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Article ; Online: Long-term adaptive response in COVID-19 vaccine recipients and the effect of a booster dose.

Perico, Luca / Todeschini, Marta / Casiraghi, Federica / Mister, Marilena / Pezzotta, Anna / Peracchi, Tobia / Tomasoni, Susanna / Trionfini, Piera / Benigni, Ariela / Remuzzi, Giuseppe

Frontiers in immunology

2023 Volume 14, Page(s) 1123158

Abstract: We examined the immune response in subjects previously infected with SARS-CoV2 and infection-naïve 9 months after primary 2-dose COVID-19 mRNA vaccination and 3 months after the booster dose in a longitudinal cohort of healthcare workers. Nine months ... ...

Abstract	We examined the immune response in subjects previously infected with SARS-CoV2 and infection-naïve 9 months after primary 2-dose COVID-19 mRNA vaccination and 3 months after the booster dose in a longitudinal cohort of healthcare workers. Nine months after primary vaccination, previously infected subjects exhibited higher residual antibody levels, with significant neutralizing activity against distinct variants compared to infection-naïve subjects. The higher humoral response was associated with higher levels of receptor binding domain (RBD)-specific IgG
MeSH term(s)	Humans ; COVID-19 Vaccines ; COVID-19/prevention & control ; RNA, Viral ; SARS-CoV-2 ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; RNA, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-02-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1123158
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Article ; Online: Bi-specific autoantigen-T cell engagers as targeted immunotherapy for autoreactive B cell depletion in autoimmune diseases.

Perico, Luca / Casiraghi, Federica / Sônego, Fabiane / Todeschini, Marta / Corna, Daniela / Cerullo, Domenico / Pezzotta, Anna / Isnard-Petit, Patricia / Faravelli, Silvia / Forneris, Federico / Thiam, Kader / Benigni, Ariela / Remuzzi, Giuseppe

Frontiers in immunology

2024 Volume 15, Page(s) 1335998

Abstract: Introduction: In autoimmune diseases, autoreactive B cells comprise only the 0.1-0.5% of total circulating B cells. However, current first-line treatments rely on non-specific and general suppression of the immune system, exposing patients to severe ... ...

Abstract	Introduction: In autoimmune diseases, autoreactive B cells comprise only the 0.1-0.5% of total circulating B cells. However, current first-line treatments rely on non-specific and general suppression of the immune system, exposing patients to severe side effects. For this reason, identification of targeted therapies for autoimmune diseases is an unmet clinical need. Methods: Here, we designed a novel class of immunotherapeutic molecules, Bi-specific AutoAntigen-T cell Engagers (BiAATEs), as a potential approach for targeting the small subset of autoreactive B cells. To test this approach, we focused on a prototype autoimmune disease of the kidney, membranous nephropathy (MN), in which phospholipase A Results: BiAATE creates an immunological synapse between autoreactive B cells bearing an CysR-specific surface Ig Discussion: Should this approach be confirmed for other autoimmune diseases, BiAATEs could represent a promising off-the-shelf therapy for precision medicine in virtually all antibody-mediated autoimmune diseases for which the pathogenic autoantigen is known, leading to a paradigm shift in the treatment of these diseases.
MeSH term(s)	Humans ; Animals ; Mice ; Autoantigens ; T-Lymphocytes ; Glomerulonephritis, Membranous ; Antibodies ; Immunotherapy ; Polyesters
Chemical Substances	Autoantigens ; Antibodies ; Polyesters
Language	English
Publishing date	2024-02-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1335998
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Article ; Online: Hypoimmunogenic Human Pluripotent Stem Cells as a Powerful Tool for Liver Regenerative Medicine.

Trionfini, Piera / Romano, Elena / Varinelli, Marco / Longaretti, Lorena / Rizzo, Paola / Giampietro, Roberta / Caroli, Annalina / Aiello, Sistiana / Todeschini, Marta / Casiraghi, Federica / Remuzzi, Giuseppe / Benigni, Ariela / Tomasoni, Susanna

International journal of molecular sciences

2023 Volume 24, Issue 14

Abstract: Induced pluripotent stem cells (iPSC) have huge potential as cell therapy for various diseases, given their potential for unlimited self-renewal and capability to differentiate into a wide range of cell types. Although autologous iPSCs represents the ... ...

Abstract	Induced pluripotent stem cells (iPSC) have huge potential as cell therapy for various diseases, given their potential for unlimited self-renewal and capability to differentiate into a wide range of cell types. Although autologous iPSCs represents the ideal source for patient-tailored regenerative medicine, the high costs of the extensive and time-consuming production process and the impracticability for treating acute conditions hinder their use for broad applications. An allogeneic iPSC-based strategy may overcome these issues, but it carries the risk of triggering an immune response. So far, several approaches based on genome-editing techniques to silence human leukocyte antigen class I (HLA-I) or II (HLA-II) expression have been explored to overcome the immune rejection of allogeneic iPSCs. In this study, we employed the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) system to delete the β2-Microglobulin (
MeSH term(s)	Humans ; Regenerative Medicine ; Pluripotent Stem Cells ; Gene Editing/methods ; Induced Pluripotent Stem Cells ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/metabolism ; Liver
Chemical Substances	Histocompatibility Antigens Class I
Language	English
Publishing date	2023-07-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241411810
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Article ; Online: Immunophenotypic Alterations in Adult Patients with Steroid-Dependent and Frequently Relapsing Nephrotic Syndrome.

Casiraghi, Federica / Todeschini, Marta / Podestà, Manuel Alfredo / Mister, Marilena / Ruggiero, Barbara / Trillini, Matias / Carrara, Camillo / Diadei, Olimpia / Villa, Alessandro / Benigni, Ariela / Remuzzi, Giuseppe

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for ... ...

Abstract	Immune dysregulation plays a key role in the pathogenesis of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS). However, in contrast with evidence from the pediatric series, no major B- or T-cell alterations have been described for adults. In these patients, treatment with rituximab allows safe discontinuation of steroids, but long-term efficacy is variable, and some patients experience NS relapses after B cell reconstitution. In this study, we aimed to determine disease-associated changes in the B and T cell phenotype of adult patients with SDND/FRNS after steroid-induced remission. We also investigated whether any of these changes in immune cell subsets could discriminate between patients who developed NS relapses after steroid-sparing treatment with rituximab from those who did not. Lymphocyte subsets in SDNS/FRNS patients (
MeSH term(s)	Humans ; Rituximab/therapeutic use ; Nephrotic Syndrome/drug therapy ; Nephrotic Syndrome/chemically induced ; Steroids/therapeutic use ; Immunophenotyping ; Recurrence ; Immunosuppressive Agents/adverse effects
Chemical Substances	Rituximab (4F4X42SYQ6) ; Steroids ; Immunosuppressive Agents
Language	English
Publishing date	2023-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24097687
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Article ; Online: A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome.

Vivarelli, Marina / Colucci, Manuela / Algeri, Mattia / Zotta, Federica / Emma, Francesco / L'Erario, Ines / Busutti, Marco / Rota, Stefano / Capelli, Chiara / Introna, Martino / Todeschini, Marta / Casiraghi, Federica / Perna, Annalisa / Peracchi, Tobia / De Salvo, Andrea / Rubis, Nadia / Locatelli, Franco / Remuzzi, Giuseppe / Ruggenenti, Piero

JCI insight

2023 Volume 8, Issue 18

Abstract: BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be ... ...

Abstract	BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.
MeSH term(s)	Child ; Young Adult ; Humans ; Nephrotic Syndrome/therapy ; Mesenchymal Stem Cells ; Glucocorticoids/therapeutic use ; Immunosuppression Therapy ; Recurrence
Chemical Substances	Glucocorticoids
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.169424
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Article ; Online: Assessment of anti-donor T cell proliferation and cytotoxic T lymphocyte-mediated lympholysis in living donor kidney transplant patients.

Rakha, Aruna / Todeschini, Marta / Casiraghi, Federica

Methods in molecular biology (Clifton, N.J.)

2014 Volume 1213, Page(s) 355–364

Abstract: Organ transplant recipients are at risk of allograft rejection, and remain dependent on lifelong immunosuppressive agents, with the attendant risks of infections, cancers, and drug toxicities. Mesenchymal stromal cells (MSCs) have emerged as an ... ...

Abstract	Organ transplant recipients are at risk of allograft rejection, and remain dependent on lifelong immunosuppressive agents, with the attendant risks of infections, cancers, and drug toxicities. Mesenchymal stromal cells (MSCs) have emerged as an alternative to the current pharmacologic immunosuppressive therapy as these cells are immune privileged and possess immunomodulatory properties. However, clinical data are incomplete regarding the efficacy of MSC therapy to control alloimmune response of the transplant recipients. Coordinated efforts should now be directed towards assays for monitoring anti-donor T cell response of MSC-treated patients to establish the pro-tolerogenic potential of MSC-based therapy. Here, we describe two useful tools to monitor MSC-mediated immunomodulation: the assessment of T cell proliferation by carboxyfluorescein succinimidyl ester (CFSE) dilution assay and the evaluation of cytotoxic T lymphocyte (CTL)-mediated lysis of (51)Cr-labeled target cells (cell-mediated lympholysis; CML) following mixed lymphocyte cultures of peripheral blood mononuclear cells (PBMCs) from kidney donors and transplant recipients.
MeSH term(s)	Cytotoxicity, Immunologic ; Flow Cytometry ; Graft Rejection/immunology ; Humans ; Kidney Transplantation ; Lymphocyte Activation/immunology ; Lymphocyte Culture Test, Mixed ; Male ; T-Lymphocytes, Cytotoxic/immunology
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-1453-1_29
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Article ; Online: Amnion epithelial cells are an effective source of factor H and prevent kidney complement deposition in factor H-deficient mice.

Casiraghi, Federica / Ordonez, Pamela Yossenaidy Rodriguez / Azzollini, Nadia / Todeschini, Marta / Rottoli, Daniela / Donadelli, Roberta / Gramignoli, Roberto / Benigni, Ariela / Noris, Marina / Remuzzi, Giuseppe

Stem cell research & therapy

2021 Volume 12, Issue 1, Page(s) 332

Abstract: Complement factor H (FH) is the main plasma regulator of the alternative pathway of complement. Genetic and acquired abnormalities in FH cause uncontrolled complement activation amplifying, with the consequent accumulation of complement components on the ...

Abstract	Complement factor H (FH) is the main plasma regulator of the alternative pathway of complement. Genetic and acquired abnormalities in FH cause uncontrolled complement activation amplifying, with the consequent accumulation of complement components on the renal glomeruli. This leads to conditions such as C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS). There is no effective therapy for these diseases. Half of the patients progress to end-stage renal disease and the condition recurs frequently in transplanted kidneys. Combined liver/kidney transplantation is a valid option for these patients, but the risks of the procedure and donor organ shortages hamper its clinical application. Therefore, there is an urgent need for alternative strategies for providing a normal FH supply. Human amnion epithelial cells (hAEC) have stem cell characteristics, including the capability to differentiate into hepatocyte-like cells in vivo.Here, we administered hAEC into the livers of newborn Cfh
MeSH term(s)	Amnion ; Animals ; Complement C3/genetics ; Complement Factor H/genetics ; Epithelial Cells ; Humans ; Kidney ; Mice
Chemical Substances	Complement C3 ; Complement Factor H (80295-65-4)
Language	English
Publishing date	2021-06-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-021-02386-7
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Article ; Online: CRISPR-Cas9-Mediated Correction of the G189R-PAX2 Mutation in Induced Pluripotent Stem Cells from a Patient with Focal Segmental Glomerulosclerosis.

Trionfini, Piera / Ciampi, Osele / Todeschini, Marta / Ascanelli, Camilla / Longaretti, Lorena / Perico, Luca / Remuzzi, Giuseppe / Benigni, Ariela / Tomasoni, Susanna

The CRISPR journal

2019 Volume 2, Page(s) 108–120

Abstract: Focal segmental glomerulosclerosis (FSGS) is defined by focal (involving few glomeruli) and segmental sclerosis of the glomerular tuft that manifests with nephrotic syndrome. Mutations in genes involved in the maintenance of structure and function of ... ...

Abstract	Focal segmental glomerulosclerosis (FSGS) is defined by focal (involving few glomeruli) and segmental sclerosis of the glomerular tuft that manifests with nephrotic syndrome. Mutations in genes involved in the maintenance of structure and function of podocytes have been found in a minority of these patients. A family with adult-onset autosomal dominant FSGS was recently found to carry a new germline missense heterozygous mutation (p.G189R) in the octapeptide domain of the transcription factor PAX2. Here, we efficiently corrected this point mutation in patient-derived induced pluripotent stem cells (iPSCs) by means of CRISPR-Cas9-based homology-directed repair. The iPSC lines were differentiated into podocytes, which were tested for their motility. Editing the PAX2 p.G189R mutation restored podocyte motility, which was altered in podocytes derived from patient iPSCs.
MeSH term(s)	Adult ; CRISPR-Associated Protein 9/genetics ; CRISPR-Cas Systems/genetics ; Cell Differentiation ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Genetic Engineering/methods ; Germ-Line Mutation/genetics ; Glomerulosclerosis, Focal Segmental/genetics ; Glomerulosclerosis, Focal Segmental/metabolism ; Glomerulosclerosis, Focal Segmental/therapy ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/physiology ; Kidney Glomerulus/metabolism ; Mutation/genetics ; PAX2 Transcription Factor/analysis ; PAX2 Transcription Factor/genetics ; Podocytes/chemistry ; Podocytes/metabolism ; Podocytes/physiology ; Polymorphism, Single Nucleotide/genetics
Chemical Substances	PAX2 Transcription Factor ; PAX2 protein, human ; CRISPR-Associated Protein 9 (EC 3.1.-)
Language	English
Publishing date	2019-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2573-1602
ISSN (online)	2573-1602
DOI	10.1089/crispr.2018.0048
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Article: Molecular Studies and an

Piras, Rossella / Iatropoulos, Paraskevas / Bresin, Elena / Todeschini, Marta / Gastoldi, Sara / Valoti, Elisabetta / Alberti, Marta / Mele, Caterina / Galbusera, Miriam / Cuccarolo, Paola / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

Frontiers in medicine

2020 Volume 7, Page(s) 579418

Abstract: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal impairment and is associated with dysregulation of the alternative complement pathway on the microvascular ... ...

Abstract	Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal impairment and is associated with dysregulation of the alternative complement pathway on the microvascular endothelium. Outcomes have improved greatly with pharmacologic complement C5 blockade. Abnormalities in complement genes (
Language	English
Publishing date	2020-11-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2020.579418
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Article ; Online: Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c

Aiello, Sistiana / Podestà, Manuel Alfredo / Rodriguez-Ordonez, Pamela Y / Pezzuto, Francesca / Azzollini, Nadia / Solini, Samantha / Carrara, Camillo / Todeschini, Marta / Casiraghi, Federica / Noris, Marina / Remuzzi, Giuseppe / Benigni, Ariela

Journal of the American Society of Nephrology : JASN

2020 Volume 31, Issue 3, Page(s) 517–531

Abstract: Background: In donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen ... ...

Abstract	Background: In donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells. Methods: We evaluated the phenotype and function of intragraft CD11c Results: Cold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M Conclusions: IL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.
MeSH term(s)	Adaptive Immunity/genetics ; Animals ; Antigen Presentation ; CD11c Antigen/immunology ; CD11c Antigen/metabolism ; Cells, Cultured ; Cold Ischemia/methods ; Disease Models, Animal ; Gene Expression Regulation/genetics ; Kidney Transplantation/adverse effects ; Kidney Transplantation/methods ; Macrophages/immunology ; Macrophages/metabolism ; Male ; Mice ; Receptors, Interleukin-1/genetics ; Receptors, Interleukin-1/immunology ; Reperfusion Injury/genetics ; Reperfusion Injury/prevention & control ; Sensitivity and Specificity ; Signal Transduction/genetics
Chemical Substances	CD11c Antigen ; Receptors, Interleukin-1 ; SIGIRR protein, human
Language	English
Publishing date	2020-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2019080778
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