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Neuroimmuno-Repair
Neuroimmuno-Repair
Principal investigator: Diego Clemente López, PhD.
E-mail: dclemente@sescam.jccm.es
Facebook: www.facebook.com/DrDiegoClemente
Twitter: @DrDiegoClemente
The Group of Neuro Immuno-Repair (GNIR) studies the nervous system - immune system relationship in the context of demyelinating diseases, specifically in multiple sclerosis. Demyelinating lesions of the central nervous system displayed by MS patients show different degrees of histopathological evolution, which in turn is matched by a different capacity for spontaneous remyelination (i.e. neural repair). The transition from the destructive to the repair phase of the disease involves several types of regulatory cells that modulate the immune response, thus allowing oligodendrocyte precursors to remyelinate naked axons. Among the regulatory cells, our group is focused on myeloid-derived suppressor cells (MDSCs) and follows three lines of research:
1. Application of MDSCs as accelerating agents in the transition from tissue destruction to neuro-repair, either directly or after ex vivo pharmacological potentiation of these cells.
2. Use of MDSCs as biomarkers of MS aggressiveness, taking into consideration both the clinical course and the degree of tissue destruction associated with the pathology.
3. Direct neuro-regenerative function of MDSCs through the proliferation, migration, differentiation or survival of oligodendrocyte precursors, or via the preservation of mature myelinating oligodendrocytes.
To study all these processes, our group employs in vitro cell cultures of oligodendrocytes and their precursors, T-lymphocytes and MDSCs (either as individual cultures or co-cultures), as well as ex vivo organotypic cerebellar cultures in which we study spontaneous remyelination after experimental demyelination. We also use the mouse model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Furthermore, we have access to samples from MS patients and control subjects, for in vivo study of the MDSC distribution and function.
Our group collaborates with several national and international groups, being members of the Center for Cooperative Networked Research in Neurodegenerative Diseases (CIBERNED), of the Spanish Multiple Sclerosis Network (REEM) and, previously, of the European platform "nEUROinflammation".
Selected publications
- Del Pilar, C., Garrido-Matilla, L., del Pozo-Filíu, L., Lebrón-Galán, R., Clemente, D., Alonso, J.R., Weruaga, E., Díaz, D. Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration. J Neuroinflammation. 2024, 21:49. doi: doi.org/10.1186/s12974-023-03000-8
- Ortega, M.C.*, Lebrón-Galán, R.*, Machín-Díaz, I., Naughton, M., Pérez-Molina, I., García-Arocha, J., García-Domínguez, J.M., Goicoechea-Briceño, H., Vila-del Sol, V., Quintanero-Casero, V., García-Montero, R., Galán, V., Calahorra, L., Camacho-Toledano, C., Martínez-Ginés, M.L., Fitzgerald, D., Clemente, D. Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis. Acta Neuropathol. 2023, 46(2):263-282. doi: 10.1007/s00401-023-02593-x. *Similar contribution.
- Roncancio-Clavijo, A., Gorostidi-Aicua, M., Alberro, A., Iribarren-López, A., Butler, R., López, R., Iribarren, J.A., Clemente, D., Marimón, J.M., Basterrechea, J., Martínez, B., Prada, A., Otaegui, D. Early biochemical analysis of COVID-19 patients helps severity prediction. PLoS One. 2023, 18(5):e0283469. doi: 10.1371/journal.pone.0283469.
- Camacho-Toledano, C., Machín-Díaz, I., Calahorra, L., Cabañas, M., Otaegui, D., Castillo-Triviño, T., Villar, M.L., Costa-Frossard, L., Comabella, M., Midaglia, L., García-Domínguez, J.M., García-Arocha, J., Ortega, M.C., Clemente, D. Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis. J. Neuroinflammation, 2022, 19(1):277. doi: 10.1186/s12974-022-02635-3.
- Calahorra, L., Camacho-Toledano, C., Serrano-Regal, M.P., Ortega,M.C., Clemente D. Regulatory Cells in Multiple Sclerosis: From Blood to Brain.Biomedicines. 2022, 10(2):335. doi: 10.3390/biomedicines10020335.
- Seillier, C., Hélie, P., Petit, G., Vivien, D., Clemente, D., Le Mauff, B., Docagne, F., Toutirais, O.Roles of the tissue-type plasminogen activator in immune response. Cell Immunol. 2022, 371:104451. doi: 10.1016/j.cellimm.2021.104451.
- del Pilar, C., Lebrón-Galán, R., Pérez-Martín, E., Pérez-Revuelta, L., Ávila-Zarza, C.A., Alonso, J.R., Clemente, D., Weruaga, E.*, Díaz, D.* The selective loss of Purkinje cells induces specific peripheral immune alterations. Front Cell Neurosci. 2021, 15:773696. doi: doi.org/10.3389/fncel.2021.773696. *Similar contribution.
- Rosa, J.M*.,Farré-Alins, V*., Ortega, M.C., Navarrete, M., López-Rodríguez, A.B., Palomino-Antolín, A., Fernández-López, E., Vila-del Sol, V., Decouty, C., Narros-Fernández, P., Clemente, D., Egea, J. TLR4 pathway impairs synap ticnumber and cerebrovascular functions through astrocyte activation following traumatic brain injury. Br J Pharmacol. 2021. 78:3395–3413. doi: 10.1111/bph.15488. (OPEN ACCESS). *Similar contribution.
- Helie, P*., Camacho-Toledano, C*., Lesec, L., Seillier, C., Miralles, A.J., Ortega, M.C., Guérit, S., Lebas, H., bardou, I., Vila-del Sol., V., Vivien, D., Le Mauff, B., Clemente, D.#, Docagne, F. #, Toutirais, O. # Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses. J Neuroinflamm. 2021. 18:52.doi: 10.1186/s12974-021-02102-5. (OPEN ACCESS) *#Similar contribution.
- Melero-Jerez, C., Fernández-Gómez, B., Lebrón-Galán, R., Ortega, M.C., Sánchez de Lara, I., Ojalvo, A.C., Clemente, D.*, de Castro, F.* Myeloid‐derived suppressor cells support remyelination in a murine model of multiple sclerosis by promoting oligodendrocyte precursor cell survival, proliferation, and differentiation. Glia. 2021. 69(4):905-924. doi: 10.1002/glia.23936. (OPEN ACCESS) * Similar contribution of both corresponding authors.
- Melero-Jerez, C., Alonso-Gómez, A., Moñivas, E., Lebrón-Galán, R., Machín-Díaz, I., de Castro, F., Clemente D. The proportion of Myeloid-Derived Suppressor Cells in the spleen is related to the severity of the clinical course and tissue damage extent in a murine model of Multiple Sclerosis.NeurobiolDis. 2020 140:104869. doi: 10.1016/j.nbd.2020.104869.(OPEN ACCESS).
- Calvo-Barreiro, L., Eixarch, H., Ponce-Alonso, M., Castillo, M., Lebrón-Galán, R., Mestre, L., Guaza, C., Clemente, D., del Campo, R., Montalbán, X., Espejo, C. A Commercial Probiotic Induces Tolerogenic and Reduces Pathogenic Responses in Experimental Autoimmune Encephalomyelitis. Cells. 2020. 8:906.doi: 10.3390/cells9040906.(OPEN ACCESS).
- Malhotra, S., Costa, C., Eixarch, H., Keller, C.W., Amman, L.S., Martínez-Banaclocha, H., Migdalia, L., Sarró, E., Machín-Díaz, I., Villar, L.M., Triviño, J.C., Oliver-Martos, B., Navarro-Parladé, L., Calvo-Barreiro, L., Matesanz, F., Vandenbroeck, K., Urcelay, E., Martínez-Ginés,M.L., Tejeda-Velarde, A., Fissolo, N., Castilló, J., Sánchez, A., Robertson, A.A.B., Clemente, D., Prinz, M., Pelegrin, P., Lünemann, J.D., Espejo, C., Montalbán, X., Comabella, M. NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis. Brain. 2020. 24:1414-1430.doi: 10.1093/brain/awaa084.
- Melero-Jerez, C., Suardíaz, M., Lebrón-Galán, R., Marín-Bañasco, C., Oliver-Martos, B., Machín-Díaz, I., Fernández, Ó., de Castro F., and Clemente D. The presence and suppressive activity of myeloid-derived suppressor cells are potentiated after interferon-β treatment in a murine model of multiple sclerosis. Neurobiol Dis 2019. 127: 13-31. https://doi.org/10.1016/j.nbd.2019.02.014 (OPEN ACCESS)
- Mecha M, Feliú A, Machín-Díaz I, Cordero C, Carrillo-Salinas FJ, Mestre L, Hernández-Torres G, Ortega-Gutiérrez S, López-Rodríguez ML, de de Castro F, Clemente D* and Guaza C*. *Corresponding author. 2-AG limits Theiler’s virus induced acute neuroinflammation by modulating microglia and promoting MDSCs. Glia. 2018. 66(7):1447-1463. doi: 10.1002/glia.23317
- Leonetti , C., Macrez, R., Pruvost, M., Hommet, Y., Bronsard, J., Fournier, A., Perrigault, M., Machín, I., Vivien, D., Clemente. D., De Castro, F., Maubert, E., Docagne, F. Tissue-type plasminogen activator exerts EGF-like chemokinetic effects on oligodendrocytes in white matter (re)myelination. Mol Neurodegener. 2017. 12:20. doi: 10.1186/s13024-017-0160-5.
- Marín-Bañasco, C., Benabdellah, K., Melero-Jerez, C., Oliver, B., Pinto-Medel, M.J. Hurtado-Guerrero, I. de Castro, F.; Clemente, D., Fernández, Ó., Martín, F., Leyva, L., Suardíaz-García, M. Gene Therapy With Mesenchymal Stem Cells Expressing IFNß Ameliorates Neuroinflammation in Experimental Models of Multiple Sclerosis. Br J Pharmacol. 2017. 174:238-253. doi: 10.1111/bph.13674
- Suardíaz, M., Clemente, D., Marin-Bañasco, C., Orpez, T., Guerrero-Hurtado, I., Pavía, P., Pinto-Medel, M.J., de Castro, F., Leyva, L., Fernández, Ó., Oliver, B. Recombinant soluble IFN receptor (sIFNAR2) exhibits intrinsic therapeutic efficacy in a murine model of Multiple Sclerosis. Neuropharmacology. 2016. 110:480-92. doi: 10.1016/j.neuropharm.2016.07.026.
- Khan, M., Schultz, S., Fleming, T., Lebrón-Galán, R., Clemente, D., Nawroth, P., Schwaninger, M. Hyperglycemia in stroke impairs polarization of monocytes/macrophages to a protective anti-inflammatory cell type. J Neurosci. 2016. 36:9313–9325. doi: 10.1523/JNEUROSCI.0473-16.2016
- Macrez R,*, Ortega MC,* Bardou I., Mehra A, Fournier A, Van der Pol SMA, Haelewyn B., Maubert M., Lesept F., Chevilley A., de Castro F, De Vries HE, Vivien D, Clemente D# and Docagne F#. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. Brain. 2016 139:2406-2419. doi: 10.1093/brain/aww172 Editor's choice in issue number 9. *#Misma contribución de estos autores.
- Melero-Jerez C, Ortega MC, Moliné-Velázquez V, Clemente D. Myeloid derived suppressor cells in inflammatory conditions of the central nervous system. Biochim Biophys Acta-Mol Basis Dis. 2016; 3: 368-380. doi: 10.1016/j.bbadis.2015.10.015.
- Moline-Velazquez V, Ortega MC, Vila-del Sol V, Melero-Jerez C, de Castro F, Clemente D. The synthetic retinoid Am80 delays recovery in a model of multiple sclerosis by modulating myeloid-derived suppressor cell fate and viability. Neurobiol Dis. 2014; 67: 149-164. doi: 10.1016/j.nbd.2014.03.017.
- Ortega MC, Cases O, Merchán P, Kozyraki R, Clemente D.* de Castro F*. *These authors equally contributed to this work. Megalin mediates the influence of Sonic Hedgehog on oligodendrocyte precursor cell migration and proliferation during development. Glia. 2012; 60:851–866. doi: 10.1002/glia.22316.
- Clemente D, Ortega MC, Arenzana FJ, de Castro F.FGF-2 and Anosmin-1 are selectively expressed in different types of multiple sclerosis lesions. J. Neurosci. 2011; 31:14899-14909. doi: 10.1523/JNEUROSCI.1158-11.2011.
- Moliné-Velázquez V, Cuervo H, Vila-del Sol V, Ortega MC, Clemente D1*, de Castro F*. *These authors equally contributed to this work. 1Corresponding author. Myeloid-derived suppressor cells limit the inflammation by promoting T lymphocyte apoptosis in the spinal cord of a murine model of multiple sclerosis. “Cover page” seleccionada para el volumen 21. Brain Pathol. 2011; 21: 678-691. doi: 10.1111/j.1750-3639.2011.00495.x.
Patents
Method for predicting the histopathological features of the lesions in a subject with a demyelinating disease of the central nervous system.
INVENTORS: de Castro, F., Clemente, D., Ortega, M.C., y Arenzana, F.J.
INTELECTUAL PROPERTY HOLDER: FUHNPAIIN
SPANISH PATENT Registration Nº:P200930661
INTERNATIONAL PATENT Registration Nº: PCT/ES2010/070584;Countries: EU, CAN, JPN, AUS
Biomarker for the histopathological classification of the lesions in a subject with demyelinating disease of the central nervous system.
INVENTORS: de Castro, F., Clemente, D., Ortega, M.C., y Arenzana, F.J.
INTELECTUAL PROPERTY HOLDER: FUHNPAIIN
SPANISH PATENT Registration Nº: P201030090
INTERNATIONAL PATENT Registration Nº PCT/ES2010/070584; Countries: EU, CAN, JPN, AUS
Personnel
Diego Clemente López: Principal Investigator; Ph.D. in Biology.
María Cristina Ortega Muñoz: Senior postdoctoral researcher; Ph.D. in Biochemistry.
Mari Paz Serrano Regal: Postdoctoral Fellow; Ph.D. in Neurosciences.
Isabel Machín Diaz: Lab Manager; BSc. in Food Technology.
María Cabañas Cotillas: Predoctoral Fellow CIBER; Ms.Sc. in Neurosciences.
Isabel Pidal Ladrón de Guevara: FPU Predoctoral Fellow. Ms.Sc. in Neurosciences.
Inmaculada Alonso García: Laboratory technician.
Cristina Martos Polo: Laboratory technician.
Patricia Mendoza de Mingo: Lab. Technician.
Research lines
- Histopathological analysis of the inflammatory lesion environment produced by multiple sclerosis.
- Screening for molecular and cellular biomarkers of multiple sclerosis severity.
- Study of myeloid-derived suppressor cells as potentiating agents of neuralrepair.
- Identification of new therapeutic targets for neuroprotection in multiple sclerosis and other diseases of the central nervous system.
Ongoing projects
- The role of IMMUnity in tackling PARKinson’s disease through a Translational NETwork (IMMUPARKNET).
P.I.: Dr. Diego Clemente López. Coordinator of the Action: Dr. Cristoforo Comi Fuencisla Matesanz del Barrio
Funded by the European Union. Cost Action CA21117. (600,000 € for the whole project).
2023-2027. Principal Investigator. (Coordinator:).
- Spanish Network of Multiple Sclerosis.
PI.: Dr. Diego Clemente López. Coordinator and P.I. of the Network: Dra. Fuencisla Matesanz del Barrio
Funded by the "Research Networks" program of the Ministry of Science and Innovation. (Reference number: RED2022-134425-T). (19.100 €)
2023-2025.
- Research Group of the Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED).
PI: Dr. Diego Clemente López
Funded by the Carlos III Health Institute. Ministry of Science and Innovation (Reference number: CB22/05/00016). (48.000 €)
Since 2023.
- A new preclinical strategy with extracellular vesicles to treat severe Multiple Sclerosis: new insight into myelin repair.
PIs: Diego Clemente López y María Cristina Ortega Muñoz
Funded by the Education, Culture and Sports Department of the regional Government of Castilla-La Mancha.(Reference: SBPLY/21/180501/000228). (113,147.65 €)
2022-2025.
- Immunoregulation in the severity of multiple sclerosis: predictive value and therapeutic perspectives.
PI: Diego Clemente López
Funded by the Health Research Fund, Instituto de Salud Carlos III (ISCIII), Ministry of Science and Innovation (Reference: PI21/00302). (196,020€)
2022-2024.
- Effect of Evobrutinib on Myeloid-derived suppressor cell activity.
PI: Dr. Diego Clemente López
Research agreement with EMD Serono R&D (308,991 €).
2020-2024.
- Myeloid-derived suppressor cells: endogenous therapeutic target for multiple sclerosis treatment
PI: Diego Clemente López..
Funded by Aciturri Aeronáutica, Fundación Galletas Coral, Embutidos y Jamones España e Hijos and Vesuvius Ibérica. (16,400 €).
2017-2023.
- Analysis of myeloid-derived suppressor cells as biomarkers of multiple sclerosis clinical course and their implication in repair strategies of the myelin sheath.
PI: Diego Clemente López.
Funded by the Multiple Sclerosis Association of Toledo and Multiple Sclerosis Association of Torrijos, Spanish Association Against Multiple Sclerosis (34,198 €)
2018-2023.
Previous grants
- Analysis of the immuno-regulatory component of the peripheral and central immune response as biomarker of disease course severity in multiple Sclerosis.
PI: Diego Clemente López
Funded by the Merck Salud Foundation, in the category of Clinical Research in Multiple Sclerosis. (30,000 €).
2020-2023.
- Research on Neurodegenerative and Demyelinating Neurological Diseases.
PI: Diego Clemente López
Funded by Bristol Myers Squibb. (10,000 €)
2021-2022.
-Myeloid-derived suppressor cells as bioindicators of the severity of the clinical course and response to treatments in multiple sclerosis (PI18/00357).
PI: Diego Clemente López.
Funded by the Health Research Fund, Instituto de Salud Carlos III (ISCIII), Ministry of Science, Innovation and Universities (255,310 €)
2019-2023.
- Spanish Network for Multiple Sclerosis-REEM (thematic program networks for cooperative research- RETICS, ISCIII).(RD16/0015/0019)
PI: Diego Clemente López.
Funded by the Health Research Fund, Instituto de Salud Carlos III (ISCIII), (112,500 €) Ministry of Economy and Competitiveness
2017-2022
- Morpho-functional analysis of myeloid-derived suppressor cells in the central nervous system of patients with progressive forms of multiple sclerosis and their relationship with disease severity and neural repair.
PIs: Diego Clemente López and María Cristina Ortega Muñoz
Funded by a Competitive Call from Esclerosis Múltiple España in collaboration with the Spanish Network for Multiple Sclerosis (25,000 €).
2019-2020.
- Study of monocytic-myeloid-derived suppressor cells in primary pprogressive multiple sclerosi, within the coordinated grant "Study of the pathophysiological mechanisms with an important role in the progressive forms of multiple sclerosis"
PI: Diego Clemente López (coordinator of the consortium: Dra. L.M. Villar).
Funded by Esclerosis Múltiple España though a competitive internal grant application of REEM. (50.000 €; 7.647,06 € to GNIR)
2018-2019.
- Linking TDP-43 pathology and leptin to Amyotrophic Lateral Sclerosis: Implications of metabolic alterations in the pathogenesis and treatment.
PI: Carmen M. Fernández-Martos.
Funded by the Education, Culture and Sports Department of the regional Government of Castilla-La Mancha. (115.500 €)
2018-2020.
- Myeloid-derived suppressor cells as novel biomarkers of the multiple sclerosis: the relation with tissue damage and neuro-repair (PI15/00963).
PI: Diego Clemente López;
Funded by the Health Research Fund, Instituto de Salud Carlos III (ISCIII), Ministry of Economy and Competitiveness (98,615 €)
2016-2018.
- Myeloid-derived suppressor cells and disease aggressiveness: a novel cell therapy to accelerate myelin repair in multiple sclerosis.
PI: Diego Clemente López
Funded by ARSEP Foundation, in the frame of the Special Call for Propossals "Myelin: from lesion to repair). (110.000 €; 50.000 € to GNIR)
2017-2018.