Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival

Ševc, Juraj; Goldberg, Danielle; Gorp, Sebastiaan van; Leerink, Marjolein; Juhás, Štefan; Juhásová, Jana; Marsala, Silvia; Hruška-Plocháň, Marián; Hefferan, Michael P.; Motlı́k, Jan; Rypáček, František; Machová, Luďka; Kakinohana, Osamu; Santucci, Camila; Johe, Karl; Lukáčová, Nadežda; Yamada, Kazuhiko; Bui, Jack D.; Maršala, Martin

doi:10.1016/j.expneurol.2013.05.017

Cited by 26 publications

(26 citation statements)

References 39 publications

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“…In our previous studies, we have demonstrated that a subpopulation of spinally grafted human spinal stem cells when grafted at the nestin-positive stage continue to express DCX at 3 months when grafted into previously ischemia-injured spinal cord segments (Cizkova et al 2007). Similarly, we have demonstrated a comparable level of DCX expression in human spinal stem cells at 6-7 weeks after spinal grafting in adult immunosuppressed naive minipigs (Usvald et al 2010) or in human embryonic stem cell-derived NSCs at 2 weeks-3 months after grafting into lumbar spinal cords of naive or ALS (SOD1 G93A ) immunosuppressed rats (Sevc et al 2013).…”

supporting

confidence: 49%

Time Course of Spinal Doublecortin Expression in Developing Rat and Porcine Spinal Cord: Implication in In Vivo Neural Precursor Grafting Studies

et al. 2014

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Expression of doublecortin (DCX), a 43-53 kDa microtubule binding protein, is frequently used as (i) an early neuronal marker to identify the stage of neuronal maturation of in vivo grafted neuronal precursors (NSCs), and (ii) a neuronal fate marker transiently expressed by immature neurons during development. Reliable identification of the origin of DCX-immunoreactive cells (i.e., host vs. graft) requires detailed spatial and temporal mapping of endogenous DCX expression at graft-targeted brain or spinal cord regions. Accordingly, in the present study, we analyzed (i) the time course of DCX expression in pre- and postnatal rat and porcine spinal cord, and (ii) the DCX expression in spinally grafted porcine-induced pluripotent stem cells (iPS)-derived NSCs and human embryonic stem cell (ES)-derived NSCs. In addition, complementary temporospatial GFAP expression study in porcine spinal cord was also performed. In 21-day-old rat fetuses, an intense DCX immunoreactivity distributed between the dorsal horn (DH) and ventral horn was seen and was still present in the DH neurons on postnatal day 20. In animals older than 8 weeks, no DCX immunoreactivity was seen at any spinal cord laminae. In contrast to rat, in porcine spinal cord (gestational period 113-114 days), DCX was only expressed during the pre-natal period (up to 100 days) but was no longer present in newborn piglets or in adult animals. Immunohistochemical analysis was confirmed with a comparable expression profile by western blot analysis. Contrary, the expression of porcine GFAP started within 70-80 days of the pre-natal period. Spinally grafted porcine iPS-NSCs and human ES-NSCs showed clear DCX expression at 3-4 weeks postgrafting. These data indicate that in spinal grafting studies which employ postnatal or adult porcine models, the expression of DCX can be used as a reliable marker of grafted neurons. In contrast, if grafted neurons are to be analyzed during the first 4 postnatal weeks in the rat spinal cord, additional markers or grafted cell-specific labeling techniques need to be employed to reliably identify grafted early postmitotic neurons and to differentiate the DCX expression from the neurons of the host.

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confidence: 49%

Time Course of Spinal Doublecortin Expression in Developing Rat and Porcine Spinal Cord: Implication in In Vivo Neural Precursor Grafting Studies

et al. 2014

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“…1A and B). 31 CD4 C and CD8 C T cells are activated by IL-2 produced by a calciumdependent Il-2 gene transcription that is blocked by tacrolimus. 33 We confirmed that the slow release of tacrolimus led to sustained immune suppression as CD8…”

Section: Resultsmentioning

confidence: 99%

Immunosurveillance and immunoediting in MMTV-PyMT-induced mammary oncogenesis

et al. 2017

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Evidence of cancer immunosurveillance and immunoediting processes has been primarily demonstrated in mouse models of chemically induced oncogenesis. Although these models are very tractable, they are characterized by high mutational loads that represent a minority of human cancers. In this study, we sought to determine whether cancer immunosurveillance and immunoediting could be demonstrated in a more clinically relevant oncogene-induced model of carcinogenesis, the MMTV-PyMT (PyMT) mammary carcinoma model. This model system in the FVB/NJ strain background was previously used to demonstrate that adaptive immunity had no role in limiting primary cancer formation and in fact promoted metastasis, thus calling into question whether cancer immunosurveillance operated in preventing the development of breast cancer. Our current study in the C57BL/6 strain backgrounds provides a different conclusion, as we report here the existence of an adaptive immunosurveillance of PyMT mammary carcinomas using two independent models of immune deficiency. PyMT mice bred onto a Rag1 ¡/¡ background or immune suppressed by chronic tacrolimus therapy both demonstrated accelerated development of mammary carcinomas. By generating a bank of cell lines from these animals, we further show that a subset of PyMT cell lines had delayed growth after transplantation into wild-type (WT) syngeneic, but not immune-deficient hosts. This reduced growth rate in immunocompetent animals was characterized by an increase in immune cell infiltration and tissue differentiation. Furthermore, loss of the immune cell infiltration that characterized immunoediting of slow growing cell lines, changed them into fast growing variants capable of progressing in the immunocompetent model. In conclusion, our study provides evidence that immunosurveillance and immunoediting of PyMT-derived cell lines modulate tumor progression in this oncogene-induced model of cancer.

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“…Though the exact function of FKBP, an immunophilin, is not clear with respect to T-lymphocyte activation, 35 formation of a pentameric complex between tacrolimus, FKBP, calcineurin A, calcineurin B, and calmodulin is known to inhibit the phosphatase activity of calcineurin. 48 Dephosphorylation of the family of NFAT transcription factors by calcineurin normally allows NFAT translocation into the nucleus, where it increases transcription of genes required for T-cell activation and proliferation. Tacrolimus is commercialized in more than 70 countries and is currently the drug of choice for immunosuppression following transplantation procedures, including heart, kidney, liver, and bone marrow transplants.…”

Section: Tacrolimusmentioning

confidence: 99%

Immunosuppressive mechanisms for stem cell transplant survival in spinal cord injury

Antonios

Farah

Cleary

et al. 2019

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Spinal cord injury (SCI) has been associated with a dismal prognosis—recovery is not expected, and the most standard interventions have been temporizing measures that do little to mitigate the extent of damage. While advances in surgical and medical techniques have certainly improved this outlook, limitations in functional recovery continue to impede clinically significant improvements. These limitations are dependent on evolving immunological mechanisms that shape the cellular environment at the site of SCI. In this review, we examine these mechanisms, identify relevant cellular components, and discuss emerging treatments in stem cell grafts and adjuvant immunosuppressants that target these pathways. As the field advances, we expect that stem cell grafts and these adjuvant treatments will significantly shift therapeutic approaches to acute SCI with the potential for more promising outcomes.

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Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival

Cited by 26 publications

References 39 publications

Time Course of Spinal Doublecortin Expression in Developing Rat and Porcine Spinal Cord: Implication in In Vivo Neural Precursor Grafting Studies

Time Course of Spinal Doublecortin Expression in Developing Rat and Porcine Spinal Cord: Implication in In Vivo Neural Precursor Grafting Studies

Immunosurveillance and immunoediting in MMTV-PyMT-induced mammary oncogenesis

Immunosuppressive mechanisms for stem cell transplant survival in spinal cord injury

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