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  1. Article ; Online: The Complement System in Kidney Transplantation

    Donata Santarsiero / Sistiana Aiello

    Cells, Vol 12, Iss 791, p

    2023  Volume 791

    Abstract: Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence ... ...

    Abstract Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
    Keywords complement activation ; kidney transplantation ; ischaemia/reperfusion injury ; delayed graft function ; alloresponse ; antibody-mediated rejection ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The Complement System in Kidney Transplantation.

    Santarsiero, Donata / Aiello, Sistiana

    Cells

    2023  Volume 12, Issue 5

    Abstract: Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence ... ...

    Abstract Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
    MeSH term(s) Humans ; Kidney Transplantation/adverse effects ; Graft Rejection ; Complement System Proteins ; Reperfusion Injury/prevention & control ; Ischemia
    Chemical Substances Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2023-03-02
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells12050791
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Tissue-Resident Macrophages in Solid Organ Transplantation: Harmful or Protective?

    Aiello, Sistiana / Benigni, Ariela / Remuzzi, Giuseppe

    Journal of immunology (Baltimore, Md. : 1950)

    2024  Volume 212, Issue 7, Page(s) 1051–1061

    Abstract: Transplanted organs carry donor immune cells into the recipient, the majority of which are tissue-resident macrophages (TRMs). The role they play in guiding the fate of the transplanted organ toward acceptance or rejection remains elusive. TRMs originate ...

    Abstract Transplanted organs carry donor immune cells into the recipient, the majority of which are tissue-resident macrophages (TRMs). The role they play in guiding the fate of the transplanted organ toward acceptance or rejection remains elusive. TRMs originate from both embryonic and bone marrow-derived precursors. Embryo-derived TRMs retain the embryonic capability to proliferate, so they are able to self-renew and, theoretically, persist for extended periods of time after transplantation. Bone marrow-derived TRMs do not proliferate and must constantly be replenished by adult circulating monocytes. Recent studies have aimed to clarify the different roles and interactions between donor TRMs, recipient monocytes, and monocyte-derived macrophages (MFs) after organ transplantation. This review aims to shed light on how MFs affect the fate of a transplanted organ by differentiating between the role of donor TRMs and that of MFs derived from graft infiltrating monocytes.
    MeSH term(s) Macrophages ; Monocytes ; Organ Transplantation ; Bone Marrow ; Embryo, Mammalian
    Language English
    Publishing date 2024-03-18
    Publishing country United States
    Document type Review ; Journal Article
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2300625
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Lysophosphatidic Acid

    Sistiana Aiello / Federica Casiraghi

    Cells, Vol 10, Iss 1390, p

    Promoter of Cancer Progression and of Tumor Microenvironment Development. A Promising Target for Anticancer Therapies?

    2021  Volume 1390

    Abstract: Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions—motility, ... ...

    Abstract Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions—motility, invasion and migration capabilities as well as resistance to apoptotic death—has been recognized by numerous studies over the last two decades. Notably, evidence has recently been accumulating that shows that LPA also contributes to the development of the tumor microenvironment (TME). Indeed, LPA plays a crucial role in inducing angiogenesis and lymphangiogenesis, triggering cellular glycolytic shift and stimulating intratumoral fibrosis. In addition, LPA helps tumoral cells to escape immune surveillance. Treatments that counter the TME components, in order to deprive cancer cells of their crucial support, have been emerging among the promising new anticancer therapies. This review aims to summarize the latest knowledge on how LPA influences both tumor cell functions and the TME by regulating the activity of its different elements, highlighting why and how LPA is worth considering as a molecular target for new anticancer therapies.
    Keywords lysophosphatidic acid ; autotaxin ; cancer ; tumor microenvironment ; fibrosis ; immune escape ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Lysophosphatidic Acid: Promoter of Cancer Progression and of Tumor Microenvironment Development. A Promising Target for Anticancer Therapies?

    Aiello, Sistiana / Casiraghi, Federica

    Cells

    2021  Volume 10, Issue 6

    Abstract: Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions-motility, ... ...

    Abstract Increased expression of the enzyme autotaxin (ATX) and the consequently increased levels of its product, lysophosphatidic acid (LPA), have been reported in several primary tumors. The role of LPA as a direct modulator of tumor cell functions-motility, invasion and migration capabilities as well as resistance to apoptotic death-has been recognized by numerous studies over the last two decades. Notably, evidence has recently been accumulating that shows that LPA also contributes to the development of the tumor microenvironment (TME). Indeed, LPA plays a crucial role in inducing angiogenesis and lymphangiogenesis, triggering cellular glycolytic shift and stimulating intratumoral fibrosis. In addition, LPA helps tumoral cells to escape immune surveillance. Treatments that counter the TME components, in order to deprive cancer cells of their crucial support, have been emerging among the promising new anticancer therapies. This review aims to summarize the latest knowledge on how LPA influences both tumor cell functions and the TME by regulating the activity of its different elements, highlighting why and how LPA is worth considering as a molecular target for new anticancer therapies.
    MeSH term(s) Humans ; Lysophospholipids/metabolism ; Neoplasm Proteins/metabolism ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy ; Phosphoric Diester Hydrolases/metabolism ; Signal Transduction ; Tumor Microenvironment
    Chemical Substances Lysophospholipids ; Neoplasm Proteins ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; alkylglycerophosphoethanolamine phosphodiesterase (EC 3.1.4.39) ; lysophosphatidic acid (PG6M3969SG)
    Language English
    Publishing date 2021-06-04
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10061390
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: An

    Gastoldi, Sara / Aiello, Sistiana / Galbusera, Miriam / Breno, Matteo / Alberti, Marta / Bresin, Elena / Mele, Caterina / Piras, Rossella / Liguori, Lucia / Santarsiero, Donata / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

    Frontiers in immunology

    2023  Volume 14, Page(s) 1112257

    Abstract: Introduction: Comprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains ... ...

    Abstract Introduction: Comprehensive genetic analysis is essential to clinical care of patients with atypical haemolytic uremic syndrome (aHUS) to reinforce diagnosis, and to guide treatment. However, the characterization of complement gene variants remains challenging owing to the complexity of functional studies with mutant proteins. This study was designed: 1) To identify a tool for rapid functional determination of complement gene variants; 2) To uncover inherited complement dysregulation in aHUS patients who do not carry identified gene variants.
    Methods: To address the above goals, we employed an ex-vivo assay of serum-induced C5b-9 formation on ADP-activated endothelial cells in 223 subjects from 60 aHUS pedigrees (66 patients and 157 unaffected relatives).
    Results: Sera taken from all aHUS patients in remission induced more C5b-9 deposition than control sera, independently from the presence of complement gene abnormalities. To avoid the possible confounding effects of chronic complement dysregulation related to aHUS status, and considering the incomplete penetrance for all aHUS-associated genes, we used serum from unaffected relatives. In control studies, 92.7% of unaffected relatives with known pathogenic variants exhibited positive serum-induced C5b-9 formation test, documenting a high sensitivity of the assay to identify functional variants. The test was also specific, indeed it was negative in all non-carrier relatives and in relatives with variants non-segregating with aHUS. All but one variants in aHUS-associated genes predicted in-silico as likely pathogenic or of uncertain significance (VUS) or likely benign resulted as pathogenic in the C5b-9 assay. At variance, variants in putative candidate genes did not exhibit a functional effect, with the exception of a
    Discussion: In conclusion, the serum-induced C5b-9 formation test in unaffected relatives of aHUS patients may be a tool for rapid functional evaluation of rare complement gene variants. When combined with exome sequencing the assay might be of help in variant selection, to identify new aHUS-associated genetic factors.
    MeSH term(s) Humans ; Complement Membrane Attack Complex/genetics ; Complement Membrane Attack Complex/metabolism ; Endothelial Cells/metabolism ; Atypical Hemolytic Uremic Syndrome/diagnosis ; Atypical Hemolytic Uremic Syndrome/genetics ; Complement System Proteins/genetics ; Complement System Proteins/therapeutic use ; Pedigree
    Chemical Substances Complement Membrane Attack Complex ; Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2023-02-09
    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.2023.1112257
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19.

    Aiello, Sistiana / Gastoldi, Sara / Galbusera, Miriam / Ruggenenti, Piero / Portalupi, Valentina / Rota, Stefano / Rubis, Nadia / Liguori, Lucia / Conti, Sara / Tironi, Matteo / Gamba, Sara / Santarsiero, Donata / Benigni, Ariela / Remuzzi, Giuseppe / Noris, Marina

    Blood advances

    2021  Volume 6, Issue 3, Page(s) 866–881

    Abstract: Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, ... ...

    Abstract Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.
    MeSH term(s) Atypical Hemolytic Uremic Syndrome ; COVID-19 ; Endothelial Cells ; Humans ; Platelet Aggregation ; SARS-CoV-2
    Language English
    Publishing date 2021-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2021005246
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Klotho in acute kidney injury: biomarker, therapy, or a bit of both?

    Aiello, Sistiana / Noris, Marina

    Kidney international

    2010  Volume 78, Issue 12, Page(s) 1208–1210

    Abstract: Acute kidney injury (AKI) diagnosis is based on an increase in serum creatinine or a decrease in urine output. To be effective, treatment of AKI should be started very early after the insult and well before the rise of serum creatinine. Thus, sensitive ... ...

    Abstract Acute kidney injury (AKI) diagnosis is based on an increase in serum creatinine or a decrease in urine output. To be effective, treatment of AKI should be started very early after the insult and well before the rise of serum creatinine. Thus, sensitive biologic markers of renal tubular injury in AKI are strongly needed. Hu et al. suggest that Klotho could be a novel biomarker and therapeutic target of ischemia-induced AKI.
    MeSH term(s) Acute Kidney Injury/metabolism ; Acute Kidney Injury/prevention & control ; Acute-Phase Proteins/metabolism ; Animals ; Biomarkers/metabolism ; Creatinine/blood ; Glucuronidase/genetics ; Glucuronidase/metabolism ; Glucuronidase/therapeutic use ; Humans ; Kidney Tubules/metabolism ; Lipocalins/metabolism ; Mice ; Mice, Transgenic ; Models, Animal ; Oxidative Stress ; Proto-Oncogene Proteins/metabolism ; Rats ; Reperfusion Injury/metabolism ; Reperfusion Injury/prevention & control
    Chemical Substances Acute-Phase Proteins ; Biomarkers ; Lcn2 protein, rat ; Lipocalins ; Proto-Oncogene Proteins ; Creatinine (AYI8EX34EU) ; Glucuronidase (EC 3.2.1.31) ; klotho protein (EC 3.2.1.31)
    Language English
    Publishing date 2010-11-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 120573-0
    ISSN 1523-1755 ; 0085-2538
    ISSN (online) 1523-1755
    ISSN 0085-2538
    DOI 10.1038/ki.2010.367
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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