Intrastriatal Ventral Mesencephalic Xenografts of Porcine Tissue in Rats: Immune Responses and Functional Effects

Larsson, Lena C.; Czech, Kimberly A.; Brundin, Patrik; Widner, Håkan

doi:10.1177/096368970000900211

Cited by 61 publications

(30 citation statements)

References 51 publications

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“…We have shown in previous studies that the porcine neural grafts mature over time, with increased TH expression and outgrowth of axons. We have demonstrated that the porcine grafts are able to restore function in the rat model of Parkinson's disease, after a maturation process that takes between 6 and 9 wk [15]. In that study, we immunosuppressed the rats with a high dose of cyclosporine A, and around 50% of the grafts were rejected at 14 wk.…”

Section: Discussionmentioning

confidence: 99%

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Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Larsson

Corbascio

Widner

et al. 2002

Xenotransplantation

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: Transplantation of embryonic human neural tissue can restore dopamine neurotransmission and improve neurological function in patients with Parkinson's disease. Logistical and ethical factors limit the availability of human embryonic allogeneic tissue. Embryonic xenogeneic neural tissue from porcine donors is an alternative form of donor tissue, but effective immunomodulatory techniques are warranted for neural xenotransplantation to become clinically feasible. We transplanted embryonic porcine ventral mesencephalic tissue into the brains of adult untreated C57BL/6 mice, untreated CD40L‐/–mice and CD40L‐/–mice that received injections of anti‐LFA‐1, CTLA4Ig or both compounds. Double‐treated CD40L‐/–mice had large grafts with high numbers of dopaminergic neurons 4 wk after transplantation. The grafts were completely devoid of lymphocytes, macrophages and activated microglia. Untreated C57BL/6 mice had rejected their grafts. Untreated CD40L‐/–mice and CD40L‐/–mice treated with monotherapy of anti‐LFA‐1 or CTLA4Ig had smaller grafts and more microglial and lymphocytic infiltration than double‐treated CD40L‐/–mice. We conclude that immunomodulation with concomitant inhibition of LFA‐1 and B7 signaling in the perioperative period in CD40L‐/–mice prevented the rejection of discordant neural xenografts. The treatment most likely reduced antigen presenting capacity and interfered with the costimulatory signaling needed for T cell activation to occur.

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Section: Discussionmentioning

confidence: 99%

“…The graft volumes and the number of TH-positive cells were obtained using a stereological analysis system described earlier [15]. A CAST-Grid software package (Interactivision, Silkeborg, Denmark) was used to obtain cell counts by randomly and systematically placing a counting frame over the delineated transplant.…”

Section: Stereological and Statistical Methodsmentioning

confidence: 99%

Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Larsson

Corbascio

Widner

et al. 2002

Xenotransplantation

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“…This suggests that such an approach might be useful clinically to improve graft survival, possibly by removing the more immunogenic cells. Conventional immunosuppressive drugs used as monotherapy (e.g., cyclosporin A or tacrolimus) do not protect grafts effectively, [65][66][67] but this can be improved if combined with other drugs such as prednisolone. 65 Short courses of treatment with molecules that block T-cell costimulation [CD40L, LFA1, and CTLA4Ig (40,41)] have resulted in very good graft survival in mice, although long-term studies are needed to determine whether this therapy could be used clinically.…”

Section: Xenogeneic Neural Graftsmentioning

confidence: 99%

Immune problems in central nervous system cell therapy

Barker¹,

Widner

2004

Neurotherapeutics

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173

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Summary:Transplantation of cells and tissues to the mammalian brain and CNS has revived the interest in the immunological status of brain and its response to grafted tissue. The previously held view that the brain was an absolute "immunologically privileged site" allowing indefinite survival without rejection of grafts of cells has proven to be wrong. Thus, the brain should be regarded as a site where immune responses can occur, albeit in a modified form, and under certain circumstances these are as vigorous as those seen in other peripheral sites. Clinical cell transplant trials have now been performed in Parkinson's disease, Huntington's disease, demyelinating diseases, retinal disorders, stroke, epilepsy, and even deafness, and normally are designed as cell replacement strategies, although implantation of genetically modified cells for supplementation of growth factors has also been tried. In addition, some disorders of the CNS for which cell therapies are being considered have an immunological basis, such as multiple sclerosis, which further complicates the situation. Embryonic neural tissue allografted into the CNS of animals and patients with neurodegenerative conditions survives, makes and receives synapses, and ameliorates behavioral deficits. The use of aborted human tissue is logistically and ethically complicated, which has lead to the search for alternative sources of cells, including xenogeneic tissue, genetically modified cells, and stem cells, all of which can and will induce some level of immune reaction. We review some of the immunological factors involved in transplantation of cells to CNS.

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“…Since cyclosporine treatment acts primarily to inhibit T lymphocyte-mediated immunity [251,252], these findings indicate the involvement of other arms of the immune system, such as innate immunity, in MSC graft rejection. In addition, cyclosporine treatment for neural xenotransplantation has been reported to be suboptimal [253,254]. Furthermore, complement factors, immunoglobulins and macrophages may be involved in immune responses against discordant xenografts, and these are not affected in a crucial way by cyclosporine treatment [255][256][257].…”

Section: Activation Of Innate Immune Response With Intracerebral Msc mentioning

confidence: 99%

Mesenchymal Stem Cell-Based Therapies for Parkinson’s Disease: Progress, Controversies and Lessons for the Future

Khoo¹,

Tao²,

D.F.³

2011

J Stem Cell Res Ther

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Scientific and clinical research interest in mesenchymal stem cells (MSCs) has increased exponentially since the identification of MSCs in the bone marrow. It is now recognized that MSCs possess the in vitro characteristics of stem cells with the abilities to proliferate, symmetrically divide, and produce multi-lineage mesodermal derivatives, making MSCs attractive candidates for use in potential cellular therapies. Furthermore, MSCs can be relatively easily isolated and expanded in culture with low tumorigenicity and teratoma formation, and have been reported to display immunomodulatory properties that may be advantageous in clinical transplantation. Discovery of the ability of MSCs to differentiate into cells of non-mesodermal tissues, particularly neural cells, has also raised the possibility of utilizing MSCs in regenerative and reparative therapies for neurological disorders. However, a number of hurdles remain to be resolved, including conflicting findings concerning the capacity of MSCs to suppress immune responses and contribute to multiple tissue lineages, highlighting the need for a greater understanding of mechanisms underlying the observed phenomena. In this review we will discuss: (1) recent advances in our understanding of MSC plasticity/transdifferentiation and immunomodulatory properties; (2) evidence for cell-based therapies, in particular MSC-based therapies for Parkinson's disease; and (3) current challenges and potential strategies for the utilization of MSCs in the treatment of Parkinson's disease.

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Intrastriatal Ventral Mesencephalic Xenografts of Porcine Tissue in Rats: Immune Responses and Functional Effects

Cited by 61 publications

References 51 publications

Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Immune problems in central nervous system cell therapy

Mesenchymal Stem Cell-Based Therapies for Parkinson’s Disease: Progress, Controversies and Lessons for the Future

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