Induction of operational tolerance to discordant dopaminergic porcine xenografts1

Larsson, Lena C.; Corbascio, Matthias; Pearson, Thomas C.; Larsen, Christian; Ekberg, Henrik; Widner, Håkan

doi:10.1097/01.tp.0000058807.45320.a2

Cited by 26 publications

(24 citation statements)

References 26 publications

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“…Among them are such widespread diseases as diabetes, end-stage renal disease, Parkinson's disease, acute and chronic liver failure, and inherited metabolic disorders. The efficacy of committed embryonic pig or human kidney (13,28), pancreas (29)(30)(31)(32)(33)(34), lung (35), heart, or intestine (35,36) as well as hepatocytes (37)(38)(39)(40) or neuronal precursors (41)(42)(43), which grew and differentiated upon implantation into SCID or nude mice or rats, has been extensively Embryonic pig pancreas tissues obtained at various gestational ages were implanted under the kidney capsule. Tissue growth and serum levels of pig insulin were evaluated 6 weeks after implantation as described in Methods.…”

Section: Discussionmentioning

confidence: 99%

Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

Eventov‐Friedman

Katchman

Shezen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Pig embryonic tissues represent an attractive option for organ transplantation. However, the achievement of optimal organogenesis after transplantation, namely, maximal organ growth and function without teratoma development, represents a major challenge. In this study, we determined distinct gestational time windows for the growth of pig embryonic liver, pancreas, and lung precursors. Transplantation of embryonic-tissue precursors at various gestational ages [from E (embryonic day) 21 to E100] revealed a unique pattern of growth and differentiation for each embryonic organ. Maximal liver growth and function were achieved at the earliest teratoma-free gestational age (E28), whereas the growth and functional potential of the pancreas gradually increased toward E42 and E56 followed by a marked decline in insulin-secreting capacity at E80 and E100. Development of mature lung tissue containing essential respiratory system elements was observed at a relatively late gestational age (E56). These findings, showing distinct, optimal gestational time windows for transplantation of embryonic pig liver, pancreas, and lung, might explain, in part, the disappointing results in previous transplantation trials and could help enhance the chances for successful implementation of embryonic pig tissue in the treatment of a wide spectrum of human diseases.fetal ͉ porcine ͉ gestational age ͉ growth potential

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Section: Discussionmentioning

confidence: 99%

Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

Eventov‐Friedman

Katchman

Shezen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Antibodies against T-cell receptor anti-TCR␣␤ and T cells have been used to enhance the survival of intracerebral neural xenografts in rats. 38,39 Larsson and colleagues 40,41 have also explored the use of blockers to T-cell costimulatory molecules as an alternative route to tolerance, therefore highlighting the value of targeting this arm of the immune response for xenograft survival.…”

Section: Immunosuppressive Drugs and Their Role In Neural Graftingmentioning

confidence: 99%

“…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. 41 The role for humoral factors in xenograft rejection has been addressed using a number of different approaches.…”

Section: Xenogeneic Neural Graftsmentioning

confidence: 99%

“…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. 41 The role for humoral factors in xenograft rejection has been addressed using a number of different approaches.…”

Section: Xenogeneic Neural Graftsmentioning

confidence: 99%

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Immune problems in central nervous system cell therapy

Barker¹,

Widner

2004

Neurotherapeutics

Self Cite

168

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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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“…more, the tolerance for xenografts within immune privileged cites is often more limited and difficult to predict (3,12,18,24). As part of the central nervous system (CNS), the retina exhibits a number of unusual immunological properIn addition to site-specific immune privilege, there is another phenomenon of interest in the context of transties, collectively known as immune privilege.…”

Section: Introductionmentioning

confidence: 99%

Retinal Progenitor Cell Xenografts to the Pig Retina: Immunological Reactions

et al. 2006

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We evaluated the host response to murine retinal progenitor cells (RPCs) following transplantation to the subretinal space (SRS) of the pig. RPCs from GFP mice were transplanted subretinally in 18 nonimmunosuppressed normal or laser-treated pigs. Evaluation of the SRS was performed on hematoxylin-eosin (H&E)-stained sections. Serum samples were taken from naive and RPC-grafted pigs and mouse-reactive antibody responses were assessed. At 1 week, histology showed a few perivascular lymphocytes consistent with a mild retinal vasculitis, and depigmentation of the RPE with large numbers of mononuclear inflammatory cells in the choroid near the transplantation site. Large choroidal infiltrates were evident at 2-5 weeks. Serum from naive and RPC-xenografted pigs contained significant levels of preformed IgG and IgM antibodies against murine antigens. Xenogeneic RPCs transplanted to the porcine SRS induced mononuclear infiltration in the choroid with graft rejection occurring over 2-5 weeks. Serum analysis confirmed that mice and pigs are discordant species; however, a cell-mediated acute mechanism appears to be responsible, rather than an antibody-mediated rejection.

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Induction of operational tolerance to discordant dopaminergic porcine xenografts1

Cited by 26 publications

References 26 publications

Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

Immune problems in central nervous system cell therapy

Retinal Progenitor Cell Xenografts to the Pig Retina: Immunological Reactions

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