Grupos de investigación - ENFERMEDADES INFECCIOSAS

Laboratorio de Referencia e Investigación en Inmunología. Unidad de Inmunología del Trasplante de Órganos


Investigador responsable: Jordi Cano Ochando. jochando@isciii.es

Entidad: Instituto de Salud Carlos III. CNM

Investigadores:

  • Isabel Cervera Hernández. CNM. ISCIII
  • Haisul Chang. CNM. ISCIII
  • María González Pérez. Universidad CEU San Pablo
  • Catarina Rodrigues Guerreiro. UCM
  • Myeloid Derived Suppressor Cells (MDSC) in Organ Transplantation. My laboratory was the first to demonstrate that monocyte-derived suppressor cells accumulate in the allograft of transplanted mice and favor the induction of indefinite allograft survival (Garcia MR et al, J Clin Invest 2010). Building upon these published observations, we reported that myeloid derived suppressor cells are also present in human kidney transplant recipients, indicating that findings in experimental transplant models have clinical implications (Luan Y et al, Am J Transplant 2010). More recently, we reviewed the critical role of MDSC from an historical point of view (Ochando J et al, Curr Transplant Rep 2015) and their potential implications in the clinic (Ochando J et al, Front Immunol 2019).
  • Regulatory Macrophages (Mreg) in Organ Transplantation. Using different genetic approaches my laboratory demonstrated that graft-infiltrating macrophages expressing the C-type lectin receptor DC-SIGN+ are responsible for the induction of transplantation tolerance (Conde P et al, Immunity 2015). These regulatory macrophages (Mreg) inhibit CD8 T cell immunity and promote Foxp3+ Treg cell expansion though CSF1-dependent mechanisms (Braza MS et al, Am J Transplant 2017). Based on the complexity of the multidimensional concept of macrophage ontogeny, activation and function, we reviewed technical advances facilitate a new roadmap for the isolation and analysis of macrophages to study their functional role in health and disease (Ginhoux F et al, Nat Immunol 2016)
  • Trained Immunity in Organ Transplantation. Consistent induction of donor-specific tolerance remains a difficult task in clinical organ transplantation, suggesting the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. My laboratory described that trained immunity represents a critical of the immune response that mediates graft loss (Ochando J et al, Am J Transplant 2020). Using an innovative nanotherapeutic approach that targets trained macrophages in vivo we were able prevent trained immunity and prolong allograft survival in transplant recipient mice (Braza MS et al, Immunity 2018). This innovative approach represents a novel therapeutic approach to induce antigen-specific immune tolerance in the clinic (Mulder WJ et al, Nat Rev Drug Discov 2019).
  • B2017/BMD3731. Nanoterapia dirigida a immunidad entrenada para la aceptación de trasplante de órganos. IP: Jordi Cano Ochando. Entidad financiadora: Comunidad de Madrid. Duración: DEL 01/01/2018 AL 31/12/2021. Financiación recibida (en euros): 716.525,75€.
  • INsTRuCT 860003. Innovative Training Network in Myeloid Cell Therapy. IP: James Hutchinson. Entidad financiadora: European Commission. Duración: DEL 01/01/20120 AL 31/12/2024. Financiación recibida (en euros): Overall (4.021,026.84€) for ISCIII (250.904.88€).
  • PID2019-110015RB-I00. Inmunidad Entrenada En Trasplante De Órganos. IP: Jordi Cano Ochando. Entidad financiadora: Ministerio de Ciencia e Innovación. Duración: DEL 01/01/2020 AL 21/12/2023. Financiación recibida (en euros): 205.700,00€.
  • Ochando J, Fayad ZA, Madsen JC, Netea MG, Mulder WJM. Trained Immunity in Organ Transplantation. Am J Transplant. 2020 Jan;20(1):10-18. PMID:31561273. IF: 7.338 / Transplantation / D1.
  • Mulder WJM, Ochando J, Joosten LAB, Fayad ZA, Netea MG. Therapeutic targeting of trained immunity. Nat Rev Drug Discov. 2019. 18(7):553-566. PMID: 30967658. IF: 64,797 / Pharmacology & Pharmacy / D1.
  • Ochando J, Ordikhani F, Boros P, Jordan S. The innate immune response to allotransplants: mechanisms and therapeutic potentials. Cell Mol Immunol. 2019. 16(4):350-356. PMID: 30804476. IF: 8,484 / Immunology / D1.
  • Braza MS, Lameijer M, Sanchez-Gaytan B, Arts R, Pérez-Medina C, Conde P, Brahmachary M, van der Touw W, Fay F, Kluza E, Kossatz S, Stroes E, Kroon J, Dress R, Salem F, Rialdi A, Reiner T, Boros P, van Leent M, Strijkers G, Calcagno C, Ginhoux F, Marazzi I, Lutgens E, Nicolaes G, Weber C, Swirski F, Nahrendorf M, Fisher E, Fayad Z, Duivenvoorden R, Netea M, Mulder WJ, and Ochando J. Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance. Immunity. 2018. 49(5):819-828. PMID:30413362. IF: 7.163 / Transplantation / D1.
  • Lameijer M, Binderup T, van Leent M, Senders M, Fay F. Seijkens T, Kroon J, Stroes E, Kjaer A, Ochando J, Reiner T, Pérez-Medina C, Calcagno C, Fischer E, Zhang B, Temel R, Swirski F, Nahrendorf M, Fayad Z, Lutgens E, Mulder W and Duivenvoorden R. Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates. Nature Biomedical Engineering. 2018. 2(5):279-292. PMID:30936448. IF: 17.135 / Engineering  Biomedical / D1.

My laboratory investigates the origin, development and immune function of regulatory macrophages (Mreg) in the context of organ transplantation. Mreg suppress the immune response and, as negative regulators of the immune response, they represent a novel therapeutic approach for manipulating the immune system towards the induction of transplantation tolerance.

More recently, my laboratory recently discovered that “trained immunity” represents a previously unrecognized pathway that prevents the induction of tolerance. To inhibit the detrimental effects of trained macrophages, we used a novel targeted therapeutic delivery approach using drug-loaded nanobiologics that specifically target macrophages in vivo. Using high-density lipoprotein (HDL) nanoparticles we are now able to specifically deliver small compounds to macrophages to enhance their suppressive effects. This research represents a compelling framework for developing novel targeted therapies that promote modulate the immune response with the concomitant clinical applications in humans.

Among the methods and techniques used in my laboratory we include:

  • Vascularized heart transplantation in mice.
  • Extraction of organs and isolation of cells for later analysis.
  • Growth and differentiation of macrophages.
  • Phenotypic characterization of macrophages by flow cytometry.
  • Isolation and purification of macrophages by FACS.
  • Analysis of gene expression by real-time RT-PCR.
  • Chromatin Immunoprecipitation Assays (ChIP).
  • Protein expression by Western blot and ELISA.
  • Microscopy techniques for the analysis of cellular processes.
  • Use of immune modulatory drugs related to trained immunity.

Our laboratory is fully equipped to carry out experiments regarding organ transplantation and trained immunity. These include microsurgery scopes, flow cytometers, FACS sorters, and all the necessary equipment to perform ChIP-PCR, ELISA, Western Blot and imaging.