EuroConferences on Cytokines - Institut Pasteur Paris France October 15-17 1997

Sponsors

màj : 21/07/98

Provided by:

(see also "Respiratory tract")

Cytokines : tools and targets for tomorrow’s therapies
(October 15-17 1997)

The last ten years have been a very productive period for cytokine research. Many of these mediators and their biological receptors are now identified and structurally characterized. The molecular mechanisms of their production and activity are more and more understood. Although cytokines have not yet unravelled all their physiological secrets, some of them are known such as the multiple pathways that control the actions of pro-inflammatory cytokines such as IL-1 and TNF. Selective activation of Th1 or Th2 subsets is now convincingly established as an important pathogenic mechanism in many human diseases. The role of cytokines in cancer, infectious diseases, allergy, inflammatory, autoimmune diseases and bone marrow transplantation is actively investigated in human. There is no other area of medecine that better illustrates how basic science can be applied for undestanding and treating human diseases. We are now reaching the phase of application of fundamental knowledge for the design of therapeutic strategies : a number of cytokines are already on the market and many others are under clinical investigation.

This conference is intended for medically-related personnel of the pharmaceutical industry, public health and basic laboratories and agencies, and hospitals. It will provide participants with the necessary background information to understand the new clinical strategies that are used to develop cytokines. The speakers are noted scientists who have made major contributions to the field and have extensive personal experience.

Chairpersons : Jean-Marc Cavaillon (Institut Pasteur, France), Charles A. Dinarello (University of Colorado Health Center, USA), Bernard Rouveix (Hôpital Cochin, France), Philippe Sansonetti (Institut Pasteur, France)

October 15 16 17, 1997

Institut Pasteur, Paris, France.

Contact : Ludovic Drye, Institut Pasteur,
C.I.S., 28 rue du Docteur Roux, 75724 Paris Cedex 15
Fax 40 61 34 05 - E.mail : ldrye (at) pasteur.fr
http://www.pasteur.fr/Conf/euroconf.html

Pre-conference associated meeting, OCTOBER 15, 1997, 2.00 p.m. (Free admission)

" IMMUNOINTERVENTION : PRESENT AND FUTURE "

Cellular and Molecular Basis

Chairmen : C. Griscelli (Inserm, Paris), F. Kourilsky (Institut Gustave Roussy, Villejuif), F. Rosen (Harvard Medical School, Boston), S. Schlossman (Dana Farber Cancer Institute, Boston)

Invited speakers : P. Debré (Hôpital Pitié-Salpétrière, Paris), N. Gualdé (Centre Anti-Cancéreux, Bordeaux), F. Lemonnier (Institut Pasteur, Paris), L. Moretta (University of Genova), W. Paul (National Institute of Health, Bethesda), M. Pierres (Centre d'Immunologie, Marseille), J. Thèze (Institut Pasteur, Paris)

and 5th Benacerraf Conference : "Anti-viral immunity" by R. Zinkernagel (Nobel Laureate of Medicine, 1996).

[Contact -> Corinne Baran (Tél. 33 1 45 68 68 86 - Fax 33 1 45 68 88 38)]

EuroConference April 1998 : New therapeutic approaches for allergic diseases of the respiratory tract

...

08:55 - 09:00 a.m. Presentation of the EuroConferences by B. Boris Vargaftig, Member of the Board of Directors, Institut Pasteur, Paris.

09:00 - 09:40 a.m.
Pharmacologically-oriented introduction to the cytokine network.

Proinflammatory cytokines such as TNF and IL-1 play a key role in the pathogenesis of inflammation and sepsis and thus represent important pharmacological targets. Anti-cytokine therapy can follow various strategies, that were also used to characterize their importance and mechanism of action. 1) Inactivation of cytokine-inducing agents such as endotoxin by means of endotoxin-binding peptides ; 2) Inhibition of cytokine synthesis. This can be achieved with non-selective inhibitors (e.g. glucocorticosteroids) or more selective ones ; 3) neutralization of circulating cytokines (e.g. with antibodies or soluble receptors) ; 4) inhibition of receptor binding with receptor antagonists (e.g. IL-1ra and chemokine mutants); and 5) inhibition of cytokine-activated signalling.

The use of cytokines as therapeutic agents is hampered by our limited understanding of their pharmacology, particularly their mode of action.

Preclinical studies are often difficult due to their species specificity and thus pharmacological results do not always correlate with therapeutic effect. General rules used for classical synthetic drugs do not apply to these molecules. There is no direct relationship between dose and activity. Cytokines are rapidly degradated and eliminated, resulting in their administration at high doses. This, and their pleiotopic effect, leads to subsequent clinical toxicity. Cytokines often act indirectly and their clinical development is focused on the preclinical identification of therapeutic surrogate and the subsequent testing of a clinical hypothesis.

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are examples of "pro-inflammatory cytokines" affecting nearly every cell either alone or in a synergistic fashion by increasing the expression of genes associated with the promotion of inflammation. The naturally occurring IL-1 receptor antagonist (IL-1Ra) reduces the severity of disease in various animal models of local and systemic inflammation. When given to humans with rheumatoid arthritis, IL-1Ra has reduced pain and joint inflammation. Monoclonal antibodies and soluble receptors to TNF specifically neutralize the activity of TNF and reduce disease in animals. Anti-TNF therapy has also reduced the severity of rheumatoid arthritis and inflammatory bowel disease in humans. However, despite reductions in death in animals using IL-1Ra or anti-TNF, in patients with septic shock, reducing 28 day mortality is restricted to a subgroup of patients, probably due to the heterogeneity of septic shock in humans.

Charles A. Dinarello
Division of Infectious Diseases, University of Colorado Health Center, Denver, U.S.A.

11:30 - 12:10 p.m.
Anti-TNFa therapy of rheumatoid arthritis : what does it teach us about the cytokine network ?

Since many proinflammatory cytokines are upregulated in rheumatoid joint, it was of interest to determine which, if any, were suitable targets for therapy. Analysis of rheumatoid synovium demonstrated that anti -TNFa was a therapeutic target. This was supported in animal models and proven in randomized clinical trials.

The rational, clinical results, mechanisms of action and prospects for the future will be reviewed.

Interleukin-10 (IL-10) recently emerged as a major endogenous anti-inflammatory mediator. Indeed, IL-10 profoundly inhibits the synthesis of proinflammatory molecules such as TNF. A number of molecules produced under stress conditions including reactive oxygen species stimulate IL-10 synthesis. Several xenobiotics which increase intracellular cAMP concentrations upregulate IL-10 synthesis and rIL-10 itself has been safely administered in humans. The potential benefits and drawbacks of these new IL-10-based anti-inflammatory therapies will be discussed.

Michel Goldman
Hôpital Erasme, Université Libre de Bruxelles, Brussel, Belgium.

Interleukin-10 (IL-10) is a cytokine with anti-inflammatory and immunosuppressive properties that was originally discovered and cloned at DNAX Institute in 1989. Animal models provided new insights into the central role of IL-10 in the pathophysiology and therapeutic approach of chronic (e.g inflammatory bowel disease, rheumatoid arthritis) and acute inflammatory disorders (e.g acute lung injury, experimental septic shock) and served as a scientific rationale for clinical use in humans. Recombinant human IL-10 (rhu-IL10) developed by Schering Plough Research Institute started in 1993. A review of the rationale, experimental design and recent findings from Clinical Pharmacology and results from safety and activity studies of rhu-IL10 in chronic inflammatory diseases will be presented.

Jean Jacques Garaud, Alexandre Lebeaut
Schering Plough Research Institute, Kenilworth, USA

3:20 - 4:00 p.m.
Biological properties and therapeutic applications of IL-12.

The first line of defense against infection is represented by the immediate response of the effector cells of innate resistance. However, complete elimination of the pathogens requires the activation of the antigen-specific adaptive immune response, mediated by T and B lymphocytes,which in a primary infection becomes effective only a few days after infection. Innate resistance and adaptive immunity are not separate, but the early inflammatory response sets the stage for the ensuing adaptive immune response, by regulating both its quality (e.g. prevalently humoral or cell-mediated) and effectiveness. Interleukin-12 is a cytokine that plays a major role in such regulatory mechanisms. As a proinflammatory cytokine, IL-12, produced a few hours after infection, induces IFN-g production and activates the phagocytic cell system and natural killer cell activity. As an immunoregulatory molecule, IL-12 facilitates differentiation of Th1 cells and cytotoxic T lymphocytes, while it inhibits Th2 cells. Because of these properties, the regulation of IL-12 production and its alteration in certain disease states have major relevance for the modulation of immune and allergic responses and recombinant IL-12 has several potential therapeutic uses in infectious diseases, allergy, and cancer.

Erythropoietin (Epo) controls the survival, proliferation and differentiation of the erythroid progenitors in the bone marrow. The main sites of Epo production are the kidney and the liver, and Epo synthesis is regulated by hypoxia. Cis- and trans-acting elements that contribute to the regulation of the Epo gene have been identified. Epo binds to a cell surface receptor that belongs to the cytokine receptor family. Epo binding induces the activation of Jak tyrosine kinase and of different intracellular pathways: Ras/MAP kinase, phosphatidylinositol 3-kinase and STATs transcription factors. However, the exact mechanisms by which the proliferation and/or the differentiation of erythroid cells are regulated after Epo stimulation are not known. The indications for treatment with recombinant Epo will be discussed.

Catherine Lacombe
Service d'Hématologie, INSERM U 363, Hôpital Cochin, Paris, France.

Thrombopoietin is a 80 KDa glycoprotein which contains two domains : the NH2 terminal domain which shows a 50 % homology with erythropoietin, contains the entire biological activity whereas the COOH terminal domain is involved in secretion and stabilisation of the molecule. Thrombopoietin has been isolated as the ligand of the c-mpl protooncogene. It is mainly synthesized by the kidney and the liver. Its plasmatic level is dependant upon the platelet mass by a mechasmism related to its clearance by platelets and megakaryocytes. Thombopoietin is the homeostatic regulator of platelet production and acts at all stages of megakaryocytopoiesis from the megakaryocyte progenitor to the platelet. However, thrombopoietin also acts on early stages of hematopoiesis, probably including true stem cells.

Thrombopoietin injection to animals, including primates, decreases platelet nadir and recovery after myeloablative regimen. Preliminary trials in man have shown that thrombopoietin injection is not toxic but has no marked effects on the platelet recovery after polychemotherapy.

William Vainchenker
INSERM U 362, Institut Gustave Roussy, Villejuif, France.

5:00 - 5:30 p.m.
New growth factor approaches to control toxicity of cancer chemotherapy.

Availability of hematological growth factors such as G-CSF has permitted to reduce some hematological toxicities associated with cancer chemotherapy, and to develop transplantation of peripheral blood stem cells. Despite these advances there is still a need to reduce mucosal toxicity and the episodes of thrombocytopenia. We will discuss data in favour of developing new growth factors to address these toxicities : Keratinocyte Growth Factor (KGF) for its ability to reduce mucosal toxicity, the recombinant form of thrombopoïetin, PEG-rHuMGDF, to increase and accelerate platelet recovery, and combination of growth factors (G-CSF, SCF, PEG-rHuMGDF) to increase the availability of blood cell progenitors in vivo or ex vivo.

09:00 - 09:45 a.m.
The Potential Role of Interleukin-2 (IL-2) in the Management of Patients with HIV Infection

Interleukin-2 (IL-2), originally known as "T cell growth factor", is a potent stimulus for the growth and differentiation of a variety of lymphoid cells, including T lymphocytes. Intermittent admnistration of this cytokine, either by infusion or subcutaneous injection can result in substantial increases in CD4 T lymphocyte counts in patients with HIV infection. These increases in cells appear to be secondary to a polyclonal expansion of functional T lymphocytes as evidenced by molecular analysis of the CD4 T lymphocyte repertoire, evaluation of responses to immunization and pooled clinical event data.

H. Cliff Lane
National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, USA

09:45 - 10:30 a.m.
Immunointervention based on Th2-type cytokines in HIV infection.

The cytokines produced by T helper lymphocytes can be divided into two subgroups : the Th1 type, including IL-2 and IFNg involved primarily in cell-mediated immunity, and the Th2 type, including IL-4, IL-5, IL-6, IL-10 and IL-13, supporting the humoral and immediate hypersensitivity responses. Some of these cytokines can also be produced by cells other that T helper lymphocytes, particularly CD8+ and gd+ T lymphocytes, as well as non lymphoid cells. Th2-type cytokines may contribute to the pathogenesis of HIV infection. IL-4 is upregulated following infection of macaques with pathogenic strains of SIV, but not with non pathogenic strains. IL-13 is expressed at a high level in HIV-infected patients, and IL-13 administration to SIV-infected macaques reproduces several clinical and biological abnormalities of HIV infection. IL-6 is involved in the growth of malignant B lymphocytes and in cachexia. The potential role of Th2-type cytokines in HIV infection has stimulated the evaluation of antagonists of these cytokines, such as anti-IL-4 mAb in primary infection or anti-IL-6 mAb in AIDS lymphomas and cachexia. Some of these evaluations are now ongoing in HIV-infected patients.

Pierre Galanaud
INSERM U131, Institut Paris-Sud sur les Cytokines, Clamart, France.

11:00 - 11:25 a.m.
Cytokines in severe infections : from pathophysiology to clinical applications.

Bacterial products are the main activators of the septic shock cascade. These molecules interact with monocytes, macrophages and endothelial cells to produce inflammatory cytokines (TNF, IL-l and IL-6) and may activate other harmful pathways such as the coagulation system, complement cascade and lipid mediators. Antibodies directed against these cytokines or soluble receptors inactivating the cytokines (e.g. IL-lra or TNF-rs) are currently investigated, but conclusive evidence of their activity is still lacking.

Michel Pierre Glauser
Division des Maladies Infectieuses, C.H.U.V., Lausanne, Switzerland.

The two main objectives for the treatment of multiple sclerosis (MS) are the prevention of the attacks and the reduction of the handicap and its progression. b Interferon, an antagonist of

g Interferon, increases T cells suppressive functions which are deficient in MS patients and reduces the cytotoxic activity of lymphocytes. With this respect, ß Interferon has been and is evaluated in MS in control studies. Results and problems raised by these treatments, as well as the place of ß Interferon and its development in the future therapeutical strategies will be discussed.

Olivier Lyon-Caen
Fédération de Neurologie, Hôpital Pitié-Salpétrière, Paris, France.

Hepatitis C is a major public health problem in France with more than 500.000 people infected. An overall increase in mortality is forthcoming if patients are not screened and treated because of the fatal risk due to cirrhosis complications : liver cancer, digestive hemorrhage and hepatic failure. Only interferon alpha has a proven efficacy in the treatment of acute and chronic hepatitis C. More than one hundred randomized trials have been performed and their meta-analysis has demonstrated the advantage of long duration regimen to modify the natural history of this disease. The interferon efficacy is explained by its antiviral, immunomodulating and antifibrotic properties. As observed for HIV it is possible that combined antiviral regimens will improve the treatment. However the priority is more to block the fibrotic consequence of this slow virus than its eradication.

Thierry Poynard
Consultation Hépato-Gastro-Entérologie - Groupe Hospitalier PitiÈ-SalpétriËre, Paris, France.

2:00 - 2:45 p.m.
Cytokines as prognostic and therapeutic agents in human cancer

Following numerous experimental models demonstrating that a potent activation of the immune system by recombinant cytokines, alone or in conjunction with immune cells, resulted in tumour regressions, clinical trials have been conducted for more than 15 years in human cancer. With the exception of renal cell cancer and melanoma, positive results have been rare and irreproductible. The new avenues of cytokine usage in human cancer explore adjuvant therapy for vaccination, inhition of cytokine induced tumour cell growth and the use of cytokines as prognostic markers to predict therapeutic responses and guide immunotherapy.

Multiple myeloma is a B cell neoplasia affecting the late stages of B cell differentiation : the plasma cells. In this disease, IL-6 was initially shown as a major tumor growth factor. The other cytokines that share with IL-6 a common transducer chain, the gp130, are also myeloma cell growth factors in vitro. Thus, in this disease, activation of the gp130 IL-6 transducer is a key event controlling tumoral cell survival and proliferation. Anti-IL-6 treatment might be useful to inhibit myeloma cell proliferation, reduce their survival and increase their sensitivity to chemotherapy.

Bernard Klein
CNRS - UMR 5535, Institut de Génétique Moléculaire, Montpellier, France.

Recombinant cytokines and cytokine gene transfer form a flexible technology that provides a new intelligence to fight cancer. Low doses of recombinant cytokines in a tumor growth area activate a strong reaction and break tolerance to tumor antigens. More efficient reactions are activated by the sustained release of a cytokine by cytokine gene engineered cells. Whether these technologies can acquire clinical significance is currently a key question. When used as a vaccine for mouse tumors, cytokine engineered tumors prompt a strong immune memory against parental tumor cells even when these were recognized as poorly or non immunogenic. By contrast, the efficacy of cytokine-based vaccines vanishes when they are used to cure mice harboring established tumors. Several cytokines are in the process of a comparative evaluation with a view to select those that are the most efficient in the progressive stages of tumor growth. Cytokine-based vaccines appear to be a new form of "soft" noninvasive treatment free from major distress and side-effects that would be available for combination with conventional management of patients expected to present tumor recurrences after a disease-free interval.

Guido Forni
Dipartimento di Scienze Cliniche e Biologiche, Universita di Torino, Orbassano, Italy.

4:45 -5:30 p.m. Round Table
Cytokines in tomorrow's therapy : pharmaco-economic consequences

Thérèse Lebrun (Inserm U21, France), H. Cliff Lane (NIAID, NIH, USA), Tony Marcel (MTC Développement, France), Fernand Sauer (European Agency for the Evaluation of Medicinal Products, UK).

Asmanet

Congrès Conçue et réalisée par: Michel Godard (at)

Top
Date de création: 15 Mars 1997 - Dernière mise à jour: 21/07/98
Le secret des correspondances transmises sur le réseau Internet n'est pas garanti.
Toute personne citée dispose d'un droit d'accès, de modification, de rectification et de suppression des données le concernant (art. 34 de la loi "Informatique et Libertés" n° 78-17 du 6 janvier 1978). Pour l'éxercer adressez-vous à Michel Godard (at)