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Clinical Experimental Immunology  

Unit of Clinical and Experimental Immunology

Innate Immunity is the very first line of defense against any invasion of the human body and represents the main research focus of our Unit of Clinical and Experimental Immunology (UCEI). We exploit innate immune responses in human pathologies with a particular focus on viral infections (HIV-1, HCMV, and SARS-CoV-2), hematologic malignances, solid gastro-enteric, brain, gynecological and thymic epithelial tumors, auto-immune and auto-inflammatory diseases and endothelial disorders. Our current research approach is based on translational human immunology with the involvement of both physician and scientists to fill the gaps and build a bridge between these two sides of modern medicine. Our research projects investigate the impact of Natural Killer (NK) cells, gamma delta (gd) T cells, Innate Lymphoid Cells (ILCs), Monocyte/Macrophages and Dendritic Cells (DCs) on the pathogenesis of human diseases. The UCEI has a full expertise in cell and molecular human immunology in association with advanced technologies such as multiparametric flow cytometry and bioinformatics approaches. The UCEI currently collaborates with several universities and research institutes in Italy, Switzerland, France, Spain, Germany Portugal, United Kingdom and Unites States. Our research is funded by Intramural programs of the Humanitas Research Hospital and the University of Milan as well as by competitive grants from Italian Ministry of Health, Fondazione Cariplo, Fondazione Umberto Veronesi, Associazione Italiana per la Ricerca sul Cancro (AIRC) and European Union.

 

The main macro-areas of research of our research interest include:

A) Innate immune-reconstitution in patients with hematologic malignances undergoing haploidentical hemapoietic stem cell transplantation

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a therapeutic option to cure hematologic malignancies. The reconstitution of immune cells is key in determining a positive or negative clinical outcome of HSCT. Hence, a better understanding of the kinetic and quality of the immune-reconstitution following HSCT can predict and therapeutically target opportunistic infections, tumor-relapse, engraftment and the onset/degree of Graft versus Leukemia (GvL) effect as wells as Graft versus Host Diseases (GvHD).  We recently disclosed the kinetic of T, B and NK cell immune-reconstitution after haplo-HSCT. Therefore, we are now exploring different innate cellular populations, including Innate Lymphoid cells (ILCs) and gdT in relation to cytomegalovirus (HCMV) infection/reactivation inhaplo-HSCT. Moreover, we are focusing our intereston phenotypic, functional and molecular characterization of the recently discovered “memory-like” NK cell subset expanded in response to a HCMV reactivation and endowed with adaptive properties.Moreover, the disclosure of this NK cell subset will allow us to optimize/customize the haplo-HSCT procedure, to improve the clearance of residual tumor cells, decreasing graft rejection, GvHD and opportunistic infection onset.

  

B) Characterization of innate cellular subsets in human solid tumors

Innate cellular populations including gd T cells, NK cells, ILCs and Dendritic cells (DCs) display a broad array of anti-tumor and pro-tumor functions by combining their rapid innate cytotoxic response with secretion of immunoregulatory cytokines. In collaboration with different clinical and surgery units in the metropolitan area of Milan, the UCEI runs several translational projects to perform comprehensive and comparative immune characterization of healthy and tumor-associated cells in both tissue and peripheral blood compartments of different human tumors such as colorectal carcinoma (CRC), primary and metastatic liver cancers and gynecological tumors. In particular, we aim to fully analyze phenotypic, functional and transcriptional anti-tumor profiles correlated to the patient-related clinical outcome such as tumor progression, response to treatment and number of metastases in order to develop new therapeutic cellular and molecular targets.

 

C) Role of endothelial dysfunction in the pathogenesis of unprovoked venous thromboembolism and in antiphospholipid syndrome-associated thrombosis

Endothelial colony-forming cells (ECFCs) are bone-marrow-derived cells that play a crucial role in endothelial homeostasis and repair. The characterization of ECFCs isolated and cultured from the peripheral blood represents a non-invasive procedure for the functional assessment of the endothelial compartment. We recently demonstrated that ECFCs obtained from patients with unprovoked venous thromboembolism (uVTE) have impaired proliferative and vasculogenic activity that could be detrimental to the maintenance of endothelial integrity in vivo, and we also demonstrated that pathologic up-regulation of TNFSF15-TNFRSF25 axis may play a causative role in the onset of uVTE. In order to deepen comprehension of differential pathogenetic mechanisms sustaining unprovoked and provoked VTE (pVTE), we are now characterizing ECFCs obtained from both uVTE and pVTE patients to identify the molecular mechanisms involved in endothelial dysfunction (ED) in uVTE patients.
Finally, we recently extended the analysis of ED also to anti-phospholipid syndrome (APS)-associated thrombosis. Thanks to patient specific-ECFC characterization, we aim to: i) assess if ED in APS is only antiphospholipid antibodies-mediated or is also antiphospholipid antibodies-independent; ii) identify the molecular pathway(s) responsible for ED.

 


D) Immune microenvironment in brain and thymic epithelial tumors and flow cytometry

This research line investigates on the immune infiltrate within high-grade glioblastoma and thymoma and thymic carcinoma to fully analyze phenotypic, functional and transcriptional anti-tumor profiles correlated to the patient-related clinical outcome such as tumor progression, response to treatment and number of metastases in order to develop new therapeutic cellular and molecular targets. Prof. Della Bella, has also a great experience and skills in flow cytometry and set up the more advanced methodologies in this field.

 

E) Targeting acute immune responses and aberrant inflammation to improve the clinical outcome of elderly SARS-Cov-2 infected patients

The disease progression in SARS-CoV-2 infected patients can be either asymptomatic or develop life-threatening pneumonia and respiratory insufficiency. While the former appears to resolve spontaneously, the latter require hospitalization and the frequent use of mechanical ventilation in intensive care units. The reasons of this dichotomy are still unknown and must be somewhat linked to the different degrees of immunity response. Therefore, a better understanding of magnitude, specificity and kinetics of anti–SARS-CoV-2 immune response is crucial to the treatment of SARS-CoV-2 infected patients. For these reasons, in our study of translational immunology we aim to disclose the impact of SARS-CoV-2 acute infections and of the related biologic treatments on the homeostasis of those immune cells naturally endowed with the highest antiviral activities: Natural Killer (NK) cells, gd T lymphocytes, Dendritic cells (DCs), and neutrophils. In particular, we will characterize their effector-functions in association with the clinical outcome of SARS-CoV-2 acutely infected patients with different sex, ages and disease progression. In fact, the main focus of our study is to target acute immune responses and aberrant inflammation to improve the clinical outcome of elderly patients as they represent the most fragile cohort of patients showing the highest rates of morbidity and mortality.

 

  

Web sites:   

http://www.biometra.unimi.it/ecm/home
https://www.humanitas-research.org/groups/domenico-mavilio-group/
https://www.unimi.it/en/ugov/person/domenico-mavilio
https://www.unimi.it/en/ugov/person/silvia-dellabella

 

           

Group Members:

Associate professor of Translational Medicine and Principal Investigator
Domenico Mavilio, M.D., Ph.D.

Associate professor of Pathology and Senior Investigator
Silvia Della Bella, M.D., Ph.D.

Senior Investigator
Dr. Joanna Mikulak, Ph.D.
Dr. Clara Di Vito, Ph.D. – Senior Investigator
Dr. Francesca Calcaterra, Ph.D – Senior Investigator

Lab Manager
Lavinia Bertolani

Bioinformatician
Sara Terzoli

PhD Student
Michela Calvi
Assunta Cancellara
Sara Franzese
Valentina Cazzetta
Alessandro Frigo

Graduate research fellow
Simone Balin
Paolo Marzano

Master Degree Student
Martina Defendi
Roberta Ciceri
Anna Carletti

 

If you want to know more, you can contact us at:

domenico.mavilio@unimi.it

silvia.dellabella@unimi.it

 

Selected Publications Domenico Mavilio


A) Publications of the last 3 years (2019-2021) (max 10)

1)Pontarini#, Lucchesi D. #, Fossati-Jimack L., Coleby R., Tentorio P., Croia C., Bombardieri M# and Mavilio D. #* NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation.
J Leukoc Biol. 2019 Mar;105(3):589-602. Impact Factor: 4.012

2)Della Bella S. #*, Calcaterra F.#, Bacci M., Carenza C., Pandolfo C., Ferrazzi P., Uva P., Pagani M., Lodigiani C.# and Mavilio D.#* Pathologic up-regulation of TNFSF15-TNFRSF25 axis sustains endothelial dysfunction in unprovoked venous thromboembolism.
Cardiovascular Research 2020 Mar 1;116(3):698-707. Impact Factor: 7.014

3)Carenza C. #, Calcaterra D#., Oriolo F., Di Vito C., Ubezio M., Della Porta M.G., Mavilio D.#* and Della Bella S.#* Costimulatory molecules and immune checkpoints are differentially expressed on different subsets of dendritic cells.
Frontiers in Immunology 2019 (section of Antigen Presenting Cell Biology) 2019, Jun 11; 10:1325. Impact Factor: 4.716

4)Mikulak J.#, Oriolo F.#, Bruni E., Roberto A., Colombo F.S., Villa A., Bosticardo M., Bortolomai I., Lo Presti E., Meraviglia S., Dieli F., Vetrano S., Danese S., Della Bella S., Carvello M.M., Sacchi M., Cugini G., Colombo G., Klinger M., Spaggiari P., Roncalli M., Prinz I., Ravens S., Di Lorenzo B., Marcenaro E., Silva-Santos B., Spinelli A. and Mavilio D.* NKp46-expressing human gut-resident intraepithelial V1 T cell subpopulation exhibits high anti-tumor activity against colorectal cancer
JCI Insight 2019 Dec 19;4(24). Impact Factor: 6.205

5)Bruni E., Cazzetta V., Donadon M., Cimino M., Torzilli G., Spata G., Leonardi G., Dieli F., Mikulak J.* # and Mavilio D.* # Chemotherapy accelerates immune-senescence and functional impairments of circulating Vd2pos T cells in elderly patients affected by liver metastatic colorectal cancer.
Journal for ImmunoTherapy of Cancer, 2019 Dec 11;7(1):347. Impact Factor: 10.252

6)Mikulak J., Di Vito C., Mavilio D.* HIV-1-induced inflammation shapes innate immunity and induces adaptive traits for NK cells.
Nature Immunology 2020 Mar;21(3):245-247. Impact Factor: 25.606

7)Mariotti J., Raiola A.M., Evangelista A., Carella A.M., Martino M., Patriarca F., Risitano A., Bramanti S., Busca A., Giaccone L., Brunello L.., Merla E., Savino L., Lotetra B., Console G., Fanin R., Sperotto A., Marano L., Marotta S., Frieri C., Sica S., Chiusolo P., Harbi S., Furst S., Santoro A., Bacigalupo A., Blaise B., Angelucci E., Mavilio D.#, Castagna L.#* and Bruno B.# Impact of Donor Age and Kinship on Clinical Outcomes after T Cell-replete Haploidentical Transplantation with Post-transplant Cyclophosphamide.
Blood Advances 2020 4(16): 3900–3912. Impact Factor: 6,686

8)Cazzetta V., Franzese S., Carenza C., Della Bella S., Mikulak and Mavilio D.* Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy.
Cancers. 2021 May 1;13(9):2184. Impact Factor: 6.639

9)Zaghi E., Calvi M., Puccio S., Spata G., Terzoli S., Peano C., Roberto A., De Paoli F., van Beek J., Mariotti J., De Philippis C., Sarina B., Mineri R., Bramanti S., Santoro A., Khanh Le-Trilling V.T., Trilling M, Marcenaro E., Castagna L., Di Vito C.*#, Lugli E. and Mavilio D.*# Single-cell profiling identifies impaired adaptive NK cells expanded after HCMV reactivation in haploidentical-HSCT.
JCI Insight. 2021 May 18:146973. Impact Factor: 8.315

10)Van Beek J.P., Puccio S., Roberto A., De Paoli F., Graziano G., Salviato E., Alvisi G., Zanon V., Scarpa A., Zaghi E., Calvi M., Di Vito C., Mineri R., Sarina B., De Philippis C., Santoro A., Mariotti J., Bramanti S., Ferrari F., Castagna L., Mavilio D. and  Lugli E. Single-cell profiling reveals the dynamics of cytomegalovirus-specific T cells in haploidentical hematopoietic stem cell transplantation.
Haematologica. 2021 Oct 1;106(10):2768-2773. Impact Factor: 9.941

 

B) Publications of the last 10 years (2011-2021) (max 10)

1)Correia D.V., Fogli M., Hudspeth K.L. Da Silva, M.G., Mavilio D. # and Silva-Santos B. *# Differentiation of human peripheral blood Vδ1+ T-cells expressing the Natural Cytotoxicity Receptor NKp30 for recognition of lymphoid leukemia cells.
Blood 2011 Jul 28;118(4):992-1001. Impact Factor: 9.898

2)Hudspeth K., Fogli M., Correia D.V., Mikulak J., Roberto A., Della Bella S., Silva-Santos B.# and Mavilio D.*# Engagement of NKp30 on Vd1 T-cells induces the production of CCL3, CCL4 and CCL5 and suppresses HIV-1 replication.
Blood, 2012 Apr 26;119(17):4013-6. Impact Factor: 9.06

3)CappellettiM., PresicceP.,CalcaterraF., Mavilio D.#andDellaBellaS.# Bright expression of CD91 identifies highly activated human dendritic cells that can be expanded by defensins.
Immunology.2015Apr;144(4):661-7. Impact Factor: 4.078

4)Roberto A., Castagna L., Gandolfi S., Zanon V., Bramanti S., Sarina B., Crocchiolo R., Todisco E., Carlo-Stella C., Tentorio P., Timofeeva I., Santoro A., Della Bella S., Roederer M., Mavilio D. #* and Lugli E. #* B-cell reconstitution after unmanipulated haploidentical bone marrow transplantation recapitulates B-cell lymphopoiesis.
Bone Marrow Transplantation. 2015 Feb;50(2):317-9. Impact Factor: 3.636

5)Roberto A., Castagna L., Zanon V., Bramanti S., Crocchiolo R., McLaren J.E., Gandolfi S., Tentorio P., Sarina B., Timofeeva I., Santoro A., Carlo-Stella C., Bruno B., Carniti C., Corradini P., Gostick E., Ladell K., Price D.A., Roederer M., Mavilio D. #* and Lugli E#*. Role of naïve-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation.
Blood. 2015 Apr 30;125(18):2855-64. Impact Factor: 11.841

6)HudspethK,DonadonM.,CiminoM.,PontariniE.,TentorioP.,PretiM., HongM., Bertoletti A., Bicciato S., Invernizzi P., Lugli E., Torzilli G., Gershwin M.E.*, Mavilio D.* Human liver-resident CD56bright/CD16neg NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways.
J Autoimmun. 2016 Jan;66:40-50. Impact Factor: 7.760

7)Mikulak J.*, Oriolo F., Portale F., Tentorio P., Lan X., Saleem M.A., Skorecki K., Singhal P.C. and Mavilio D.* Impact of APOL1 polymorphism and IL-1 priming in the entry and persistence of HIV-1 in human podocytes.
Retrovirology, 2016 Sept. 6,13(63). Impact Factor: 3.897

8)Calcaterra F, Brambilla L., Colombo E., Tourlaki A., Veraldi S., Carenza C.,Mavilio D. # and Della Bella S. #*. Increased frequency and vasculogenic potential of endothelial colony-forming cells in patients with Kaposi's sarcoma.
Journal of Investigative Dermatology, (2017) 137(7), 1533-1540. Impact Factor: 6.448

9)Donadon M., Hudspeth K, Cimino M., Di Tommaso L., Preti M., Tentorio P., Roncalli M., Mavilio D.#* and Torzilli G.# Increased infiltration of Natural Killer and T cells in colorectal liver metastases improves patient overall survival.
Journal of Gastrointestinal Surgery 2017J Aug;21(8):1226-1236. Impact Factor: 2.813

10) Roberto A, Di Vito C., Zaghi E., Mazza E.M.C., Capucetti A., Calvi M., Tentorio P., Zanon V., Sarina B., Mariotti J., Bramanti S., Tenedini E., Tagliafico E., Bicciato S., ù Santoro A., Roederer M., Marcenaro E., Castagna L., Lugli E#*. and Mavilio D.#*. The early expansion of anergic NKG2Apos/CD56dim/CD16neg natural killer represents a therapeutic target in haploidentical haematopoietic stem cell transplantation.
Haematologica. 2018 Aug;103(8):1390-1402. Impact Factor: 7.570


* Corresponding Author / # Shared Authorship

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