Neuroimmuno-Repair

Group of Neuro Immuno-Repair (GNIR)

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 various national and international groups and is a member  of the Spanish Network of Multiple Sclerosis and of the European platform "nEUROinflammation".

 

 

Selected publications 

 

- 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 synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury. Br J Pharmacol. 2021. 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. 

 

Leticia Calahorra Melero: Postdoctoral fellow; Ph.D. in Biomedical Investigation.

 

Celia Camacho Toledano: Predoctoral fellow; M.Sc. in Immunology Research. 

 

Isabel Machín Diaz: Lab Manager; BSc. in Food Technology. 

 

Jennifer García Arocha: Laboratory technician.

 

Inmaculada Alonso García: Laboratory 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

 

- Effect of Evobrutinib on Myeloid-derived suppressor cell activity.

P.I. Dr. Diego Clemente López

ResearchAgreementwith Merck (200.000 €).

2020-2022.

 

 

- Analysis of the immuno-regulatory component of the peripheral and central immune response as biomarker of disease course severity in multiple Sclerosis.

IP: Diego Clemente López

Funded by the Merck Salud Foundation, in the category of Clinical Research in Multiple Sclerosis. (30,000 €).

2020-2023.

 

 

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 €)

2019-2021.

 

- 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

2017-2021.

 

- 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.

Funded by a Competitive Call from Esclerosis Múltiple España in collaboration with the the Spanish Network for Multiple Sclerosis (25,000 €).

2019-2020.

 

- 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 €).

2017-2020.

 

- 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 (31,768 €)

2018-2020.

 

 

 

 Previous grants

 

 

-  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.