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Cardiovascular receptors as drug targets
.....
MOLECULAR
MEDICINE
TODAY,
MARCH
Dendritic cellsin human disease Studies by Nina Bhardwaj (Rockefeller University, New York, NY, USA) with influenza virus showed that dendritic cells can directly activate proliferation of virus-specific memory CTLs in the absence of helper T cells or exogenous cytokines, although addition of IL-12 augments this response. Activation of CTLs is mediated by either live or killed virus. This, again, supports the contention that exogenous, non-replicating antigen can enter the cytoplasm. Dendritic cells are targets for HIV-1 infection and, despite expression of the chemokine receptor CXCR4 (Jacques Banchereau, Schering-Plough, Dardilly, France;
:(:
.
Meetings
1997
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 expression of IL-12, CD80 and CD86 by the dendritic 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).
::
Gosse J. Aedema, University Hospital, Nijmegen, The Netherlands), the co-receptor for lymphotropic 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 distinctfrom those infectingT cells (Stella Knight, ImperialCollege 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 lowlevel or unproductive infection of dendritic cells. Dendritic cells that have been exposed to tumour 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 subsequent tumour challenge. The recent identification 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 immunostimulatory properties of the dendritic cell might be enhanced by transduction with genes encoding GM-CSF, IL-2, IL-12 and IFN-~, (Thomas Teuting, University of Pittsburgh, Pittsburgh, PA, USA). Clinical studies employing such dendriticcell-based therapies are now under way in lymphoma 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 numerous aspects of dendritic cell development and function, and how this is being applied for therapeutic 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 allergy, 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 generation 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 vascular wall in the understanding of the effects of pharmacological agents. The direct effect of autonomic (mainly sympathetic) nerves and circulating 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 released by the endothelium modulate vascular smooth muscle activity; they include vasorelaxants such as prostacyclin, nitric oxide (NO) and endothelium-derived hyperpolarizing factor; and vasoconstrictors such as superoxide anions, peroxides, thromboxane and endothelin. The release 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 mechanisms and potential for pharmacological intervention.
Adrenoceptors Investigation of the classic adrenoceptor system has been rekindled by the development of l
Copyright ©1997 Elsevier Science Ltd, All rights reserved. 1357 - 4310/97/$17.00
PII: $1357-4310(97)01007-1
101
Meetings
selective antagonists for one or more of the (~- and/or !3-adrenoceptor subtypes (Robert R. Ruffolo, SmithKline Beecham, King of Prus PA, USA). This interest focuses p on c~l-adrenoceptor antagonist: were developed to reduce blood and the !3fadrenoceptor antago provide 'cardiosetective' [3 blockaq ment of hypertension and angin~ most promising events in this fielc studies indicating that, in congesti, 13-adrenoceptor antagonists ma __., . . . . . . mortality and hospitalization (Robert R. Ruffolo).
Renin-angiotensin, kinins and nitric oxide A large number of associations were demonstrated between various cardiovascular and renal diseases and polymorphism of the gene for angiotensin-converting enzyme (ACE) that results from either insertion or deletion of sequences. Fran(;ois Cambien [Institut National de la Sant6 et de la Recherche Medicale (INSERM) S.C. 7, Paris, France] gave several examples of this association, including the remarkable finding that intense physical activity is associated with a large increase in left ventricular mass in ACE subtype D carriers, but not in carriers of other ACE alleles. Another topic of current interest is the clinical experience with novel angiotensin II AT1receptor antagonists (Michel Burnier, University Hospital, Lausanne, Switzerland). These agents have the same overall effects as ACE inhibitors without inducing a cough. Because the AT1 receptor antagonists have only been used for a short period of time, it remains to be seen whether they induce all the beneficial clinical effects of ACE inhibitors. Recent findings on novel agonists and antagonists of bradykinin B~ and B2 receptors were reviewed; Domenico Regoli (Faculte de M~decine, Sherbrooke, Canada) presented the interesting concept that B2 receptor agonists might open the blood-brain barrier and could therefore be of use to facilitate drug delivery to the central nervous system. Jean-Claude Stoclet (Faculte de Pharmacie, IIIkirch, France) pointed out that the pharmacological challenge for the use of drugs that affect levels of NO in the treatment of cardiovascular diseases is to modulate NO tissue levels or its activity within physiological limits.
Adenosine, purinergic and 5-HT receptor-ligand systems The complexity of the various receptor subtypes and cardiovascular responses to agonists and 10:2
antagonists for the adenosine, purinergic and 5-HT receptor-ligand systems is quite staggering (Daniel Hoyer, Sandoz Pharma, Basel, Switzerland; Bertil Fredholm, Karolinska Institute, Stockholm, Sweden; Geoffrey Burnstock, University College London, London, UK). The genes for 15 5-HT receptors, 4 adenosine receptors and 6 subclasses of purinergic receptors have already been cloned. The greatest challenges in this field are: (1) to design agonists or antagonists that are selective for the various receptor subtypes; (2) to elucidate the physiological role of the various receptors; and (3) to devise useful pharmacological agents to interfere specifically with the effects mediated by a particular receptor subtype.
Vasopressin receptors The genes for the three human receptors for pituitary vasopressin have been cloned: V1 (vascular), V2 (renal) and V3. Marc Thibonnier (University Hospital of Cleveland, Cleveland, OH, USA), using spontaneous mutations, sitedirected mutagenesis and computer modeling, has identified key residues involved in agonist and antagonist binding and signal transduction pathways. Such information should lead to highly potent and specific peptide and non-peptide vasopressin analogs to be used in human cardiovascular and renal diseases. Ferenc Lazlo (Attila Jozsef University of Sciences, Szeged, Hungary) indicated that the V1 receptor antagonists might protect against damage to the gastric mucosa in hemorrhagic shock.
Endothelin receptors The use of endothelin receptor antagonists is a novel therapeutic strategy to treat cardiovascular and renal diseases such as acute renal failure or systemic and pulmonary hypertension. Martine Clozel (F. Hoffman La Roche, Basel, Switzerland) reported on promising clinical trials with one of these antagonists (bosentan). David Webb (Western General Hospital, Edinburgh, UK) presented his interesting evidence in
Natriuretic peptides and their receptors Natriureticpeptides (NPs) are a familyof peptides that includes atrial natriuretic factor (ANF), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). All of them interact in a complex manner with other regulators of cardiovascular and renal functions and have vasorelaxant and natriuretic properties. Guanylate cyclase (GCA and GCB) receptors mediate all the known cardiovascular and renal effects of NPs, whereas clearance (C) receptors remove NPs from the circulation and play a fundamental role in the plasma homeostasis of the hormone. In vivo blockade of C receptors by specific ligands is a novel therapeutic strategy to enhance and prolong the hypotensive and natriuretic effects of endogenous ANF (Thomas Maack, Cornell University Medical College, New York, NY, USA). BNP shows promise in the treatment of acute heart failure, particularly to decrease central venous pressure and pulmonary hypertension (John Lewicki, Scios Inc., Mountain View, CA, USA).
Concluding remarks Sixty participants attended the conference and the presentations generated great interest and debate. The advances in the understanding of cardiovascular receptors presented raise the expectation that several new drugs for the treatment of cardiovascular diseases are likely to be developed in the near future.
MOLECULAR
MEDICINE
TODAY,
MARCH
Dendritic cellsin human disease Studies by Nina Bhardwaj (Rockefeller University, New York, NY, USA) with influenza virus showed that dendritic cells can directly activate proliferation of virus-specific memory CTLs in the absence of helper T cells or exogenous cytokines, although addition of IL-12 augments this response. Activation of CTLs is mediated by either live or killed virus. This, again, supports the contention that exogenous, non-replicating antigen can enter the cytoplasm. Dendritic cells are targets for HIV-1 infection and, despite expression of the chemokine receptor CXCR4 (Jacques Banchereau, Schering-Plough, Dardilly, France;
:(:
.
Meetings
1997
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 expression of IL-12, CD80 and CD86 by the dendritic 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).
::
Gosse J. Aedema, University Hospital, Nijmegen, The Netherlands), the co-receptor for lymphotropic 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 distinctfrom those infectingT cells (Stella Knight, ImperialCollege 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 lowlevel or unproductive infection of dendritic cells. Dendritic cells that have been exposed to tumour 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 subsequent tumour challenge. The recent identification 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 immunostimulatory properties of the dendritic cell might be enhanced by transduction with genes encoding GM-CSF, IL-2, IL-12 and IFN-~, (Thomas Teuting, University of Pittsburgh, Pittsburgh, PA, USA). Clinical studies employing such dendriticcell-based therapies are now under way in lymphoma 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 numerous aspects of dendritic cell development and function, and how this is being applied for therapeutic 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 allergy, 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 generation 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 vascular wall in the understanding of the effects of pharmacological agents. The direct effect of autonomic (mainly sympathetic) nerves and circulating 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 released by the endothelium modulate vascular smooth muscle activity; they include vasorelaxants such as prostacyclin, nitric oxide (NO) and endothelium-derived hyperpolarizing factor; and vasoconstrictors such as superoxide anions, peroxides, thromboxane and endothelin. The release 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 mechanisms and potential for pharmacological intervention.
Adrenoceptors Investigation of the classic adrenoceptor system has been rekindled by the development of l
Copyright ©1997 Elsevier Science Ltd, All rights reserved. 1357 - 4310/97/$17.00
PII: $1357-4310(97)01007-1
101
Meetings
selective antagonists for one or more of the (~- and/or !3-adrenoceptor subtypes (Robert R. Ruffolo, SmithKline Beecham, King of Prus PA, USA). This interest focuses p on c~l-adrenoceptor antagonist: were developed to reduce blood and the !3fadrenoceptor antago provide 'cardiosetective' [3 blockaq ment of hypertension and angin~ most promising events in this fielc studies indicating that, in congesti, 13-adrenoceptor antagonists ma __., . . . . . . mortality and hospitalization (Robert R. Ruffolo).
Renin-angiotensin, kinins and nitric oxide A large number of associations were demonstrated between various cardiovascular and renal diseases and polymorphism of the gene for angiotensin-converting enzyme (ACE) that results from either insertion or deletion of sequences. Fran(;ois Cambien [Institut National de la Sant6 et de la Recherche Medicale (INSERM) S.C. 7, Paris, France] gave several examples of this association, including the remarkable finding that intense physical activity is associated with a large increase in left ventricular mass in ACE subtype D carriers, but not in carriers of other ACE alleles. Another topic of current interest is the clinical experience with novel angiotensin II AT1receptor antagonists (Michel Burnier, University Hospital, Lausanne, Switzerland). These agents have the same overall effects as ACE inhibitors without inducing a cough. Because the AT1 receptor antagonists have only been used for a short period of time, it remains to be seen whether they induce all the beneficial clinical effects of ACE inhibitors. Recent findings on novel agonists and antagonists of bradykinin B~ and B2 receptors were reviewed; Domenico Regoli (Faculte de M~decine, Sherbrooke, Canada) presented the interesting concept that B2 receptor agonists might open the blood-brain barrier and could therefore be of use to facilitate drug delivery to the central nervous system. Jean-Claude Stoclet (Faculte de Pharmacie, IIIkirch, France) pointed out that the pharmacological challenge for the use of drugs that affect levels of NO in the treatment of cardiovascular diseases is to modulate NO tissue levels or its activity within physiological limits.
Adenosine, purinergic and 5-HT receptor-ligand systems The complexity of the various receptor subtypes and cardiovascular responses to agonists and 10:2
antagonists for the adenosine, purinergic and 5-HT receptor-ligand systems is quite staggering (Daniel Hoyer, Sandoz Pharma, Basel, Switzerland; Bertil Fredholm, Karolinska Institute, Stockholm, Sweden; Geoffrey Burnstock, University College London, London, UK). The genes for 15 5-HT receptors, 4 adenosine receptors and 6 subclasses of purinergic receptors have already been cloned. The greatest challenges in this field are: (1) to design agonists or antagonists that are selective for the various receptor subtypes; (2) to elucidate the physiological role of the various receptors; and (3) to devise useful pharmacological agents to interfere specifically with the effects mediated by a particular receptor subtype.
Vasopressin receptors The genes for the three human receptors for pituitary vasopressin have been cloned: V1 (vascular), V2 (renal) and V3. Marc Thibonnier (University Hospital of Cleveland, Cleveland, OH, USA), using spontaneous mutations, sitedirected mutagenesis and computer modeling, has identified key residues involved in agonist and antagonist binding and signal transduction pathways. Such information should lead to highly potent and specific peptide and non-peptide vasopressin analogs to be used in human cardiovascular and renal diseases. Ferenc Lazlo (Attila Jozsef University of Sciences, Szeged, Hungary) indicated that the V1 receptor antagonists might protect against damage to the gastric mucosa in hemorrhagic shock.
Endothelin receptors The use of endothelin receptor antagonists is a novel therapeutic strategy to treat cardiovascular and renal diseases such as acute renal failure or systemic and pulmonary hypertension. Martine Clozel (F. Hoffman La Roche, Basel, Switzerland) reported on promising clinical trials with one of these antagonists (bosentan). David Webb (Western General Hospital, Edinburgh, UK) presented his interesting evidence in
Natriuretic peptides and their receptors Natriureticpeptides (NPs) are a familyof peptides that includes atrial natriuretic factor (ANF), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). All of them interact in a complex manner with other regulators of cardiovascular and renal functions and have vasorelaxant and natriuretic properties. Guanylate cyclase (GCA and GCB) receptors mediate all the known cardiovascular and renal effects of NPs, whereas clearance (C) receptors remove NPs from the circulation and play a fundamental role in the plasma homeostasis of the hormone. In vivo blockade of C receptors by specific ligands is a novel therapeutic strategy to enhance and prolong the hypotensive and natriuretic effects of endogenous ANF (Thomas Maack, Cornell University Medical College, New York, NY, USA). BNP shows promise in the treatment of acute heart failure, particularly to decrease central venous pressure and pulmonary hypertension (John Lewicki, Scios Inc., Mountain View, CA, USA).
Concluding remarks Sixty participants attended the conference and the presentations generated great interest and debate. The advances in the understanding of cardiovascular receptors presented raise the expectation that several new drugs for the treatment of cardiovascular diseases are likely to be developed in the near future.