Human Natural Antibodies Cytotoxic to Pig Embryonic Brain Cells Recognize Novel Non-Galα1,3Gal-Based Xenoantigens

Sumitran, Suchitra; Liu, Jining; Czech, Kimberly A.; Christensson, Birger; Widner, Håkan; Holgersson, Jan

doi:10.1006/exnr.1999.7181

Cited by 35 publications

(18 citation statements)

References 65 publications

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“…The major conclusion is that the T‐cell mediated rejection of tissues that exists across species barriers can be modulated using immunosuppressive drug therapies such as CsA (for review see Refs [9,31]). More recently, in vitro analyses reveal that human serum antibody and complement mediate cell lysis of porcine neural cells [32]. This indicates that strategies to block complement activation could improve cell transplantation outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Systemic complement blockade and the use of transgenic (CD59, HT) fetal cells has provided us with the maximum barrier to humoral‐mediated immune attack [17,33,34], which correlated with in vivo graft survival. These results are relevant to human therapy due to significant complement‐mediated lysis of porcine neurons caused by human serum [32].…”

Section: Discussionmentioning

confidence: 99%

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Immune parameters relevant to neural xenograft survival in the primate brain

Cicchetti

Fodor

Deacon

et al. 2003

Xenotransplantation

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The lack of supply and access to human tissue has prompted the development of xenotransplantation as a potential clinical modality for neural cell transplantation. The goal of the present study was to achieve a better understanding of the immune factors involved in neural xenograft rejection in primates. Initially, we quantified complement mediated cell lysis of porcine fetal neurons by primate serum and demonstrated that anti-C5 antibody treatment inhibited cell death. We then developed an immunosuppression protocol that included in vivo anti-C5 monoclonal antibody treatment, triple drug therapy (cyclosporine, methylprednisolone, azathioprine) and donor tissue derived from CD59 or H-transferase transgenic pigs and applied it to pig-to-primate neural cell transplant models. Pre-formed alphaGal, induced alphaGal and primate anti-mouse antibody (PAMA) titers were monitored to assess the immune response. Four primates were transplanted. The three CD59 neural cell recipients showed an induced anti-alphaGal response, whereas the H-transferase neural cell recipient exhibited consistently low anti-alphaGal titers. Two of these recipients contained surviving grafts as detected by immunohistochemistry using selected neural markers. Graft survival correlated with high dose cyclosporine treatment, complete complement blockade and the absence of an induced PAMA response to the murine anti-C5 monoclonal antibodies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immune parameters relevant to neural xenograft survival in the primate brain

Cicchetti

Fodor

Deacon

et al. 2003

Xenotransplantation

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“…Sumitran et al. [24] showed that pig embryonic neural tissue is sensitive to antibody dependent cellular cytotoxicity in the presence of human natural antibodies, an effect mainly mediated by antibodies against antigens distinct from Galα1,3Gal. Similarly it has been shown that α‐galactosidase treatment did not protect porcine aortic endothelial cells from ADCC mediated by IgG antibodies in normal sera [25].…”

Section: Discussionmentioning

confidence: 99%

Continued production of xenoimmune antibodies 6–8 years after clinical transplantation of fetal pig islet‐like cell‐clusters

Lindeborg¹,

Kumagai‐Braesch²,

Tibell

et al. 2001

Xenotransplantation

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We have monitored the humoral immune responses of 10 type I diabetic patients, xenotransplanted with fetal porcine islet-like cell clusters for up to 8 years after xenotransplantation. We investigated the immunoglobulin subclass distribution as well as specificity differences of xenoreactive antibodies. Hemagglutintion tests, using pig erythrocytes, showed that some patients maintained higher titers of xenoreactive IgM antibodies during the entire follow up period, compared with pretransplant levels. In microcytotoxicity tests all but one patient tested showed higher than pretransplant levels of cytotoxic antibodies against pig peripheral blood mononuclear cells (PBMC) 6-8 years after transplantation. Levels of Gal alpha 1,3Gal specific antibodies, were also high. Antibody dependent cellular cytotoxicity (ADCC) activity against a Gal alpha 1,3Gal expressing human B cell line was detected in four patients while ADCC reactivity against adult pig islet cells was detected in only two patients, 6-8 years after transplantation. Immune sera collected 30 days and 1 year after transplantation showed positive staining of adult pig islet cells in fluoromicroscopy whereas sera from later time points did not. Western blot experiments showed that some patients had IgG1 antibodies reactive against epitopes on pig cells other than Gal alpha 1,3Gal, while xenoreactive IgM and IgG2 antibodies mainly reacted with Gal alpha 1,3Gal-containing epitopes as shown by absorption experiments. These results show that patients continue to produce higher than pretransplant levels of IgM and IgG2 xenospecific antibodies against Gal alpha 1,3Gal for extended time periods following xenotransplantation. Some patients also produce xenoreactive IgG1 antibodies directed against non-Gal alpha 1,3Gal epitopes.

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“…In addition to the known antigens, there are three non-␣-1,3-Gal epitopes on embryonic porcine dopaminergic cells reactive with IgM present in the human serum. 68 Transgenic porcine VM tissue, expressing either the human complement inhibitor CD59 or human ␣-1,2-fucosyltransferase in combination with a recipient treatment with anti-C5 antibodies (H transferase), survives up to 12 weeks in parkinsonian primates. 69 However, the level of expression of these human complement regulatory proteins is generally low in transgenic embryonic pig brain.…”

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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Human Natural Antibodies Cytotoxic to Pig Embryonic Brain Cells Recognize Novel Non-Galα1,3Gal-Based Xenoantigens

Cited by 35 publications

References 65 publications

Immune parameters relevant to neural xenograft survival in the primate brain

Immune parameters relevant to neural xenograft survival in the primate brain

Continued production of xenoimmune antibodies 6–8 years after clinical transplantation of fetal pig islet‐like cell‐clusters

Immune problems in central nervous system cell therapy

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