Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

Garofalo, Stefano; Cocozza, Germana; Porzia, Alessandra; Inghilleri, Maurizio; Raspa, Marcello; Scavizzi, Ferdinando; Aronica, Eleonora; Bernardini, Giovanni; Peng, Ling; Ransohoff, Richard M.; Santoni, Angela; Limatola, Cristina

doi:10.1038/s41467-020-15644-8

Cited by 111 publications

(174 citation statements)

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“…Our study did not investigate the mechanisms involved in clinical improvement. The suggested role of natural killer cells [ 44 ] and regulatory T cells [ 45 , 46 ] is in line with the mechanism of action of MSC described by other authors [ 47 – 50 ]. Some studies indicated that human neural stem cells transplanted into a spinal cord in patients with ALS differentiated into neurons which were still detected 2.5 years after administration; however, it is not known whether the same happens after administration of MSC [ 51 ].…”

Section: Discussionsupporting

confidence: 77%

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Barczewska

Maksymowicz

Zdolińska-Malinowska

et al. 2020

Stem Cell Rev and Rep

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Objective Amyotrophic lateral sclerosis (ALS) is still incurable. Although different therapies can affect the health and survival of patients. Our aim is to evaluate the effect of umbilical mesenchymal stem cells administrated intrathecally to patients with amyotrophic lateral sclerosis on disability development and survival. Methods This case-control study involved 67 patients treated with Wharton’s jelly mesenchymal stem cells (WJ-MSC). The treated patients were paired with 67 reference patients from the PRO-ACT database which contains patient records from 23 ALS clinical studies (phase 2/3). Patients in the treatment and reference groups were fully matched in terms of race, sex, onset of symptoms (bulbar/spinal), FT9 disease stage at the beginning of therapy and concomitant amyotrophic lateral sclerosis medications. Progression rates prior to treatment varied within a range of ± 0.5 points. All patients received three intrathecal injections of Wharton’s jelly-derived mesenchymal stem cells every two months at a dose of 30 × 10 6 cells. Patients were assessed using the ALSFRS-R scale. Survival times were followed-up until March 2020. Results Median survival time increased two-fold in all groups. In terms of progression, three response types measured in ALSFRS-R were observed: decreased progression rate ( n = 21, 31.3%), no change in progression rate ( n = 33, 49.3%) and increased progression rate ( n = 13, 19.4%). Risk-benefit ratios were favorable in all groups. No serious adverse drug reactions were observed. Interpretation Wharton’s jelly-derived mesenchymal stem cells therapy is safe and effective in some ALS patients, regardless of the clinical features and demographic factors excluding sex. The female sex and a good therapeutic response to the first administration are significant predictors of efficacy following further administrations. Graphical Abstract Medical therapeutic experiment with retrospective case-control analyses Electronic supplementary material The online version of this article (10.1007/s12015-020-10016-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Barczewska

Maksymowicz

Zdolińska-Malinowska

et al. 2020

Stem Cell Rev and Rep

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“…4A ). Data to support this neuroprotective to neurotoxic shift came largely from studies in mutant hSOD1 ALS models, in which the initial presymptomatic and early symptomatic phases are dominated by anti-inflammatory immune responses (anti-inflammatory microglia, Treg and Th2 CD4 T cells), whereas late symptomatic and terminal stages are dominated by proinflammatory immune responses (proinflammatory microglia and astrocytes, inflammatory monocytes, cytotoxic CD8 T cells, Th1 and Th17 CD4 T cells, NK cells and neutrophils) ( Henkel et al , 2013 ; Zhao et al , 2013 ; Murdock et al , 2017 ; Sheean et al , 2018 ; Choi et al , 2020 ; Garofalo et al , 2020 ; Jin et al , 2020 ). As previously discussed, once that a hyperinflammatory state of microglia or astrocytes is established, these glial cells directly become toxic and can kill motoneurons ( Roberts et al , 2013 ; Re et al , 2014 ; Zhao et al , 2015 ).…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

“…NK cells infiltrate the motor cortex and the spinal cord of ALS patients and mouse models; NK cells kill motoneurons via NK2GD, reduce Treg infiltration and mediate microglial proinflammatory polarization via IFN-γ ( Garofalo et al , 2020 ).…”

mentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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“…This allows it to effectively deliver siRNA to a variety of different cell types including primary and stem cells, as well as immune cells such as primary T cells (Figure 7D), natural killer cells ( Figure 7E), and macrophages ( Figure 7F), which are otherwise highly challenging for nucleic acid delivery. 5,[24][25][26] American Chemical Society.…”

Section: Self-assembling Supramolecular Pamam Dendrimersmentioning

confidence: 99%

“…By employing different small and simple amphiphilic building units, we have successfully constructed various supramolecular dendrimers for the delivery of drugs, nucleic acid therapeutics, and bioimaging agents. [1][2][3][4][5][18][19][20][21][22][23][24][25][26][27] It is worth mentioning that amphiphilic dendrimers can also readily self-assemble into vesicle structures known as "dendrimersomes". 28,29 The dendrimersome concept-which differs from the supramolecular dendrimer concept described in the present work-was inaugurated by Percec et al, 28 and has been investigated extensively as a means of mimicking membranes in biological applications.…”

Section: Introductionmentioning

confidence: 99%

Self-Assembling Supramolecular Dendrimers for Biomedical Applications: Lessons Learned from Poly(amidoamine) Dendrimers

et al. 2020

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Conspectus Dendrimers, notable for their well-defined radial structures with numerous terminal functionalities, hold great promise for biomedical applications such as drug delivery, diagnostics, and therapeutics. However, their translation into clinical use has been greatly impeded by their challenging stepwise synthesis and difficult purification. To circumvent these obstacles, we have pioneered a self-assembly approach to constructing noncovalent supramolecular dendrimers using small amphiphilic dendrimer building units which can be easily synthesized and purified. By virtue of their amphipathic nature, the small amphiphilic dendrimers are able to self-assemble and generate large supramolecular dendrimers via noncovalent weak interactions such as van der Waals forces, H bonds, and electrostatic interactions. The so-created noncovalent dendrimers can mimic covalent dendrimers not only in terms of the radial structural feature emanating from a central core but also in their capacity to deliver drugs and imaging agents for biomedical applications. The noncovalent supramolecular dendrimers can be easily synthesized and modulated with regard to size, shape, and properties by varying the nature of the hydrophobic and hydrophilic entities as well as the dendrimer generation and terminal functionalities, ensuring their adaptability to specific applications. In particular, the dendritic structure of the amphiphilic building units permits the creation of large void spaces within the formed supramolecular dendrimers for the physical encapsulation of drugs, while the large number of surface functionalities can be exploited for both physical and chemical conjugation of pharmaceutic agents for drug delivery. Poly(amidoamine) (PAMAM) dendrimers are the most intensively studied for biomedical applications by virtue of their excellent biocompatibility imparted by their peptide-mimicking amide backbones and numerous interior and terminal amine functionalities. We present a short overview of our self-assembly strategy for constructing supramolecular PAMAM dendrimers for biomedical applications. Specifically, we start with the introduction of dendrimers and their synthesis, focusing on the innovative self-assembly synthesis of supramolecular dendrimers. We then detail the representative examples of the noncovalent supramolecular PAMAM dendrimers established in our group for the delivery of anticancer drugs, nucleic acid therapeutics, and imaging agents, either within the dendrimer interior or at the dendrimer terminals on the surface. Some of the supramolecular dendrimer nanosystems exhibit outstanding performance, excelling the corresponding clinical anticancer therapeutics and imaging agents. This self-assembly approach to creating supramolecular dendrimers is completely novel in concept yet easy to implement in practice, offering a fresh perspective for exploiting the advantageous features of dendrimers in biomedical applications.

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Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

Cited by 111 publications

References 50 publications

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Self-Assembling Supramolecular Dendrimers for Biomedical Applications: Lessons Learned from Poly(amidoamine) Dendrimers

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