Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis
Personalized medicine; Responder and non-responder Medicina personalizada; Respondedor y no respondedor Medicina personalitzada; Contestador i no contestador Background The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to d...
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| creator | Camacho‑Toledano, Celia Machín Díaz, Isabel Calahorra Melero, L Cabañas‑Cotillas, María Otaegui, David Midaglia Fernandez, Luciana Castillo-Trivino, Tamara Comabella Lopez, Manuel |
| description | Personalized medicine; Responder and non-responder
Medicina personalizada; Respondedor y no respondedor
Medicina personalitzada; Contestador i no contestador
Background
The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.
Methods
Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.
Results
Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.
Conclusion
Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of |
| format | Article |
| fullrecord | <record><control><sourceid>csuc_XX2</sourceid><recordid>TN_cdi_csuc_recercat_oai_recercat_cat_11351_8573</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>oai_recercat_cat_11351_8573</sourcerecordid><originalsourceid>FETCH-csuc_recercat_oai_recercat_cat_11351_85733</originalsourceid><addsrcrecordid>eNqdi7EKwkAQRNNYiPoP-wMBQwjai2JpYR_Ou724uJc9dhMhf28Cgr3FMLzHzLqwGyrlJ6pjSBOyUCjDrN4YwMacFc1EwSOzgVOETiTAgyQ5faEaSIThiYAxknd-WjhS3wlTmofUQxp5oMwI5hlVjGxbrKJjw923N8X-cr6frqW30beKHtW7oRVHP1hSVXVTtcfmUNd_XD4a1lH5</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis</title><source>Recercat</source><creator>Camacho‑Toledano, Celia ; Machín Díaz, Isabel ; Calahorra Melero, L ; Cabañas‑Cotillas, María ; Otaegui, David ; Midaglia Fernandez, Luciana ; Castillo-Trivino, Tamara ; Comabella Lopez, Manuel</creator><creatorcontrib>Camacho‑Toledano, Celia ; Machín Díaz, Isabel ; Calahorra Melero, L ; Cabañas‑Cotillas, María ; Otaegui, David ; Midaglia Fernandez, Luciana ; Castillo-Trivino, Tamara ; Comabella Lopez, Manuel</creatorcontrib><description>Personalized medicine; Responder and non-responder
Medicina personalizada; Respondedor y no respondedor
Medicina personalitzada; Contestador i no contestador
Background
The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.
Methods
Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.
Results
Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.
Conclusion
Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.
This work was supported by the Instituto de Salud Carlos III (PI18/00357, RD16-0015/0019, PI21/00302, all co-funded by the European Union), the Fundación Merck Salud (FMS_2020_MS), Esclerosis Múltiple España (REEM-EME-S5 and REEM-EME_2018), ADEMTO, ATORDEM and AELEM. CC-T holds a predoctoral fellowship from the Instituto de Salud Carlos III (FI19/00132, co-funded by the European Union). LC and JG-A were hired under PI18/00357 and RD16/0015/0019, respectively. DC, MCO and IM-D were hired by SESCAM.</description><language>eng</language><publisher>BMC</publisher><subject>ANATOMY ; ANATOMÍA ; Autoimmune Diseases of the Nervous System ; Biological Factors ; biomarcadores ; Biomarkers ; Cells ; CHEMICALS AND DRUGS ; COMPUESTOS QUÍMICOS Y DROGAS ; células ; células mieloides ; células supresoras de origen mieloide ; Demyelinating Autoimmune Diseases, CNS ; DISEASES ; drug therapy ; ENFERMEDADES ; enfermedades autoinmunes desmielinizantes del SNC ; enfermedades autoinmunitarias del sistema nervioso ; enfermedades del sistema nervioso ; Esclerosi múltiple - Tractament ; esclerosis múltiple ; factores biológicos ; farmacoterapia ; Immunosupressió ; Marcadors bioquímics ; Multiple Sclerosis ; Myeloid-Derived Suppressor Cells ; Myeloid Cells ; Nervous System Diseases ; Other subheadings ; Otros calificadores</subject><creationdate>2022-11</creationdate><rights>Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,776,881,26951</link.rule.ids><linktorsrc>$$Uhttps://recercat.cat/handle/11351/8573$$EView_record_in_Consorci_de_Serveis_Universitaris_de_Catalunya_(CSUC)$$FView_record_in_$$GConsorci_de_Serveis_Universitaris_de_Catalunya_(CSUC)$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>Camacho‑Toledano, Celia</creatorcontrib><creatorcontrib>Machín Díaz, Isabel</creatorcontrib><creatorcontrib>Calahorra Melero, L</creatorcontrib><creatorcontrib>Cabañas‑Cotillas, María</creatorcontrib><creatorcontrib>Otaegui, David</creatorcontrib><creatorcontrib>Midaglia Fernandez, Luciana</creatorcontrib><creatorcontrib>Castillo-Trivino, Tamara</creatorcontrib><creatorcontrib>Comabella Lopez, Manuel</creatorcontrib><title>Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis</title><description>Personalized medicine; Responder and non-responder
Medicina personalizada; Respondedor y no respondedor
Medicina personalitzada; Contestador i no contestador
Background
The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.
Methods
Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.
Results
Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.
Conclusion
Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.
This work was supported by the Instituto de Salud Carlos III (PI18/00357, RD16-0015/0019, PI21/00302, all co-funded by the European Union), the Fundación Merck Salud (FMS_2020_MS), Esclerosis Múltiple España (REEM-EME-S5 and REEM-EME_2018), ADEMTO, ATORDEM and AELEM. CC-T holds a predoctoral fellowship from the Instituto de Salud Carlos III (FI19/00132, co-funded by the European Union). LC and JG-A were hired under PI18/00357 and RD16/0015/0019, respectively. DC, MCO and IM-D were hired by SESCAM.</description><subject>ANATOMY</subject><subject>ANATOMÍA</subject><subject>Autoimmune Diseases of the Nervous System</subject><subject>Biological Factors</subject><subject>biomarcadores</subject><subject>Biomarkers</subject><subject>Cells</subject><subject>CHEMICALS AND DRUGS</subject><subject>COMPUESTOS QUÍMICOS Y DROGAS</subject><subject>células</subject><subject>células mieloides</subject><subject>células supresoras de origen mieloide</subject><subject>Demyelinating Autoimmune Diseases, CNS</subject><subject>DISEASES</subject><subject>drug therapy</subject><subject>ENFERMEDADES</subject><subject>enfermedades autoinmunes desmielinizantes del SNC</subject><subject>enfermedades autoinmunitarias del sistema nervioso</subject><subject>enfermedades del sistema nervioso</subject><subject>Esclerosi múltiple - Tractament</subject><subject>esclerosis múltiple</subject><subject>factores biológicos</subject><subject>farmacoterapia</subject><subject>Immunosupressió</subject><subject>Marcadors bioquímics</subject><subject>Multiple Sclerosis</subject><subject>Myeloid-Derived Suppressor Cells</subject><subject>Myeloid Cells</subject><subject>Nervous System Diseases</subject><subject>Other subheadings</subject><subject>Otros calificadores</subject><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>XX2</sourceid><recordid>eNqdi7EKwkAQRNNYiPoP-wMBQwjai2JpYR_Ou724uJc9dhMhf28Cgr3FMLzHzLqwGyrlJ6pjSBOyUCjDrN4YwMacFc1EwSOzgVOETiTAgyQ5faEaSIThiYAxknd-WjhS3wlTmofUQxp5oMwI5hlVjGxbrKJjw923N8X-cr6frqW30beKHtW7oRVHP1hSVXVTtcfmUNd_XD4a1lH5</recordid><startdate>20221119</startdate><enddate>20221119</enddate><creator>Camacho‑Toledano, Celia</creator><creator>Machín Díaz, Isabel</creator><creator>Calahorra Melero, L</creator><creator>Cabañas‑Cotillas, María</creator><creator>Otaegui, David</creator><creator>Midaglia Fernandez, Luciana</creator><creator>Castillo-Trivino, Tamara</creator><creator>Comabella Lopez, Manuel</creator><general>BMC</general><scope>XX2</scope></search><sort><creationdate>20221119</creationdate><title>Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis</title><author>Camacho‑Toledano, Celia ; Machín Díaz, Isabel ; Calahorra Melero, L ; Cabañas‑Cotillas, María ; Otaegui, David ; Midaglia Fernandez, Luciana ; Castillo-Trivino, Tamara ; Comabella Lopez, Manuel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-csuc_recercat_oai_recercat_cat_11351_85733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>ANATOMY</topic><topic>ANATOMÍA</topic><topic>Autoimmune Diseases of the Nervous System</topic><topic>Biological Factors</topic><topic>biomarcadores</topic><topic>Biomarkers</topic><topic>Cells</topic><topic>CHEMICALS AND DRUGS</topic><topic>COMPUESTOS QUÍMICOS Y DROGAS</topic><topic>células</topic><topic>células mieloides</topic><topic>células supresoras de origen mieloide</topic><topic>Demyelinating Autoimmune Diseases, CNS</topic><topic>DISEASES</topic><topic>drug therapy</topic><topic>ENFERMEDADES</topic><topic>enfermedades autoinmunes desmielinizantes del SNC</topic><topic>enfermedades autoinmunitarias del sistema nervioso</topic><topic>enfermedades del sistema nervioso</topic><topic>Esclerosi múltiple - Tractament</topic><topic>esclerosis múltiple</topic><topic>factores biológicos</topic><topic>farmacoterapia</topic><topic>Immunosupressió</topic><topic>Marcadors bioquímics</topic><topic>Multiple Sclerosis</topic><topic>Myeloid-Derived Suppressor Cells</topic><topic>Myeloid Cells</topic><topic>Nervous System Diseases</topic><topic>Other subheadings</topic><topic>Otros calificadores</topic><toplevel>online_resources</toplevel><creatorcontrib>Camacho‑Toledano, Celia</creatorcontrib><creatorcontrib>Machín Díaz, Isabel</creatorcontrib><creatorcontrib>Calahorra Melero, L</creatorcontrib><creatorcontrib>Cabañas‑Cotillas, María</creatorcontrib><creatorcontrib>Otaegui, David</creatorcontrib><creatorcontrib>Midaglia Fernandez, Luciana</creatorcontrib><creatorcontrib>Castillo-Trivino, Tamara</creatorcontrib><creatorcontrib>Comabella Lopez, Manuel</creatorcontrib><collection>Recercat</collection></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Camacho‑Toledano, Celia</au><au>Machín Díaz, Isabel</au><au>Calahorra Melero, L</au><au>Cabañas‑Cotillas, María</au><au>Otaegui, David</au><au>Midaglia Fernandez, Luciana</au><au>Castillo-Trivino, Tamara</au><au>Comabella Lopez, Manuel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis</atitle><date>2022-11-19</date><risdate>2022</risdate><abstract>Personalized medicine; Responder and non-responder
Medicina personalizada; Respondedor y no respondedor
Medicina personalitzada; Contestador i no contestador
Background
The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients.
Methods
Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients’ peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed.
Results
Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment.
Conclusion
Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.
This work was supported by the Instituto de Salud Carlos III (PI18/00357, RD16-0015/0019, PI21/00302, all co-funded by the European Union), the Fundación Merck Salud (FMS_2020_MS), Esclerosis Múltiple España (REEM-EME-S5 and REEM-EME_2018), ADEMTO, ATORDEM and AELEM. CC-T holds a predoctoral fellowship from the Instituto de Salud Carlos III (FI19/00132, co-funded by the European Union). LC and JG-A were hired under PI18/00357 and RD16/0015/0019, respectively. DC, MCO and IM-D were hired by SESCAM.</abstract><pub>BMC</pub><oa>free_for_read</oa></addata></record> |
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| subjects | ANATOMY ANATOMÍA Autoimmune Diseases of the Nervous System Biological Factors biomarcadores Biomarkers Cells CHEMICALS AND DRUGS COMPUESTOS QUÍMICOS Y DROGAS células células mieloides células supresoras de origen mieloide Demyelinating Autoimmune Diseases, CNS DISEASES drug therapy ENFERMEDADES enfermedades autoinmunes desmielinizantes del SNC enfermedades autoinmunitarias del sistema nervioso enfermedades del sistema nervioso Esclerosi múltiple - Tractament esclerosis múltiple factores biológicos farmacoterapia Immunosupressió Marcadors bioquímics Multiple Sclerosis Myeloid-Derived Suppressor Cells Myeloid Cells Nervous System Diseases Other subheadings Otros calificadores |
| title | Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis |
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