Stimulatory Autoantibodies to the PDGF Receptor in Scleroderma
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《新英格兰医药杂志》
To the Editor: In the study reported by Baroni et al. (June 22 issue),1 stimulatory antibodies to the platelet-derived growth factor (PDGF) receptor (PDGFR) were found in patients with scleroderma, and these autoantibodies appeared to play a role in the pathogenesis of the disease. The authors report that the stimulatory activity of the antibodies was higher in patients with early, limited scleroderma than in those with late disease. Pulmonary arterial hypertension (PAH), a life-threatening complication of scleroderma, is found in more than 15% of patients with this disease.2 PDGF involvement in the progression of PAH, presumably by increasing the proliferation and migration of pulmonary vascular smooth-muscle cells, has been reported previously.3,4 Stimulatory antibodies to the PDGFR might have biologic activity not only on fibroblast cells, but also on pulmonary vascular smooth-muscle cells, resulting in the development of PAH in patients with scleroderma. Further clinical studies that examine the development of PAH in patients with highly stimulatory antibodies against the PDGFR should lead to a greater understanding of the pathologic importance of these types of antibodies.
Hiroshi Okamoto, M.D., Ph.D.
Tokyo Women's Medical University
Tokyo 1620054, Japan
hokamoto@ior.twmu.ac.jp
References
Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006;354:2667-2676.
Ramirez A, Varga J. Pulmonary arterial hypertension in systemic sclerosis: clinical manifestations, pathophysiology, evaluation, and management. Treat Respir Med 2004;3:339-352.
Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821.
Barst RJ. PDGF signaling in pulmonary arterial hypertension. J Clin Invest 2005;115:2691-2694.
To the Editor: The article by Baroni et al. and the accompanying editorial by Tan1 describe how signaling pathways triggered by autoantibodies against the PDGFR in patients with scleroderma may contribute to the activated phenotype of fibroblasts, and they comment on the potential therapeutic implications of this finding (e.g., the use of decoy receptors). We would like to broaden this discussion by presenting a therapeutic approach derived from their articles — blocking PDGFR signaling with a compound currently available in clinical practice. Imatinib mesylate, an inhibitor of the tyrosine kinase activity of the fusion protein BCR-ABL generated in chronic myeloid leukemia (CML),2 is not completely selective and inhibits the tyrosine kinase activity of the C-KIT receptor and PDGFR. Imatinib has a good safety profile and has been approved to treat not only CML, but also gastrointestinal stromal tumors bearing activating mutations of these receptors.2,3,4 Since 22% of patients with scleroderma in the study by Baroni et al. had autoantibodies that recognized conformational epitopes, blocking signaling might be more efficient than other strategies. If antibodies to the PDGFR play a role in the pathogenesis of scleroderma, imatinib might be a promising therapeutic option for this challenging disease.
Ester Lozano, Ph.D.
Marta Segarra, Ph.D.
Maria C. Cid, M.D.
Institut d'Investigacions Biomèdiques August Pi i Sunyer
08036 Barcelona, Spain
mccid@clinic.ub.es
References
Tan FK. Autoantibodies against PDGF receptor in scleroderma. N Engl J Med 2006;354:2709-2711.
Druker BJ, Tamura S, Buchdunger E, et al. Effects of selective inhibitor of the Abl tyrosine kinase in the growth of Bcr/Abl positive cells. Nat Med 1996;2:561-566.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-4349.
Baselga J. Targeting tyrosine kinases in cancer: the second wave. Science 2006;312:1175-1178.
The authors reply: Lozano and colleagues speculate that blocking PDGFR activation with imatinib mesylate, a tyrosine kinase inhibitor, might be therapeutically rewarding in scleroderma. However, autoantibodies against PDGFR represent only one side of the molecular picture in this disease. Our data suggest that the phenotype of fibroblasts from patients with scleroderma is maintained by a self-perpetuating loop that links the H-Ras gene activation of the extracellular signal-regulated kinases 1 and 2 (Ha-Ras-ERK1/2) to the reactive oxygen species (ROS). Each one of these molecules can induce the next. The inhibition of the PDGFR in the presence of excess ROS does not completely inhibit the system, at least during short periods of treatment.1 This lack of inhibition might prevent a therapeutic benefit if the PDGFR signaling alone is blocked. ROS generated in vivo in fibroblasts from patients with scleroderma freely diffuse and activate the Ha-Ras-ERK1/2–ROS cycle in adjacent fibroblasts and epithelia, irrespective of PDGFR activation.1 Thus, fibrosis in scleroderma can be perpetuated and progress, even without considerable PDGFR activation.
An understanding of the signaling cascade triggered by autoantibodies against PDGFR provides the means and tools to target the components of the loop (Ras, ROS, and PDGFR). For example, Ha-Ras is very sensitive to farnesyl transferase inhibitors or statins,2 antioxidants may reduce ROS, and anti-CD20 may down-regulate B cells. Since each of these various elements may play a dominant role among patients, we think that integrated combination protocols are more likely to succeed.
Okamoto correctly notes that PDGF has been implicated in the endothelial-cell dysfunction that characterizes PAH. Do positive antibodies to the PDGFR play a role in PAH? The PDGFR has not been present in all endothelial cells tested; in our study, not all patients with scleroderma had PAH, although serum from these patients expressed stimulatory autoantibodies to PDGFR.
Agonistic antibodies may work in smooth-muscle cells. These cells are responsive to PDGF and other cytokines, and under special conditions they might contract and proliferate. We think that the lung would be a good place to search for agonistic cytokines that stimulate smooth-muscle cells.
Armando Gabrielli, M.D.
Silvia Svegliati Baroni, Ph.D.
Università Politecnica delle Marche
60020 Ancona, Italy
a.gabrielli@univpm.it
Enrico V. Avvedimento, M.D., Ph.D.
Università Federico II
80131 Naples, Italy
References
Svegliati S, Cancello R, Sambo P, et al. Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK 1/2: amplification of ROS and Ras in systemic sclerosis fibroblasts. J Biol Chem 2005;280:36474-36482.
Sabbatini M, Santillo M, Pisani A, et al. Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury. Am J Physiol Renal Physiol 2006;290:F1408-F1415.
The editorialist replies: I thank Lozano and colleagues for their comments. Many agents have been tested for the treatment for scleroderma, and clinical trials in scleroderma have unique obstacles.1 However, the first positive placebo-controlled trial (for cyclophosphamide) reported by Tashkin et al. in the same issue of the Journal demonstrated that these obstacles are not insurmountable.2 The promise of the results reported by Baroni et al. is the potential for therapies aimed at specific targets in the disease pathway leading to scleroderma. If antibody-mediated PDGFR activation is indeed a key to the pathogenesis of scleroderma, then treatments aimed at inhibiting the production of PDGFR-stimulating autoantibodies by B-cell depletion (e.g., with rituximab or other means) could be used to attenuate the extracellular signal that promotes fibrosis. As stated by Lozano and colleagues, intracellular PDGFR signaling could be antagonized by imatinib mesylate. In this case, the bioassay developed by Baroni and colleagues will facilitate the high-throughput screening in vitro of a variety of promising, therapeutic small molecules for new studies in vivo.
Filemon K. Tan, M.D., Ph.D.
University of Texas Medical School at Houston
Houston, TX 77030
References
Seibold JR, Furst DE, Clements PJ. Why everything (or nothing) seems to work in the treatment of scleroderma. J Rheumatol 1992;19:673-676.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666.
Hiroshi Okamoto, M.D., Ph.D.
Tokyo Women's Medical University
Tokyo 1620054, Japan
hokamoto@ior.twmu.ac.jp
References
Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006;354:2667-2676.
Ramirez A, Varga J. Pulmonary arterial hypertension in systemic sclerosis: clinical manifestations, pathophysiology, evaluation, and management. Treat Respir Med 2004;3:339-352.
Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821.
Barst RJ. PDGF signaling in pulmonary arterial hypertension. J Clin Invest 2005;115:2691-2694.
To the Editor: The article by Baroni et al. and the accompanying editorial by Tan1 describe how signaling pathways triggered by autoantibodies against the PDGFR in patients with scleroderma may contribute to the activated phenotype of fibroblasts, and they comment on the potential therapeutic implications of this finding (e.g., the use of decoy receptors). We would like to broaden this discussion by presenting a therapeutic approach derived from their articles — blocking PDGFR signaling with a compound currently available in clinical practice. Imatinib mesylate, an inhibitor of the tyrosine kinase activity of the fusion protein BCR-ABL generated in chronic myeloid leukemia (CML),2 is not completely selective and inhibits the tyrosine kinase activity of the C-KIT receptor and PDGFR. Imatinib has a good safety profile and has been approved to treat not only CML, but also gastrointestinal stromal tumors bearing activating mutations of these receptors.2,3,4 Since 22% of patients with scleroderma in the study by Baroni et al. had autoantibodies that recognized conformational epitopes, blocking signaling might be more efficient than other strategies. If antibodies to the PDGFR play a role in the pathogenesis of scleroderma, imatinib might be a promising therapeutic option for this challenging disease.
Ester Lozano, Ph.D.
Marta Segarra, Ph.D.
Maria C. Cid, M.D.
Institut d'Investigacions Biomèdiques August Pi i Sunyer
08036 Barcelona, Spain
mccid@clinic.ub.es
References
Tan FK. Autoantibodies against PDGF receptor in scleroderma. N Engl J Med 2006;354:2709-2711.
Druker BJ, Tamura S, Buchdunger E, et al. Effects of selective inhibitor of the Abl tyrosine kinase in the growth of Bcr/Abl positive cells. Nat Med 1996;2:561-566.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-4349.
Baselga J. Targeting tyrosine kinases in cancer: the second wave. Science 2006;312:1175-1178.
The authors reply: Lozano and colleagues speculate that blocking PDGFR activation with imatinib mesylate, a tyrosine kinase inhibitor, might be therapeutically rewarding in scleroderma. However, autoantibodies against PDGFR represent only one side of the molecular picture in this disease. Our data suggest that the phenotype of fibroblasts from patients with scleroderma is maintained by a self-perpetuating loop that links the H-Ras gene activation of the extracellular signal-regulated kinases 1 and 2 (Ha-Ras-ERK1/2) to the reactive oxygen species (ROS). Each one of these molecules can induce the next. The inhibition of the PDGFR in the presence of excess ROS does not completely inhibit the system, at least during short periods of treatment.1 This lack of inhibition might prevent a therapeutic benefit if the PDGFR signaling alone is blocked. ROS generated in vivo in fibroblasts from patients with scleroderma freely diffuse and activate the Ha-Ras-ERK1/2–ROS cycle in adjacent fibroblasts and epithelia, irrespective of PDGFR activation.1 Thus, fibrosis in scleroderma can be perpetuated and progress, even without considerable PDGFR activation.
An understanding of the signaling cascade triggered by autoantibodies against PDGFR provides the means and tools to target the components of the loop (Ras, ROS, and PDGFR). For example, Ha-Ras is very sensitive to farnesyl transferase inhibitors or statins,2 antioxidants may reduce ROS, and anti-CD20 may down-regulate B cells. Since each of these various elements may play a dominant role among patients, we think that integrated combination protocols are more likely to succeed.
Okamoto correctly notes that PDGF has been implicated in the endothelial-cell dysfunction that characterizes PAH. Do positive antibodies to the PDGFR play a role in PAH? The PDGFR has not been present in all endothelial cells tested; in our study, not all patients with scleroderma had PAH, although serum from these patients expressed stimulatory autoantibodies to PDGFR.
Agonistic antibodies may work in smooth-muscle cells. These cells are responsive to PDGF and other cytokines, and under special conditions they might contract and proliferate. We think that the lung would be a good place to search for agonistic cytokines that stimulate smooth-muscle cells.
Armando Gabrielli, M.D.
Silvia Svegliati Baroni, Ph.D.
Università Politecnica delle Marche
60020 Ancona, Italy
a.gabrielli@univpm.it
Enrico V. Avvedimento, M.D., Ph.D.
Università Federico II
80131 Naples, Italy
References
Svegliati S, Cancello R, Sambo P, et al. Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK 1/2: amplification of ROS and Ras in systemic sclerosis fibroblasts. J Biol Chem 2005;280:36474-36482.
Sabbatini M, Santillo M, Pisani A, et al. Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury. Am J Physiol Renal Physiol 2006;290:F1408-F1415.
The editorialist replies: I thank Lozano and colleagues for their comments. Many agents have been tested for the treatment for scleroderma, and clinical trials in scleroderma have unique obstacles.1 However, the first positive placebo-controlled trial (for cyclophosphamide) reported by Tashkin et al. in the same issue of the Journal demonstrated that these obstacles are not insurmountable.2 The promise of the results reported by Baroni et al. is the potential for therapies aimed at specific targets in the disease pathway leading to scleroderma. If antibody-mediated PDGFR activation is indeed a key to the pathogenesis of scleroderma, then treatments aimed at inhibiting the production of PDGFR-stimulating autoantibodies by B-cell depletion (e.g., with rituximab or other means) could be used to attenuate the extracellular signal that promotes fibrosis. As stated by Lozano and colleagues, intracellular PDGFR signaling could be antagonized by imatinib mesylate. In this case, the bioassay developed by Baroni and colleagues will facilitate the high-throughput screening in vitro of a variety of promising, therapeutic small molecules for new studies in vivo.
Filemon K. Tan, M.D., Ph.D.
University of Texas Medical School at Houston
Houston, TX 77030
References
Seibold JR, Furst DE, Clements PJ. Why everything (or nothing) seems to work in the treatment of scleroderma. J Rheumatol 1992;19:673-676.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666.