tumour or antimicrobial immunity. Finally, we discuss the potential clinical implications of this new field.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo.

The maturation status of dendritic cells (DCs) determines whether they prime or tolerize T cells. We targeted ovalbumin peptide exclusively to DCs in situ using an antibody to DEC-205 and studied the interaction of DCs with naive CD4(+) T cells in tolerizing or priming conditions. We used two-photon microscopy to simultaneously track antigen-specific OT-II T cells, nonspecific T cells and DCs in lymph nodes of living mice. In both tolerance and immunity, OT-II cells arrested on DCs near high endothelial venules beginning shortly after extravasation and regained their baseline speed by 18 h. Thus, early antigen-dependent T cell arrest on DCs is a shared feature of tolerance and priming associated with activation and proliferation.

Animals↗
PubMed2000

Differentiation of antigen-presenting cells (dendritic cells and macrophages) for therapeutic application in patients with lymphoma.

The recent clinical trial in lymphoma using tumor antigen-loaded DCs (Hsu et al, Nature Med 1996; 2: 52) demonstrates the efficiency of the use of professional antigen presenting cells (APCs) for taking up, processing and presenting tumor protein in a vaccine strategy in cancer. However, the production of large quantities of clinical grade APCs remains to be resolved. Here, we describe that both dendritic cells (DCs) and macrophages (MOs) can be efficiently differentiated in large numbers from lymphoma patients in spite of their disease and previous therapy. These cells were produced using the VAC and MAK cell processors according to standard operating procedures. DCs and MOs were differentiated from circulating monocytes in gas permeable hydrophobic bags, with 2% autologous serum and in the presence of GM-CSF and IL-13 or GM-CSF alone, respectively. DCs and MOs were then purified by counter flow centrifugation. Phenotypic, morphological and functional analysis showed that cells differentiated from patients with lymphoma present quite similar features to DCs and MOs produced from monocytes of healthy donors. Moreover, we show that MOs, when combined with CD20 antibody (Rituximab), can efficiently engulf tumor cells and propose that a such combination could be used for initiating a clinical trial in lymphoma. Thus, the possibility of producing functional DC and MOs in large amounts in conditions compatible with therapeutic application will allow the development of new immune strategies to eradicate lymphoma.

Adult↗
PubMed2002

Homeostatic T cell proliferation in a T cell-dendritic cell coculture system.

Naive T cells do not proliferate in normal individuals in the absence of antigen stimulation, but they proliferate spontaneously when T cells are severely depleted. We show here that coculture of syngeneic dendritic cells (DC) with naive T cells expressing a single T cell receptor also results in T cell proliferation in the absence of foreign antigen. As in lymphopenic mice, where T cell proliferation depends upon DC, this response in the coculture system requires interaction of the T cells' T cell receptor with self-peptide-MHCs on DC. This in vitro proliferation also requires soluble factors, including IL-15 secreted by DC, and can be inhibited potently by cell-cell contact with CD4+CD25+ regulatory T cells. The coculture system described may illuminate mechanisms that maintain stable numbers of T cells in normal individuals.

Animals↗
PubMed2003

CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions.

The major histocompatibility complex (MHC) class II transactivator (CIITA) is the 'master coactivator' of MHC class II genes. To identify new targets of CIITA, we analyzed cDNA microarrays of dendritic cells (DCs) from CIITA-deficient, MHC class II-deficient and control mice. We found the semaphorin receptor plexin-A1 was expressed in DCs, but not in other immune cells, and was strongly induced by CIITA. RNA interference by short hairpin RNA specific for plexin-A1, but not a single-nucleotide mutant, greatly reduced plexin-A1 expression and T cell stimulation by protein- or peptide-antigen-pulsed DCs.Plexin-A1 is not required for peptide binding to MHC. These data indicate involvement of plexin-A1 in T cell-DC interactions but not antigen processing or binding.

Animals↗
PubMed2002

Extension, retraction and contraction in the formation of a dendritic cell dendrite: distinct roles for Rho GTPases.

The morphology of antigen-presenting dendritic cells (DC) is characterized by the possession of numerous long arborizing processes known as dendrites. The formation of these processes by DC, both in the periphery and in lymphoid organs, is believed to contribute to the remarkable efficiency with which they take up, process and present antigen to T cells. However, the process of dendrite formation and the signaling pathways that lead to the formation of these dendrites remain obscure. In this study we describe an in vitro model in which human immature DC form long processes similar to those formed in vivo. The formation of these processes involves initial attachment of a cell protrusion to the extracellular matrix substrate, and subsequent movement of the cell body away from the adhesion site, leaving behind a long slender dendrite. Dendrite formation, but not their maintenance, was found to be dependent on the activity of Rho GTPases. More specifically, Cdc42 and Rac1 were both required for the migration step of process formation, promoting cell spreading and extension. In contrast, Rho, and its downstream effector p160ROCK, regulated the release of adhesions to the substratum, and associated cellular contraction. Consequently, inhibition of Rho/p160ROCK leads to the formation of longer dendrites. DC therefore coordinate adhesion and protrusion to perform a specialized process of cellular morphogenesis, which differentiates these cells from all other cells of the immune system and may contribute to their distinctive function.

Cell Adhesion↗
PubMed1997

Functions of CD40 on B cells, dendritic cells and other cells.

CD40 is a cell surface receptor that belongs to the tumor necrosis factor receptor family. It was first identified and functionally characterized on B lymphocytes; however, in recent years it has become clear that CD40 expression is much broader, as it is found on monocytes, dendritic cells, hematopoietic progenitors, endothelial cells and epithelial cells. Although initially identified for its activation properties, CD40 is also able to transduce negative signals in various cell types. It is presently accepted that CD40 plays a critical role in the regulation of immune responses. The past year has seen considerable progress in the identification of intracellular molecules mediating CD40 signaling. Furthermore, it has been established that ligation of CD40 ligand (CD40L) delivers signals to the CD40L bearing cells themselves. Finally, the critical role of CD40-CD40L interactions in the development of various disease states has been fully appreciated.

Animals↗
PubMed1985

Accessory cell function of thoracic duct nonlymphoid cells, dendritic cells, and splenic adherent cells in the Brown-Norway rat.

Thoracic duct lymph of lymphadenectomized Brown-Norway (BN) rats is highly enriched for nonlymphoid cells (NLC) which share several characteristics with splenic dendritic cells (DC), e.g., the binding of monoclonal antibody OX2. The accessory cell activity of NLC was analyzed by comparing these cells with DC and splenic adherent cells (SAC). In concanavalin A (Con A)-induced T-cell proliferation NLC, like DC, were very effective accessory cells at low cell numbers, as a consequence of an efficient induction of interleukin 2 (IL-2) production and IL-2 responsiveness. Responses in the presence of SAC were poor, even after the addition of excess IL-2. A fourfold enhancement of accessory cell activity of SAC was achieved by the depletion of FcR-positive cells, which were responsible for suppression of the Con A response. Low responsiveness of BN rats with respect to Lewis rats can in part be explained by a higher suppressive activity of macrophages in the BN rat.

Animals↗
PubMed1984

Veiled cells--"dendritic cells" of the peripheral lymph.

The veiled cells (VC) of afferent lymph can be classified with dendritic cells (DC) of tissues on the basis of morphology, surface markers, cytochemical staining and function. VC form a population of cells, shown to carry antigens, in transit from the peripheral tissues to the paracortical areas of the lymph nodes. They can stimulate lymphocyte proliferation with antigens in vitro when added as less than 1% of the mononuclear cell population. They may initiate responses to foreign antigens such as keyhole limpet haemocyanin and 1-fluoro-2,4-dinitrobenzene (DNFB) and to alloantigen in the mixed leucocyte reaction or during grafting. VC may also be involved in antigen presentation in inflammatory and autoimmune diseases.

Animals↗