Effects of Immunosuppressive Treatment on Host Responses Against Intracerebral Porcine Neural Tissue Xenografts in Rats

Wennberg, Lars; Czech, Kimberly A.; Larsson, Lena C.; Mirza, Bilal; Bennet, William; Song, Z.; Widner, Håkan

doi:10.1097/00007890-200106270-00016

Cited by 37 publications

(18 citation statements)

References 47 publications

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“…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%

Immune problems in central nervous system cell therapy

Barker¹,

Widner

2004

Neurotherapeutics

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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Section: Xenogeneic Neural Graftsmentioning

confidence: 99%

Immune problems in central nervous system cell therapy

Barker¹,

Widner

2004

Neurotherapeutics

168

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“…Despite this, neural xenografts in the brain of untreated recipients are rejected (8,9) with very rare exceptions (10). Studies have shown that a combination of immunosuppressive drugs can be used to overcome the rejection process of porcine xenografts in rats (11,12), but not in mice. No treatment so far has led to any significant graft survival in mice except blocking the costimulatory signals lymphocyte function antigen (LFA)-1 and B7 in CD40L-deficient mice (13).…”

Section: Triple-treated Mice Showed a Normal Rejection Process Of Thementioning

confidence: 99%

Induction of operational tolerance to discordant dopaminergic porcine xenografts1

Larsson

Corbascio²,

Pearson³

et al. 2003

Transplantation

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“…In a meta-analysis, the rate of neural xenograft survival with cyclosporine A monotherapy was around 75%, but most of the models included in the meta-analysis were concordant [9]. Combinations of immunosuppresssive drugs are more effective [19], but chronic systemic immunosuppression carries risks of opportunistic infections and tumor development. Since Parkinson's disease is not life threatening and the treatment perspective should be very long, a selective short-term immunotherapy would be desirable.…”

Section: Introductionmentioning

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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: 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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Effects of Immunosuppressive Treatment on Host Responses Against Intracerebral Porcine Neural Tissue Xenografts in Rats

Cited by 37 publications

References 47 publications

Immune problems in central nervous system cell therapy

Immune problems in central nervous system cell therapy

Induction of operational tolerance to discordant dopaminergic porcine xenografts1

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

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