• 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).

Referencia del proyecto: INsTRuCT 860003

Título: Innovative Training Network in Myeloid Cell Therapy

Investigador principal: 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€)

Referencia del proyecto: PID2019-110015RB-I00

Título: Inmunidad Entrenada En Trasplante De Órganos

Investigador principal: Jordi Cano Ochando

Entidad financiadora: Ministerio de Ciencia e Innovación

Duración: DEL 01/01/2020 AL 21/12/2023

Financiación recibida (en euros): 205.400,00€

Referencia del proyecto: ID:101037867

Título: VACCELERATE-European Corona Vaccine Trial

Investigador principal: Jordi Cano Ochando

Entidad financiadora: Union Europea H2020

Duración: DEL 28/01/2021 AL 27/01/2024

Financiación recibida (en euros): Overall (983.043,75€) for ISCIII (477.128.84€)

Referencia del proyecto: ID: 101119855

Título: Innovative Applications of Extracorporeal Photopheresis in Solid Organ Transplantation

Investigador principal: Jordi Cano Ochando

Entidad financiadora: Union Europea (HORIZON-MSCA-2022-DN-01)

Duración: DEL 01/09/2023 AL 31/08/2027

Financiación recibida (en euros): 251.971,20€)

Referencia del proyecto: ID: PI23CIII00057

Título: Reprogramación in vivo de células mieloides como nueva nanoimmunoterapia contra el cáncer y trasplante de órganos

Investigador principal: Jordi Cano Ochando

Entidad financiadora: Instituto de Salud Carlos III

Duración: 01/01/2024 – 31/12/2026

Financiación recibida (en euros): 172,000€.

1. Ochando J, Mulder WJM, Madsen JC, Netea MG, Duivenvoorden R. Trained immunity - basic concepts and contributions to immunopathology. Nat Rev Nephrol. 2023 Jan;19(1):23-37. doi: 10.1038/s41581-022-00633-5. Epub 2022 Oct 17. PMID: 36253509

2. Schwarz M, Torre D, Lozano-Ojalvo D, Tan AT, Tabaglio T, Mzoughi S, Sanchez-Tarjuelo R, Le Bert N, Lim JME, Hatem S, Tuballes K, Camara C, Lopez-Granados E, Paz-Artal E, Correa-Rocha R, Ortiz A, Lopez-Hoyos M, Portoles J, Cervera I, Gonzalez-Perez M, Bodega-Mayor I, Conde P, Oteo-Iglesias J, Borobia AM, Carcas AJ, Frías J, Belda-Iniesta C, Ho JSY, Nunez K, Hekmaty S, Mohammed K, Marsiglia WM, Carreño JM, Dar AC, Berin C, Nicoletti G, Della Noce I, Colombo L, Lapucci C, Santoro G, Ferrari M, Nie K, Patel M, Barcessat V, Gnjatic S, Harris J, Sebra R, Merad M, Krammer F, Kim-Schulze S, Marazzi I, Bertoletti A, Ochando J, Guccione E. Rapid, scalable assessment of SARS-CoV-2 cellular immunity by whole-blood PCR. Nat Biotechnol. 2022. PMID: 35697804.

3. Gonzalez-Perez M, Montes-Casado M, Conde P, Cervera I, Baranda J, Berges-Buxeda MJ, Perez-Olmeda M, Sanchez-Tarjuelo R, Utrero-Rico A, Lozano-Ojalvo D, Torre D, Schwarz M, Guccione E, Camara C, Llópez-Carratalá MR, Gonzalez-Parra E, Portoles P, Ortiz A, Portoles J, Ochando J. Development of Potent Cellular and Humoral Immune Responses in Long-Term Hemodialysis Patients After 1273-mRNA SARS-CoV-2 Vaccination. Front Immunol 2022. PMID: 35401504.

4. Lozano-Ojalvo D, Camara C, Lopez-Granados E, Nozal P, Del Pino-Molina L, Bravo-Gallego LY, Paz-Artal E, Pion M, Correa-Rocha R, Ortiz A, Lopez-Hoyos M, Iribarren ME, Portoles J, Rojo-Portoles MP, Ojeda G, Cervera I, Gonzalez-Perez M, Bodega-Mayor I, Montes-Casado M, Portoles P, Perez-Olmeda M, Oteo J, Sanchez-Tarjuelo R, Pothula V, Schwarz M, Brahmachary M, Tan AT, Le Bert N, Berin C, Bertoletti A, Guccione E, Ochando J. Differential effects of the second SARS-CoV-2 mRNA vaccine dose on T cell immunity in naive and COVID-19 recovered individuals. Cell Reports. 2021. PMID: 34390647.
5. Borobia AM, Carcas AJ, Pérez-Olmeda M, Castaño L, Bertran MJ, García-Pérez J, Campins M, Portolés A, González-Pérez M, García Morales MT, Arana-Arri E, Aldea M, Díez-Fuertes F, Fuentes I, Ascaso A, Lora D, Imaz-Ayo N, Barón-Mira LE, Agustí A, Pérez-Ingidua C, Gómez de la Cámara A, Arribas JR, Ochando J, Alcamí J, Belda-Iniesta C, Frías J; CombiVacS Study Group. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet 2021. PMID: 34181880.

6. van Leent MMT, Meerwaldt AE, Berchouchi A, Toner YC, Burnett ME, Klein ED, Verschuur AVD, Nauta SA, Munitz J, Prévot G, van Leeuwen EM, Ordikhani F, Mourits VP, Calcagno C, Robson PM, Soultanidis G, Reiner T, Joosten RRM, Friedrich H, Madsen JC, Kluza E, van der Meel R, Joosten LAB, Netea MG, Ochando J, Fayad ZA, Pérez-Medina C, Mulder WJM, Teunissen AJP. A modular approach toward producing nanotherapeutics targeting the innate immune system. Sci Adv. 2021 Mar 5;7(10):eabe7853. doi: 10.1126/sciadv.abe7853. Print 2021 Mar. PMID: 33674313.

7. Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, Duivenwoorden R, Fanucchi S, Fayad Z, Fuchs E, Hamon M, Jeffrey KL, Khan N, Joosten LAB, Kaufmann E, Latz E, Matarese G, van der Meer JWM, Mhlanga M, Moorlag SJCFM, Mulder WJM, Naik S, Novakovic B, O'Neill L, Ochando J, Ozato K, Riksen NP, Sauerwein R, Sherwood ER, Schlitzer A, Schultze JL, Sieweke MH, Benn CS, Stunnenberg H, Sun J, van de Veerdonk FL, Weis S, Williams DL, Xavier R, Netea MG. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2021. PMID: 33293712.

8. Priem B, van Leent MMT, Teunissen AJP, Sofias AM, Mourits VP, Willemsen L, Klein ED, Oosterwijk RS, Meerwaldt AE, Munitz J, Prévot G, Vera Verschuur A, Nauta SA, van Leeuwen EM, Fisher EL, de Jong KAM, Zhao Y, Toner YC, Soultanidis G, Calcagno C, Bomans PHH, Friedrich H, Sommerdijk N, Reiner T, Duivenvoorden R, Zupančič E, Di Martino JS, Kluza E, Rashidian M, Ploegh HL, Dijkhuizen RM, Hak S, Pérez-Medina C, Bravo-Cordero JJ, de Winther MPJ, Joosten LAB, van Elsas A, Fayad ZA, Rialdi A, Torre D, Guccione E, Ochando J, Netea MG, Griffioen AW, Mulder WJM. Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition. 2020. PMID: 33125893.

9. Ochando J, Fayad ZA, Madsen JC, Netea MG, Mulder WJM. Trained Immunity in Organ Transplantation. Am J Transplant. 2020. PMID:31561273.

10. Mulder WJM, Ochando J, Joosten LAB, Fayad ZA, Netea MG. Therapeutic targeting of trained immunity. Nat Rev Drug Discov. 2019. PMID: 30967658.

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.