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Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first Sylvia Cohen-Kaminsky1,2,3, Aure´lie Hautefort1,2,3, Laura Price5, Marc Humbert1,2,3,4 and Fre´de´ric Perros1,2,3 1
Universite´ Paris-Sud, Faculte´ de Me´decine, Le Kremlin-Biceˆtre, F-94276, France INSERM UMR-S 999, Hypertension Arte´rielle Pulmonaire: Physiopathologie et Innovation The´rapeutique, LabEx LERMIT, Le Plessis-Robinson, F-92350, France 3 Centre Chirurgical Marie Lannelongue, De´partement de recherche Me´dicale, Le Plessis-Robinson, F-92350, France 4 AP-HP, DHU TORINO, Centre National de Re´fe´rence de l’Hypertension Pulmonaire Se´ve`re, Service de Pneumologie et Re´animation Respiratoire, Hoˆpital Biceˆtre, Le Kremlin-Biceˆtre, F94270, France 5 Pulmonary Hypertension Service, Royal Brompton Hospital, SW3 6NP, UK 2
Inflammation is important for the initiation and the maintenance of vascular remodeling in most of the animal models of pulmonary arterial hypertension (PAH), and therapeutic targeting of inflammation in these models blocks PAH development. In humans, pulmonary vascular lesions of PAH are the source of cytokine and chemokine production, related to inflammatory cell recruitment and lymphoid neogenesis. Circulating autoantibodies to endothelial cells and to fibroblasts have been reported in 10– 40% of patients with idiopathic PAH, suggesting a possible role for autoimmunity in the pathogenesis of pulmonary vascular lesions. Current specific PAH treatments have immunomodulatory properties, and some studies have demonstrated a correlation between levels of circulating inflammatory mediators and patient survival. New immunopathological approaches to PAH should enable the development of innovative treatments for this severe condition.
Introduction Pulmonary arterial hypertension (PAH) is a devastating disease in which pulmonary vascular remodeling leads to an increased pulmonary vascular resistance resulting in right-heart failure and early death (Fig. 1). It is understood that inflammation and autoimmunity can contribute to PAH pathobiology (Fig, 1, Box 1). The main expected action of current PAH therapeutics is the decrease in pulmonary vascular resistance through the induction of pulmonary artery vasodilatation (prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulators) [1,2]. These treatments do not however afford a cure, and mainly only relieve symptoms and improve health-related quality of life in PAH patients. Thus, new treatments interfering with different mechanisms of PAH pathobiology are required to block disease progression. The presence of pulmonary vascular inflammation and, more specifically, of an Corresponding author:. Perros, F. ([email protected], [email protected])
adaptive immune response characterized by pulmonary lymphoid neogenesis in PAH patients [3] indicates that new drugs targeting the immunological component of the disease could be considered. As a proof of concept there is evidence that the current PAH therapeutics could have immunomodulatory properties and case reports have suggested that immunosuppressive agents and several targeted immunotherapeutic approaches could improve PAH. Here, we review and evaluate these three aspects of immunomodulatory approaches in PAH.
Anti-inflammatory therapies in autoimmune-diseaseassociated PAH Recent reviews have focused on evidence of inflammation in PAH and highlighted the role of inflammation and autoimmunity into disease pathophysiology [4–7]. These highlight the potential of immunotherapy to control disease outcome, and even the treatment of at-risk patients such as those with connective tissue disease or infectious diseases. Immunosuppressive drugs have
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1359-6446/06/$ - see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.04.007
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Pathobiology of PAH
Immune system Immune cell infiltration Reviews POST SCREEN
Inflammation Tertiary lymphoid tissues Dysimmunity, altered treg function Proinflammatory cytokines Autoimmunity Ig deposits in the lung Circulating autoantibodies
Disease modifiers predisposing factors
Tertiary lymphoid tissue
Genetics Epigenetics
Pulmonary circulation Vascular remodeling
Increased arterial presure EC dysfunction, SMC hyperplasia Metabolic changes Vasoconstriction Hyperproliferation Resistance to apoptosis
Environment Drugs and toxins Gender and hormones Hypoxia Hypercoagulability
Plexiform lesion
Heart Right heart remodeling
Right heart hypertrophy and dilation Pericardial effusion Fibrosis Cardiac cell hypertrophy Inflammation Contractile dysfunction Myocardial ischemia
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FIGURE 1
Inflammation and immune mechanisms can contribute to pulmonary vascular remodeling. On the left, a lymphoid follicle with a germinal center, reflecting a local adaptive immune response, is adjacent to a plexiform lesion, the pathognomonic lesion of idiopathic pulmonary arterial hypertension (PAH). Cardiac hypertrophy is a direct consequence of chronic increases of pulmonary artery pressure as a result of pulmonary vascular remodeling. PAH will lead to right-heart failure and death. Abbreviations: EC, endothelial cell; SMC, smooth muscle cell.
been widely tested in experimental models of PAH. Not surprisingly, immunosuppressive agents such as dexamethasone, mycophenolate mofetil, cyclosporine and etanercept improve pulmonary hypertension (PH) in animal models [8]. Although these results are intriguing, we readily acknowledge the limitation of these models and their ability to predict the molecules that might be effective therapy in humans. Immunosuppressive or
BOX 1
Paradigms of autoimmunity in pulmonary arterial hypertension (PAH) Female predominance [59–61]. Association of inflammatory, infectious and autoimmune diseases with PAH [6]. Defects in Treg cells [45,62–67]. Presence of circulating autoantibodies [68–78]. Pathophysiologic role of autoantibodies in vitro [72,73]. Perivascular lymphoid neogenesis–pulmonary tertiary follicles [3]. Ig deposits in vascular lesions [3,45,57–59,61,62,73–75,77–79]. Transfer of the disease from diseased animals to healthy animals [79].
2
anti-inflammatory treatment could also improve hemodynamics and clinical parameters in PAH-associated conditions such as systemic lupus erythematosus (SLE), mixed connective tissue disease and HIV/HHV8-associated Castleman’s disease [9,10]; however they have no effect in systemic sclerosis/sclerodermaassociated PAH (SSc-PAH) [10], a disease in which PAH is a leading cause of worsening and death. In a retrospective cohort of 28 cases of PAH associated with connective tissue diseases reported before the advent of specific PAH therapy, five of the 12 patients with SLEassociated PAH reported a positive effect of cyclophosphamide or glucocorticoids (considered as responders under immunosuppression alone), whereas none of the six SSc-PAH cases responded to immunosuppressive agents [10]. Similar findings were reported later, with about half of the patients with SLE-associated PAH considered as responders to immunosuppressive therapy on the basis of clinical and hemodynamic parameters [11]. Patients with less severe PAH at the time of diagnosis were considered more likely to benefit from immunosuppressive therapy, further suggesting that early immunosuppressive treatment at the time of diagnosis should be considered in future trials. Despite the limited data supporting the efficacy of immunosuppressive therapy, current guidelines suggest immunosuppression, most commonly
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in combination with PAH-specific agents, can be considered in PAH associated with SLE or mixed connective tissue disease [11].
Immunomodulatory properties of current specific PAH therapeutics Currently, three pathological pathways are targeted (the endothelin, nitric oxide and prostacyclin pathways) and four classes of therapeutic drugs specific to PAH are available: prostacyclin (epoprostenol) and its analogs (treprostinil, iloprost, beraprost); endothelin receptor antagonists (bosentan, ambrisentan, macitentan); phosphodiesterase type 5 inhibitors (PDE5i) (sildenafil, tadalafil); and soluble guanylate cyclase stimulators (riociguat). All these treatments act on endothelial dysfunction, aiming at inducing vasodilation and reducing vascular cell growth. However, it is interesting to note that these molecules also display immunomodulatory properties that could participate in their efficacy. Prostacyclin and its analogs target IP receptors, inducing vasodilation and inhibiting platelet aggregation. Apart from these expected effects, it has been demonstrated that prostacyclin has anti-inflammatory properties. In animal models of asthma, iloprost reduces migration and maturation of dendritic cells [12] and epoprostenol prevents the recruitment of Th2 CD4+ cells [13]. In vitro, prostacyclin analogs inhibit the capacity of T lymphocytes to produce proinflammatory cytokines [14] and there is a dose– response inhibition of alveolar macrophage activation after lipopolysaccharide (LPS) stimulation through nuclear factor (NF)-kB inhibition [15]. Moreover, prostacyclin analogs reduce in vitro the adhesion of lymphocytes to endothelial cells, and decrease the expression of adhesion molecules and cytokines through a cAMPdependent mechanism [16]. In type 2 diabetes, a disease with an inflammatory vascular component, patients treated with beraprost display a decrease in vascular cell adhesion molecule (VCAM)-1 (i.e. adhesion molecule and inflammatory marker) levels in the systemic circulation [17]. In PAH patients, epoprostenol treatment induced a significant decrease in plasma monocyte chemoattractant protein (MCP)-1, a chemokine reported to be elevated in this population [18], the expression of which has been shown to be higher in the lungs of PAH patients and promoting monocyte, T cell and B cell migration to the site of inflammation [19]. However, conflicting data exist that suggest that epoprostenol did not change elevated levels of MCP-1 in a study that focused on treatment-naive patients newly started on epoprostenol [20]. This group also did interesting in vitro experiments suggesting that prostacyclin did not attenuate CD40L-stimulated endothelial MCP-1 release. Similarly, circulating neutrophils from PAH patients secreted more inflammatory mediators compared with controls; an inflammatory state inhibited by iloprost [21]. Moreover, prostacyclin analogs suppressed LPS-induced macrophage inflammatory protein (MIP)-1a production in human monocytes via the IP receptor and cAMP pathway [22]. Finally, endothelial cell activation, one of the pathobiological features of PAH, is decreased in patients treated with prostacyclin analogs associated with endothelin receptor antagonist [23,24]. Endothelin 1 (ET-1), a potent vasoconstrictor involved in the pathobiology of PAH, also possesses proinflammatory properties through activation of the NF-kB transcription factor [25], and through the increase in vascular permeability and in neutrophil activation [26]. In animal models of airway inflammation and
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asthma, bosentan, a nonselective ET-1 receptor antagonist (blocks ETA and ETB receptors), allows a significant drop in the vascular permeability [27] as well as in the level of the proinflammatory cytokines in broncho-alveolar lavage through NF-kB inhibition [28]. Moreover, bosentan reduces adhesion molecule expression and MCP-1 secretion from endothelial cells pre-treated with the Creactive protein [29]. It has been demonstrated in ischemia/reperfusion models that ambrisentan, a selective ETA receptor antagonist, has immunomodulatory properties by inducing a reduction in proinflammatory gene expression. These properties allow protective effects on vascular and neuronal activation [30,31]. Finally, ET-1 receptor inhibition induces an alteration of the lymphocyte maturation and of the capacity of dendritic cells to present antigens to lymphocytes [32]. In PAH patients bosentan reduces inflammation through a decrease in intercellular adhesion molecule (ICAM)-1 and interleukin (IL)-6 levels in blood, which are correlated to hemodynamic improvement [33]. Immunomodulatory effects of PDE5i occur through cGMP pathway modulation. In animal models of airway inflammation [34,35], sildenafil reduces inflammation, mucus production and leukocyte infiltration. Moreover, sildenafil restores antitumoral immunity by suppression of arginase-1 and inducible nitric oxide synthase expression: enzymes required for the immunosuppressive effect of myeloid-derived suppressor cells recruited in growing tumors [36]. No study has investigated the immunomodulatory effect of PDE5i in PAH. However, a recent study has demonstrated an immunosuppressive effect of sildenafil in healthy male mice, whereas there was an enhanced immunological response in healthy female mice. Thus, PDE5i possesses immunomodulatory properties that seem to be gender specific [37]. Finally, the strong anti-inflammatory properties of other PDEi, such as PDE4i, the antiproliferative action and favorable effects on endothelial function point to PDE5i as a potential treatment for autoimmune diseases [38]. In summary, current therapeutics of PAH modulate each stage of the inflammatory process – by decreasing adhesion molecule expression on the endothelial cell surface, by inhibiting the secretion of proinflammatory cytokines and by preventing effector cell activation such as that of lymphocytes and dendritic cells.
Targeted immunotherapy in idiopathic PAH Although current PAH treatments possess immunomodulatory properties [6], there is no approved therapeutic specifically targeting the inflammatory processes. However, some case studies demonstrated beneficial effects of such strategies.
Glucocorticosteroids Anti-inflammatory, immunosuppressive and antiproliferative effects of glucocorticosteroids (GC) are well established [39]. Their efficacy in PAH associated with SLE or with mixed connective tissue disease (CTD) (but not with SSc-PAH) has been demonstrated in a case series [10]. In addition, some echocardiographic and clinical parameters were improved in a case of idiopathic PAH (iPAH) (without CTD) treated with prednisolone for co-existent idiopathic thrombocytopenic purpura [40]. Moreover, there was a dramatic clinical deterioration of PAH symptoms after completion of GC treatment, leading to pulmonary transplantation. In summary, it is possible that some forms of PAH (which should be identified by novel biomarkers) could benefit from steroids.
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PAH is a rare but serious complication in SLE patients. In a SLE patient who developed a progressive and severe PAH, resistant to specific PAH treatments and to high levels of corticoids, rituximab allowed a major clinical and hemodynamic improvement [41,42]. Rituximab is a humanized murine monoclonal antibody against CD20 antigen [43]. It is effective against malignant cells expressing CD20 antigen (i.e. stage III–IV follicular lymphoma and large B cell non-Hodgkin’s lymphoma) [44]. More generally, rituximab targets most B lymphocytes. This therapeutic antibody is effective in many autoimmune diseases, such as SLE with glomerulonephritis and antiphospholipid antibody syndrome [41]. In the USA, rituximab is approved for the treatment of rheumatoid arthritis and Wegener’s granulomatosis. Pathophysiological mechanisms responsible for the development of PAH in SLE are poorly understood. Although a direct pulmonary vascular injury by immunologic factors has not been clearly demonstrated, circulating antinuclear antibody, immunoglobulin and complement molecules have been detected in the wall of pulmonary arteries of PAH patients [3,45], which supports an implication of the immune system in the SLE-associated PAH pathogenesis. Rituximab induces a targeted depletion of cellular lines expressing CD20 antigen. This allows a remission of SLE patients through a decrease in autoreactive B cells in peripheral lymphoid tissue. This reduction is frequently associated with a decrease in circulating autoantibodies characteristic of SLE, probably inducing a reduction in immune complex formation and complement activation. Moreover, rituximab seems to reduce the formation of autoantibody-containing immune complexes, which otherwise stimulate various cells from innate immunity (i.e. dendritic cells and macrophages) to produce and secrete proinflammatory cytokines. Other favorable effects of rituximab might also be independent from antibody production because this treatment also decreases the availability of B cells to stimulate autoreactive T cells through their expression of co-stimulatory molecules and autoantigen presentation. Moreover, rituximab can normalize costimulation molecule expression (i.e. CD40 and CD80) on residual B lymphocytes [46] and can decrease the expression of their cognate ligand (CD40L/CD154) on T lymphocytes [47]. These effects could block vicious cycles of autoreactive T cell activation. Deletion of activated B lymphocytes could also reduce cytokine and chemokine levels generated by these B cells, which otherwise modify the local environment in the proinflammatory milieu. Therefore, rituximab could inhibit the induction and perpetuation of pulmonary lymphoid neogenesis and, more comprehensively, local and systemic inflammation present in iPAH patients. Hence, cases of idiopathic or associated PAH exposed to rituximab should be carefully screened to detect potential beneficial effects of this molecule on PAH evolution. Such reports could provide the basis for the use of rituximab in PAH. Indeed, a clinical trial is already in progress in SSc-PAH (ClinicalTrials.gov Identifier: NCT01086540).
Anti-IL-6-receptor antibody Cytokines are essential to orchestrate the immune response. In autoimmunity, uncontrolled inflammation contributes to tissue injury through a dysfunctional local cytokine network, which not only triggers but also maintains the immune disorder to transition 4
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toward a chronic disease. The proinflammatory cytokine IL-6 plays a central part in these processes. Indeed, results from experimental models of autoimmunity and from clinical trials show that IL-6 neutralization allows a significant improvement in patients suffering from Castleman’s disease and polyarthritis rheumatoid diseases [48]. IL-6 is crucial to the development of an immune response and more particularly in T-cell-dependent inflammation [48]. Indeed, IL-6 contributes to B cells and monocyte/macrophage differentiation and T cell activation. This cytokine is even central to the adaptive immune response, through a role in the generation of the germinal center, somatic hypermutations, affinity maturation of immunoglobulin and plasma cell differentiation. In animal models of autoimmune diseases, IL-6 is involved in the generation of the T-cell-dependant autoimmune response (i.e. the Th17 response in particular) and in the humoral response. Thus, IL-6 acts on a broad variety of cells including immunocompetent and hematopoietic cells to induce their proliferation and differentiation [48]. Overproduction of this cytokine is recurrent in many autoimmune diseases such as rheumatoid arthritis, SLE, Castleman’s disease and systemic juvenile idiopathic arthritis (SJIA), and is responsible for many of the clinical symptoms associated with these diseases [48]. On the basis of these observations, the anti-IL6-receptor monoclonal antibody tocilizumab has been developed for rheumatoid arthritis, SJIA and Castleman’s diseases [49]. In PAH, IL-6 seems to play an important part and might be a promising therapeutic target. Indeed, this cytokine appears to be involved in the endothelial and smooth muscle cell proliferation occurring in PAH lesions [50]. Serum IL-6 levels are elevated in PAH patients [51] and appear to be associated with poor prognosis [52,53], without correlation to hemodynamic variables [54]. This probably reflects independent markers of right-heart function and potential factors involved in PAH physiopathology. Moreover, bosentan (antagonist of endothelin receptors) exerts anti-inflammatory properties by decreasing the ICAM-1 and IL-6 levels in blood, which are correlated to hemodynamic improvement [33]. Finally, lung-specific IL-6 overexpression induces PAH in mice [50]. Some studies have reported cases of PAH patients treated with tocilizumab: one CTD-associated PAH [55] and two PAH associated with Castleman’s disease [56,57]. In all of these three cases, tocilizumab was given to treat the primary inflammatory and autoimmune disorders but allowed an improvement in clinical and hemodynamic parameters. Tocilizumab was even beneficial in a PAH patient severely affected and receiving maximum therapy (i.e. prostacyclin, bosentan and sildenafil) [56]. These three patients showed high levels of circulating IL-6, and tocilizumab might provide a significant therapeutic benefit in PAH patients characterized by a higher level of IL-6 such as CTD-PAH and, possibly, in some subsets of iPAH.
Concluding remarks Considerable progress has been made in demonstrating inflammatory and autoimmune mechanisms in PAH. However, no major autoantigen involved in disease pathogenesis has been clearly defined and the precise mechanisms by which inflammation triggers and sustains vascular remodeling and, as a consequence, heart failure remain to be clarified. Although in the monocrotaline-induced PH rat model kinetics studies have clearly shown that inflammation precedes vascular remodeling [58], there is no
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Arguments for anti-CD20 as a targeted therapy of inflammation and autoimmunity in pulmonary arterial hypertension (PAH) Severe vascular remodeling and B cell infiltration in pulmonary hypertension (PH) induced in athymic rats, supporting the role of B cells [80]. Circulating autoantibodies in human and experimental PH [4]. Tertiary lymphoid follicles with germinal centers and Ig deposits in vascular lesions [3]. Evidence of beneficial effect of anti-CD20 in Sugen/hypoxia experimental model of PH [81]. Ongoing clinical trial in systemic sclerosis/scleroderma-associated PAH (SSc-PAH) patients (NCT01086540; http://clinicaltrials.gov/).
PAH therapies and to evaluate drug–drug interactions of novel immunosuppressive agents in combination with PAH-targeted therapies. Although some data might support an anti-CD20 strategy in human PAH (Box 2), including beneficial effects in an animal preclinical model of PAH and an ongoing clinical trial in SSc-PAH patients, there is currently no robust clinical evidence to recommend such treatments in PAH.
Conflicts of interest Professor Humbert has served as an advisory board member for Actelion, Aires, Bayer, Novartis and Pfizer, and received consultancy and lecture fees from Actelion, Aires, Bayer, GlaxoSmithKline, Novartis and Pfizer. Dr Perros has a relationship with Bayer. He received an Investigator Sponsored Study (ISS) grant.
Acknowledgments chronic animal model that specifically addresses immune mechanisms in PAH and that could be used to help define novel treatments. Taking into account the poor safety profile and the secondary effects of existing immunosuppressive drugs [8], testing these drugs in preclinical models relevant to PAH would help to design large-scale randomized trials in combination with current
Sylvia Cohen-Kaminisky received funding from the Fondation pour la Recherche Me´dicale (FRM) (grant number: DEQ20100318257). Aure´lie Hautefort is supported by a PhD grant from Re´gion Ile de France (CORDDIM). Fre´de´ric Perros receives funding from National Funding Agency for Research (ANR) (Grant: ANR-13-JSV1-001).
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58 Gillespie, M.N. et al. (1988) Interleukin 1 bioactivity in the lungs of rats with monocrotaline-induced pulmonary hypertension. Proc. Soc. Exp. Biol. Med. 187, 26–32 59 Girerd, B. et al. (2010) Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir. Res. 11, 73 60 Pugh, M.E. and Hemnes, A.R. (2010) Development of pulmonary arterial hypertension in women: interplay of sex hormones and pulmonary vascular disease. Womens Health 6, 285–296 61 Larkin, E.K. et al. (2012) Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186, 892–896 62 Austin, E.D. et al. (2010) T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension. Respir. Med. 104, 454–462 63 Ulrich, S. et al. (2008) Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respir. Int. Rev. Thorac. Dis. 75, 272–280 64 Huertas, A. et al. (2012) Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur. Respir. J. 40, 895–904 65 Savai, R. et al. (2012) Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186, 897–908 66 Tamosiuniene, R. et al. (2011) Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ. Res. 109, 867–879 67 Perros, F. et al. (2008) Understanding the role of CD4+CD25(high) (so-called regulatory) T cells in idiopathic pulmonary arterial hypertension. Respir. Int. Rev. Thorac. Dis. 75, 253–256 68 Tamby, M.C. et al. (2005) Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 60, 765–772 69 Terrier, B. et al. (2010) Antifibroblast antibodies from systemic sclerosis patients bind to {alpha}-enolase and are associated with interstitial lung disease. Ann. Rheum. Dis. 69, 428–433 70 Terrier, B. et al. (2008) Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 177, 1128–1134 71 Karmochkine, M. et al. (1996) High prevalence of antiphospholipid antibodies in precapillary pulmonary hypertension. J. Rheumatol. 23, 286–290 72 Riboldi, P. et al. (2003) Endothelium as a target for antiphospholipid antibodies. Immunobiology 207, 29–36 73 Bussone, G. et al. (2012) IgG from patients with pulmonary arterial hypertension and/or systemic sclerosis binds to vascular smooth muscle cells and induces cell contraction. Ann. Rheum. Dis. 71, 596–605 74 Renaudineau, Y. et al. (2002) Antiendothelial cell antibodies in systemic lupus erythematosus. Autoimmun. Rev. 1, 365–372 75 Negi, V.S. et al. (1998) Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J. Rheumatol. 25, 462–466 76 Arends, S.J. et al. (2010) Prevalence of anti-endothelial cell antibodies in idiopathic pulmonary arterial hypertension. Eur. Respir. J. 35, 923–925 77 Quismorio, F.P., Jr et al. (1984) Immunopathologic and clinical studies in pulmonary hypertension associated with systemic lupus erythematosus. Semin. Arthritis Rheum. 13, 349–359 78 Dib, H. et al. (2012) Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur. Respir. J. 39, 1405–1414 79 Colvin, K.L. et al. (2013) Bronchus-associated lymphoid tissue in pulmonary hypertension produces pathologic autoantibodies. Am. J. Respir. Crit. Care Med. 188, 1126–1136 80 Taraseviciene-Stewart, L. et al. (2007) Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am. J. Respir. Crit. Care Med. 175, 1280–1289 81 Mizuno, S. et al. (2012) Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization. Am. J. Respir. Cell. Mol. Biol. 47, 679–687
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Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first Sylvia Cohen-Kaminsky1,2,3, Aure´lie Hautefort1,2,3, Laura Price5, Marc Humbert1,2,3,4 and Fre´de´ric Perros1,2,3 1
Universite´ Paris-Sud, Faculte´ de Me´decine, Le Kremlin-Biceˆtre, F-94276, France INSERM UMR-S 999, Hypertension Arte´rielle Pulmonaire: Physiopathologie et Innovation The´rapeutique, LabEx LERMIT, Le Plessis-Robinson, F-92350, France 3 Centre Chirurgical Marie Lannelongue, De´partement de recherche Me´dicale, Le Plessis-Robinson, F-92350, France 4 AP-HP, DHU TORINO, Centre National de Re´fe´rence de l’Hypertension Pulmonaire Se´ve`re, Service de Pneumologie et Re´animation Respiratoire, Hoˆpital Biceˆtre, Le Kremlin-Biceˆtre, F94270, France 5 Pulmonary Hypertension Service, Royal Brompton Hospital, SW3 6NP, UK 2
Inflammation is important for the initiation and the maintenance of vascular remodeling in most of the animal models of pulmonary arterial hypertension (PAH), and therapeutic targeting of inflammation in these models blocks PAH development. In humans, pulmonary vascular lesions of PAH are the source of cytokine and chemokine production, related to inflammatory cell recruitment and lymphoid neogenesis. Circulating autoantibodies to endothelial cells and to fibroblasts have been reported in 10– 40% of patients with idiopathic PAH, suggesting a possible role for autoimmunity in the pathogenesis of pulmonary vascular lesions. Current specific PAH treatments have immunomodulatory properties, and some studies have demonstrated a correlation between levels of circulating inflammatory mediators and patient survival. New immunopathological approaches to PAH should enable the development of innovative treatments for this severe condition.
Introduction Pulmonary arterial hypertension (PAH) is a devastating disease in which pulmonary vascular remodeling leads to an increased pulmonary vascular resistance resulting in right-heart failure and early death (Fig. 1). It is understood that inflammation and autoimmunity can contribute to PAH pathobiology (Fig, 1, Box 1). The main expected action of current PAH therapeutics is the decrease in pulmonary vascular resistance through the induction of pulmonary artery vasodilatation (prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulators) [1,2]. These treatments do not however afford a cure, and mainly only relieve symptoms and improve health-related quality of life in PAH patients. Thus, new treatments interfering with different mechanisms of PAH pathobiology are required to block disease progression. The presence of pulmonary vascular inflammation and, more specifically, of an Corresponding author:. Perros, F. ([email protected], [email protected])
adaptive immune response characterized by pulmonary lymphoid neogenesis in PAH patients [3] indicates that new drugs targeting the immunological component of the disease could be considered. As a proof of concept there is evidence that the current PAH therapeutics could have immunomodulatory properties and case reports have suggested that immunosuppressive agents and several targeted immunotherapeutic approaches could improve PAH. Here, we review and evaluate these three aspects of immunomodulatory approaches in PAH.
Anti-inflammatory therapies in autoimmune-diseaseassociated PAH Recent reviews have focused on evidence of inflammation in PAH and highlighted the role of inflammation and autoimmunity into disease pathophysiology [4–7]. These highlight the potential of immunotherapy to control disease outcome, and even the treatment of at-risk patients such as those with connective tissue disease or infectious diseases. Immunosuppressive drugs have
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1359-6446/06/$ - see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.04.007
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Pathobiology of PAH
Immune system Immune cell infiltration Reviews POST SCREEN
Inflammation Tertiary lymphoid tissues Dysimmunity, altered treg function Proinflammatory cytokines Autoimmunity Ig deposits in the lung Circulating autoantibodies
Disease modifiers predisposing factors
Tertiary lymphoid tissue
Genetics Epigenetics
Pulmonary circulation Vascular remodeling
Increased arterial presure EC dysfunction, SMC hyperplasia Metabolic changes Vasoconstriction Hyperproliferation Resistance to apoptosis
Environment Drugs and toxins Gender and hormones Hypoxia Hypercoagulability
Plexiform lesion
Heart Right heart remodeling
Right heart hypertrophy and dilation Pericardial effusion Fibrosis Cardiac cell hypertrophy Inflammation Contractile dysfunction Myocardial ischemia
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FIGURE 1
Inflammation and immune mechanisms can contribute to pulmonary vascular remodeling. On the left, a lymphoid follicle with a germinal center, reflecting a local adaptive immune response, is adjacent to a plexiform lesion, the pathognomonic lesion of idiopathic pulmonary arterial hypertension (PAH). Cardiac hypertrophy is a direct consequence of chronic increases of pulmonary artery pressure as a result of pulmonary vascular remodeling. PAH will lead to right-heart failure and death. Abbreviations: EC, endothelial cell; SMC, smooth muscle cell.
been widely tested in experimental models of PAH. Not surprisingly, immunosuppressive agents such as dexamethasone, mycophenolate mofetil, cyclosporine and etanercept improve pulmonary hypertension (PH) in animal models [8]. Although these results are intriguing, we readily acknowledge the limitation of these models and their ability to predict the molecules that might be effective therapy in humans. Immunosuppressive or
BOX 1
Paradigms of autoimmunity in pulmonary arterial hypertension (PAH) Female predominance [59–61]. Association of inflammatory, infectious and autoimmune diseases with PAH [6]. Defects in Treg cells [45,62–67]. Presence of circulating autoantibodies [68–78]. Pathophysiologic role of autoantibodies in vitro [72,73]. Perivascular lymphoid neogenesis–pulmonary tertiary follicles [3]. Ig deposits in vascular lesions [3,45,57–59,61,62,73–75,77–79]. Transfer of the disease from diseased animals to healthy animals [79].
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anti-inflammatory treatment could also improve hemodynamics and clinical parameters in PAH-associated conditions such as systemic lupus erythematosus (SLE), mixed connective tissue disease and HIV/HHV8-associated Castleman’s disease [9,10]; however they have no effect in systemic sclerosis/sclerodermaassociated PAH (SSc-PAH) [10], a disease in which PAH is a leading cause of worsening and death. In a retrospective cohort of 28 cases of PAH associated with connective tissue diseases reported before the advent of specific PAH therapy, five of the 12 patients with SLEassociated PAH reported a positive effect of cyclophosphamide or glucocorticoids (considered as responders under immunosuppression alone), whereas none of the six SSc-PAH cases responded to immunosuppressive agents [10]. Similar findings were reported later, with about half of the patients with SLE-associated PAH considered as responders to immunosuppressive therapy on the basis of clinical and hemodynamic parameters [11]. Patients with less severe PAH at the time of diagnosis were considered more likely to benefit from immunosuppressive therapy, further suggesting that early immunosuppressive treatment at the time of diagnosis should be considered in future trials. Despite the limited data supporting the efficacy of immunosuppressive therapy, current guidelines suggest immunosuppression, most commonly
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in combination with PAH-specific agents, can be considered in PAH associated with SLE or mixed connective tissue disease [11].
Immunomodulatory properties of current specific PAH therapeutics Currently, three pathological pathways are targeted (the endothelin, nitric oxide and prostacyclin pathways) and four classes of therapeutic drugs specific to PAH are available: prostacyclin (epoprostenol) and its analogs (treprostinil, iloprost, beraprost); endothelin receptor antagonists (bosentan, ambrisentan, macitentan); phosphodiesterase type 5 inhibitors (PDE5i) (sildenafil, tadalafil); and soluble guanylate cyclase stimulators (riociguat). All these treatments act on endothelial dysfunction, aiming at inducing vasodilation and reducing vascular cell growth. However, it is interesting to note that these molecules also display immunomodulatory properties that could participate in their efficacy. Prostacyclin and its analogs target IP receptors, inducing vasodilation and inhibiting platelet aggregation. Apart from these expected effects, it has been demonstrated that prostacyclin has anti-inflammatory properties. In animal models of asthma, iloprost reduces migration and maturation of dendritic cells [12] and epoprostenol prevents the recruitment of Th2 CD4+ cells [13]. In vitro, prostacyclin analogs inhibit the capacity of T lymphocytes to produce proinflammatory cytokines [14] and there is a dose– response inhibition of alveolar macrophage activation after lipopolysaccharide (LPS) stimulation through nuclear factor (NF)-kB inhibition [15]. Moreover, prostacyclin analogs reduce in vitro the adhesion of lymphocytes to endothelial cells, and decrease the expression of adhesion molecules and cytokines through a cAMPdependent mechanism [16]. In type 2 diabetes, a disease with an inflammatory vascular component, patients treated with beraprost display a decrease in vascular cell adhesion molecule (VCAM)-1 (i.e. adhesion molecule and inflammatory marker) levels in the systemic circulation [17]. In PAH patients, epoprostenol treatment induced a significant decrease in plasma monocyte chemoattractant protein (MCP)-1, a chemokine reported to be elevated in this population [18], the expression of which has been shown to be higher in the lungs of PAH patients and promoting monocyte, T cell and B cell migration to the site of inflammation [19]. However, conflicting data exist that suggest that epoprostenol did not change elevated levels of MCP-1 in a study that focused on treatment-naive patients newly started on epoprostenol [20]. This group also did interesting in vitro experiments suggesting that prostacyclin did not attenuate CD40L-stimulated endothelial MCP-1 release. Similarly, circulating neutrophils from PAH patients secreted more inflammatory mediators compared with controls; an inflammatory state inhibited by iloprost [21]. Moreover, prostacyclin analogs suppressed LPS-induced macrophage inflammatory protein (MIP)-1a production in human monocytes via the IP receptor and cAMP pathway [22]. Finally, endothelial cell activation, one of the pathobiological features of PAH, is decreased in patients treated with prostacyclin analogs associated with endothelin receptor antagonist [23,24]. Endothelin 1 (ET-1), a potent vasoconstrictor involved in the pathobiology of PAH, also possesses proinflammatory properties through activation of the NF-kB transcription factor [25], and through the increase in vascular permeability and in neutrophil activation [26]. In animal models of airway inflammation and
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asthma, bosentan, a nonselective ET-1 receptor antagonist (blocks ETA and ETB receptors), allows a significant drop in the vascular permeability [27] as well as in the level of the proinflammatory cytokines in broncho-alveolar lavage through NF-kB inhibition [28]. Moreover, bosentan reduces adhesion molecule expression and MCP-1 secretion from endothelial cells pre-treated with the Creactive protein [29]. It has been demonstrated in ischemia/reperfusion models that ambrisentan, a selective ETA receptor antagonist, has immunomodulatory properties by inducing a reduction in proinflammatory gene expression. These properties allow protective effects on vascular and neuronal activation [30,31]. Finally, ET-1 receptor inhibition induces an alteration of the lymphocyte maturation and of the capacity of dendritic cells to present antigens to lymphocytes [32]. In PAH patients bosentan reduces inflammation through a decrease in intercellular adhesion molecule (ICAM)-1 and interleukin (IL)-6 levels in blood, which are correlated to hemodynamic improvement [33]. Immunomodulatory effects of PDE5i occur through cGMP pathway modulation. In animal models of airway inflammation [34,35], sildenafil reduces inflammation, mucus production and leukocyte infiltration. Moreover, sildenafil restores antitumoral immunity by suppression of arginase-1 and inducible nitric oxide synthase expression: enzymes required for the immunosuppressive effect of myeloid-derived suppressor cells recruited in growing tumors [36]. No study has investigated the immunomodulatory effect of PDE5i in PAH. However, a recent study has demonstrated an immunosuppressive effect of sildenafil in healthy male mice, whereas there was an enhanced immunological response in healthy female mice. Thus, PDE5i possesses immunomodulatory properties that seem to be gender specific [37]. Finally, the strong anti-inflammatory properties of other PDEi, such as PDE4i, the antiproliferative action and favorable effects on endothelial function point to PDE5i as a potential treatment for autoimmune diseases [38]. In summary, current therapeutics of PAH modulate each stage of the inflammatory process – by decreasing adhesion molecule expression on the endothelial cell surface, by inhibiting the secretion of proinflammatory cytokines and by preventing effector cell activation such as that of lymphocytes and dendritic cells.
Targeted immunotherapy in idiopathic PAH Although current PAH treatments possess immunomodulatory properties [6], there is no approved therapeutic specifically targeting the inflammatory processes. However, some case studies demonstrated beneficial effects of such strategies.
Glucocorticosteroids Anti-inflammatory, immunosuppressive and antiproliferative effects of glucocorticosteroids (GC) are well established [39]. Their efficacy in PAH associated with SLE or with mixed connective tissue disease (CTD) (but not with SSc-PAH) has been demonstrated in a case series [10]. In addition, some echocardiographic and clinical parameters were improved in a case of idiopathic PAH (iPAH) (without CTD) treated with prednisolone for co-existent idiopathic thrombocytopenic purpura [40]. Moreover, there was a dramatic clinical deterioration of PAH symptoms after completion of GC treatment, leading to pulmonary transplantation. In summary, it is possible that some forms of PAH (which should be identified by novel biomarkers) could benefit from steroids.
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Anti-CD20 antibody
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PAH is a rare but serious complication in SLE patients. In a SLE patient who developed a progressive and severe PAH, resistant to specific PAH treatments and to high levels of corticoids, rituximab allowed a major clinical and hemodynamic improvement [41,42]. Rituximab is a humanized murine monoclonal antibody against CD20 antigen [43]. It is effective against malignant cells expressing CD20 antigen (i.e. stage III–IV follicular lymphoma and large B cell non-Hodgkin’s lymphoma) [44]. More generally, rituximab targets most B lymphocytes. This therapeutic antibody is effective in many autoimmune diseases, such as SLE with glomerulonephritis and antiphospholipid antibody syndrome [41]. In the USA, rituximab is approved for the treatment of rheumatoid arthritis and Wegener’s granulomatosis. Pathophysiological mechanisms responsible for the development of PAH in SLE are poorly understood. Although a direct pulmonary vascular injury by immunologic factors has not been clearly demonstrated, circulating antinuclear antibody, immunoglobulin and complement molecules have been detected in the wall of pulmonary arteries of PAH patients [3,45], which supports an implication of the immune system in the SLE-associated PAH pathogenesis. Rituximab induces a targeted depletion of cellular lines expressing CD20 antigen. This allows a remission of SLE patients through a decrease in autoreactive B cells in peripheral lymphoid tissue. This reduction is frequently associated with a decrease in circulating autoantibodies characteristic of SLE, probably inducing a reduction in immune complex formation and complement activation. Moreover, rituximab seems to reduce the formation of autoantibody-containing immune complexes, which otherwise stimulate various cells from innate immunity (i.e. dendritic cells and macrophages) to produce and secrete proinflammatory cytokines. Other favorable effects of rituximab might also be independent from antibody production because this treatment also decreases the availability of B cells to stimulate autoreactive T cells through their expression of co-stimulatory molecules and autoantigen presentation. Moreover, rituximab can normalize costimulation molecule expression (i.e. CD40 and CD80) on residual B lymphocytes [46] and can decrease the expression of their cognate ligand (CD40L/CD154) on T lymphocytes [47]. These effects could block vicious cycles of autoreactive T cell activation. Deletion of activated B lymphocytes could also reduce cytokine and chemokine levels generated by these B cells, which otherwise modify the local environment in the proinflammatory milieu. Therefore, rituximab could inhibit the induction and perpetuation of pulmonary lymphoid neogenesis and, more comprehensively, local and systemic inflammation present in iPAH patients. Hence, cases of idiopathic or associated PAH exposed to rituximab should be carefully screened to detect potential beneficial effects of this molecule on PAH evolution. Such reports could provide the basis for the use of rituximab in PAH. Indeed, a clinical trial is already in progress in SSc-PAH (ClinicalTrials.gov Identifier: NCT01086540).
Anti-IL-6-receptor antibody Cytokines are essential to orchestrate the immune response. In autoimmunity, uncontrolled inflammation contributes to tissue injury through a dysfunctional local cytokine network, which not only triggers but also maintains the immune disorder to transition 4
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toward a chronic disease. The proinflammatory cytokine IL-6 plays a central part in these processes. Indeed, results from experimental models of autoimmunity and from clinical trials show that IL-6 neutralization allows a significant improvement in patients suffering from Castleman’s disease and polyarthritis rheumatoid diseases [48]. IL-6 is crucial to the development of an immune response and more particularly in T-cell-dependent inflammation [48]. Indeed, IL-6 contributes to B cells and monocyte/macrophage differentiation and T cell activation. This cytokine is even central to the adaptive immune response, through a role in the generation of the germinal center, somatic hypermutations, affinity maturation of immunoglobulin and plasma cell differentiation. In animal models of autoimmune diseases, IL-6 is involved in the generation of the T-cell-dependant autoimmune response (i.e. the Th17 response in particular) and in the humoral response. Thus, IL-6 acts on a broad variety of cells including immunocompetent and hematopoietic cells to induce their proliferation and differentiation [48]. Overproduction of this cytokine is recurrent in many autoimmune diseases such as rheumatoid arthritis, SLE, Castleman’s disease and systemic juvenile idiopathic arthritis (SJIA), and is responsible for many of the clinical symptoms associated with these diseases [48]. On the basis of these observations, the anti-IL6-receptor monoclonal antibody tocilizumab has been developed for rheumatoid arthritis, SJIA and Castleman’s diseases [49]. In PAH, IL-6 seems to play an important part and might be a promising therapeutic target. Indeed, this cytokine appears to be involved in the endothelial and smooth muscle cell proliferation occurring in PAH lesions [50]. Serum IL-6 levels are elevated in PAH patients [51] and appear to be associated with poor prognosis [52,53], without correlation to hemodynamic variables [54]. This probably reflects independent markers of right-heart function and potential factors involved in PAH physiopathology. Moreover, bosentan (antagonist of endothelin receptors) exerts anti-inflammatory properties by decreasing the ICAM-1 and IL-6 levels in blood, which are correlated to hemodynamic improvement [33]. Finally, lung-specific IL-6 overexpression induces PAH in mice [50]. Some studies have reported cases of PAH patients treated with tocilizumab: one CTD-associated PAH [55] and two PAH associated with Castleman’s disease [56,57]. In all of these three cases, tocilizumab was given to treat the primary inflammatory and autoimmune disorders but allowed an improvement in clinical and hemodynamic parameters. Tocilizumab was even beneficial in a PAH patient severely affected and receiving maximum therapy (i.e. prostacyclin, bosentan and sildenafil) [56]. These three patients showed high levels of circulating IL-6, and tocilizumab might provide a significant therapeutic benefit in PAH patients characterized by a higher level of IL-6 such as CTD-PAH and, possibly, in some subsets of iPAH.
Concluding remarks Considerable progress has been made in demonstrating inflammatory and autoimmune mechanisms in PAH. However, no major autoantigen involved in disease pathogenesis has been clearly defined and the precise mechanisms by which inflammation triggers and sustains vascular remodeling and, as a consequence, heart failure remain to be clarified. Although in the monocrotaline-induced PH rat model kinetics studies have clearly shown that inflammation precedes vascular remodeling [58], there is no
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Arguments for anti-CD20 as a targeted therapy of inflammation and autoimmunity in pulmonary arterial hypertension (PAH) Severe vascular remodeling and B cell infiltration in pulmonary hypertension (PH) induced in athymic rats, supporting the role of B cells [80]. Circulating autoantibodies in human and experimental PH [4]. Tertiary lymphoid follicles with germinal centers and Ig deposits in vascular lesions [3]. Evidence of beneficial effect of anti-CD20 in Sugen/hypoxia experimental model of PH [81]. Ongoing clinical trial in systemic sclerosis/scleroderma-associated PAH (SSc-PAH) patients (NCT01086540; http://clinicaltrials.gov/).
PAH therapies and to evaluate drug–drug interactions of novel immunosuppressive agents in combination with PAH-targeted therapies. Although some data might support an anti-CD20 strategy in human PAH (Box 2), including beneficial effects in an animal preclinical model of PAH and an ongoing clinical trial in SSc-PAH patients, there is currently no robust clinical evidence to recommend such treatments in PAH.
Conflicts of interest Professor Humbert has served as an advisory board member for Actelion, Aires, Bayer, Novartis and Pfizer, and received consultancy and lecture fees from Actelion, Aires, Bayer, GlaxoSmithKline, Novartis and Pfizer. Dr Perros has a relationship with Bayer. He received an Investigator Sponsored Study (ISS) grant.
Acknowledgments chronic animal model that specifically addresses immune mechanisms in PAH and that could be used to help define novel treatments. Taking into account the poor safety profile and the secondary effects of existing immunosuppressive drugs [8], testing these drugs in preclinical models relevant to PAH would help to design large-scale randomized trials in combination with current
Sylvia Cohen-Kaminisky received funding from the Fondation pour la Recherche Me´dicale (FRM) (grant number: DEQ20100318257). Aure´lie Hautefort is supported by a PhD grant from Re´gion Ile de France (CORDDIM). Fre´de´ric Perros receives funding from National Funding Agency for Research (ANR) (Grant: ANR-13-JSV1-001).
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www.drugdiscoverytoday.com Please cite this article in press as: S. Cohen-Kaminsky, et al., Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.04.007
