M e e t i n g s

Dendritic from basic to therapeu Fourth International Sympq Fundamental and Clinical 1 Venice, Italy, 5-10 October 1

Primary cellular immune responses require anti- gen to be presented by bone marrow-derived dendritic cells. Dendritic cells acquire antigen in the periphery and then migrate to the T-cell- dependent areas of secondary lymphoid tissues, where they cluster and stimulate the proliferation of antigen-specific T cells. This recent sympo- sium was attended by over 500 delegates and we report here on new developments in both basic and clinical aspects of this growing field.

Dendritic cell development It is well established that dendritic cells are de- rived from CD34 ÷ bone marrow and cord blood progenitors, but there remains conflicting evi- dence regarding their subsequent development. In humans, CD34 ÷ progenitors cultured in granu- Iocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor c< (TNF-e) and c-Kit ligand give rise to dendritic cells via two dif- ferent pathways. One pathway yields pure den- dritic cells and the other passes through an HLA- DR+CD14 ÷ intermediate cell type that can then differentiate into monocytes or dendritic cells (James Young, Rockefeller University, New York,

Stephen Robinson* MRCP Clinical Research Fellow

Steven Patterson PhD MRC Scientist

Antigen Presentation Research G~oup. Imperial College School of Medicine at Northwick Park Institute for Medical Research. Watford Road. Harrow, Middlesex, UK HA1 3UJ. Tel: +44 181 869 3497 Fax: +44 181 869 3532 *e-mail: sp.robinson@ic.ac.uk

NY, USA). In vitro culture of peripheral blood monocytes in GM-CSF and interleukin 4 (IL-4) also results in the generation of 'typical' dendritic cells (Christopher Caux, Schering-Plough, Dardilly, France). Dendritic cell development is closely related to that of monocytes, but Ken Shortman (The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia) also re- ported a lymphoid pathway of differentiation in mice, resulting in the generation of T cells, natural killer (NK) cells and CD8 ÷ dendritic cells. The relevance of these in vitro studies to in vivo ontogeny requires further clarification but these studies have enabled large numbers of human dendritic cells to be generated for basic and therapeutic studies.

Dendritic cell migration and function The expression of cutaneous leukocyte antigen (CLA) on human peripheral blood dendritic cell progenitors identifies cells that will home to the epidermis to become Langerhans cells (Dirk Strunk, University of Vienna, Vienna, Austria). In mice, dendritic cell homing to skin was shown to be directed, in part, by the cutaneous production of transforming growth factor 13 (TGF-13) (Mark Udey, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA). When dendritic cells arrive in peripheral tissues, anti- gen uptake and processing are initiated. In hu- mans and mice, dendritic cells are thought to use a mannose receptor to capture microbial anti- gens and direct them into the antigen-processing pathway. The complexity of this pathway was re- vealed by cryo-immunoelectron microscopy studies in a human B-cell line that identified six distinct endosomal-pathway-associated com- partments (Monique Kleijmer, Utrecht University, Utrecht, The Netherlands). The mannose recep- tor was not found in endosomes containing class II major histocompatibility (MHC) antigen, sug- gesting that the mannose receptor unloads its

ligand and recycles to the cell surface before the ligand is routed to class II MHC-containing com- partments (Agnes Tan, University Hospital, Leiden, The Netherlands; Anneke Engering, Free University, Amsterdam, The Netherlands).

Immunological dogma states that exogenous antigens are presented by MHC class II whereas MHC class I can only present endogenously syn- thesized antigen. This was questioned by reports showing that exogenous antigen can (1) access the cytoplasm, (2) enter the MHC class I antigen- processing pathway and (3) be presented to CD8 ÷ cytotoxic T lymphocytes (CTLs) (Colin Watts, University of Dundee, Dundee, UK; Marloes DeBruijn, University Hospital, Leiden, The Netherlands). This has implications for vac- cine design but the mechanisms involved are unknown.

The movement of dendritic cells out of periph- eral tissues to lymphoid tissue occurs under the influence of cytokines such as GM-CSF, TNF-(x and interleukin 113 (IL-113) (Marie Cumberbatch, Zeneca, Macclesfield, UK). This is associated with the upregulation of the hyaluronic acid receptor CD44 [Johannes Weiss, Freiburg University, Freiburg, Germany; H. Haegel- Kronenberger, Institut National de la Sant~ et de la Recherche Medicale (INSERM) CJF, Strasbourg, France].

Within lymphoid tissue, dendritic cells present antigen to specific T cells and provide the co- stimulatory signals necessary for the induction of T-cell-proliferative immune responses by the sur- face expression of CD40, CD80 and CD86, as well as by cytokine secretion. The production of interleukin 12 (IL-12), TNF-~ and IL-1 by the den- dritic cell promotes the differentiation of T cells into the Thl subset of mature T cells, with their characteristic cytokine-producing phenotype (Anne O'Garra, DNAX, Pale Alto, CA, USA). Dendritic cells precultured in the presence of prostaglandin E2, however, can stimulate Th2

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M e e t i n g s

development (Pawel Kalinski, University of Amsterdam, Amsterdam, The Netherlands). Subsequently, T cells signal back to the dendritic cell via CD40-CD40-1igand and T-cell receptor (TCR)-MHC interactions to induce further ex- pression of IL-12, CD80 and CD86 by the den- dritic cell (Franz Koch, University of Innsbruck, Innsbruck, Austria). Dendritic cells can also stimulate B cells directly via CD40 and IL-12, without CD4 ÷ T-cell help (Bertrand Dubois, Schering-Plough, Dardilly, France).

Dendritic cells in human disease Studies by Nina Bhardwaj (Rockefeller University, New York, NY, USA) with influenza virus showed that dendritic cells can directly activate prolifer- ation of virus-specific memory CTLs in the ab- sence of helper T cells or exogenous cytokines, although addition of IL-12 augments this re- sponse. Activation of CTLs is mediated by either live or killed virus. This, again, supports the con- tention that exogenous, non-replicating antigen can enter the cytoplasm. Dendritic cells are tar- gets for HIV-1 infection and, despite expression of the chemokine receptor CXCR4 (Jacques Banchereau, Schering-Plough, Dardilly, France;

Gosse J. Aedema, University Hospital, Nijmegen, The Netherlands), the co-receptor for lympho- tropic strains, they are preferentially infected by macrophage-tropic strains of this virus (Paul Cameron, Macfarlane Burnet Centre for Medical Research, Melbourne, Australia), some of which are distinct from those infecting T cells (Stella Knight, Imperial College of Medicine, Harrow, UK). Dendritic cells lack the SP1 transcription factor required for the efficient expression from the HIV long terminal repeat (Angela Granelli-Pipemo, Rockefeller University, New York, NY, USA), suggesting low- level or unproductive infection of dendritic cells.

Dendritic cells that have been exposed to tu- mour antigens in vitro are capable of eliciting anti-tumour immune responses when returned to tumour-bearing animals. This results in both tumour regression and protection against sub- sequent tumour challenge. The recent identifi- cation of a variety of human tumour-associated antigens (TAAs) and the ability to generate large numbers of dendritic cells in vitro have raised the possibility of using such an approach in patients. Dendritic cells might be induced to present TAAs by co-culturing them with tumour cells or purified tumour antigen, or by transduction with DNA

coding for the TAA of interest (Martin Cheever, Department of Medicine, University of Washington, Seattle, WA, USA). Furthermore, the immunos- timulatory properties of the dendritic cell might be enhanced by transduction with genes encod- ing GM-CSF, IL-2, IL-12 and IFN-~, (Thomas Teuting, University of Pittsburgh, Pittsburgh, PA, USA). Clinical studies employing such dendritic- cell-based therapies are now under way in lym- phoma patients, and objective improvement has been observed in some cases (Claudia Benike, Stanford University School of Medicine, Pale Alto, CA, USA). Studies in melanoma patients are about to commence (Michael Lotze, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA).

Concluding remarks The symposium provided an update on numer- ous aspects of dendritic cell development and function, and how this is being applied for thera- peutic benefit. However, the optimal conditions for the development of immunogenic dendritic cells remain to be defined. The role that dendritic cells might play in the induction of tolerance to antigens, and thus autoimmune disease and al- lergy, remains to be explored.

Cardiovascular receptors as drug targets EurOConferences' Cardiovascular Receptors as Drug Targets Institut Pasteur, Paris, France, 3-4 October 1996

This two-day conference, organized by the Pasteur Institute, addressed state-of-the-art knowledge in the field of cardiovascular receptor-ligand systems. Such knowledge is essential for the development of the next gener- ation of drugs in the treatment of cardiovascular diseases, which continue to be the prime cause of morbidity and mortality in industrialized nations. Initially, Paul Vanhoutte (Instituts de Recherches Internationales Servier, Courbevoie, France) discussed the complexities of the vascu- lar wall in the understanding of the effects of pharmacological agents. The direct effect of au- tonomic (mainly sympathetic) nerves and circu- lating hormones such as angiotensin and natri-

uretic peptides on vascular smooth muscle receptors is modulated by the degree of activity of surrounding tissue cells. Numerous factors re- leased by the endothelium modulate vascular smooth muscle activity; they include vasorelax- ants such as prostacyclin, nitric oxide (NO) and endothelium-derived hyperpolarizing factor; and vasoconstrictors such as superoxide anions, per- oxides, thromboxane and endothelin. The re- lease of these substances is, in turn, governed by (1) shearing forces exerted by the flowing blood; (2) circulating hormones such as vasopressin and catecholamines; (3) platelet products such as 5-hydroxytryptamine (5-HT or serotonin) and ADP; and (4) thrombin and locally produced

autacoids. The potential to affect different cell types must be considered in the understanding of the complex, and sometimes bewildering, end results of drug action in affecting vascular function and blood pressure.

During the meeting, the main cardiovascular receptor-ligand systems were discussed, from the molecular level to their in vivo effects, with particular emphasis on physiological mecha- nisms and potential for pharmacological intervention.

Adrenoceptors Investigation of the classic adrenoceptor system has been rekindled by the development of

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