Immunobiology of Xenografting in Rodents

Thomas, Francis T.; Marchman, W.; Carobbi, A; DeMasi, Richard J.; Araneda, D; Patselas, T.; Larkin, Ernest W.; Pittman, K; Alqaisi, Munther; Haisch, Carl E.; Thomas, Judith M.

doi:10.1007/978-3-642-97323-9_9

Cited by 11 publications

(5 citation statements)

References 20 publications

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“…A very odd observation was finding that hamster heart transplanted into so called nude rats is rejected as fast as-or even faster-than hearts from normal rats (allotransplantation) [23]. Nude rats are said not to have any thymus tissue and one would expect-as they would not reject allo rat hearts-that they would not reject hamster hearts either.…”

Section: Difficult Concordant Xenotransplantationmentioning

confidence: 99%

Xenotransplantation

Kemp

1996

Journal of Internal Medicine

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Section: Difficult Concordant Xenotransplantationmentioning

confidence: 99%

Xenotransplantation

Kemp

1996

Journal of Internal Medicine

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“…The ␣1,3GT (Ϫ/Ϫ) mice we describe here may represent a useful alternative small animal for this work, since it can be anticipated that the naturally occurring anti-Gal antibodies in an ␣1,3GT (Ϫ/Ϫ) murine graft recipient will lead to hyperacute graft rejection of a transplanted organ taken from an ␣1,3GT (ϩ/ϩ), Gal␣133Gal-positive, but otherwise syngeneic donor mouse. The extensive experience with organ transplants in mice (33), the well defined histocompatibility loci in this species (34), and highly developed systems for murine transgenesis represent additional advantages of this system for the study of anti-Gal-dependent hyperacute organ transplant rejection. Studies are currently in progress to study hyperacute transplant rejection utilizing these ␣1,3GT (Ϫ/Ϫ) mice.…”

Section: Gal␣13gal-deficient Mice 21439mentioning

confidence: 99%

Oocyte Galα1,3Gal Epitopes Implicated in Sperm Adhesion to the Zona Pellucida Glycoprotein ZP3 Are Not Required for Fertilization in the Mouse

Thall

Malý

Lowe

1995

Journal of Biological Chemistry

386

254

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The Gal␣133Gal structure is displayed on the zona pellucida glycoprotein ZP3 on murine oocytes. This trisaccharide has been implicated in sperm-zona pellucida adhesive events thought to be essential to fertilization in the mouse. To determine directly if this molecule is required for fertilization, we have generated mice that are deficient in a gene (␣1,3GT) encoding the UDPGal:␤-D-Gal-␣133Gal-galactosyltransferase enzyme responsible for Gal␣133Gal synthesis and expression. These mice develop normally and exhibit no gross phenotypic abnormalities. The Gal␣133Gal epitope is absent from the vascular endothelium and other tissues in ␣1,3GT (؊/؊) adult mice. By contrast, ␣1,3GT (؊/؊) mice, like humans, develop naturally occurring anti-␣-galactoside antibodies normally absent in wild type mice. Female ␣1,3GT (؊/؊) mice yield oocytes that are devoid of the Gal␣133Gal epitope; however, these mice are fully fertile. These observations indicate that the Gal␣133Gal moiety is not essential to sperm-oocyte interactions leading to fertilization or to essentially normal development. They further suggest that ␣1,3GT (؊/؊) mice will find utility for exploring approaches to diminish anti-Gal-dependent hyperacute xenograft rejection, which presents a major barrier to the use of porcine and other non-primate organs for xenotransplantation in humans.Fertilization in mammals involves an adhesive interaction between sperm and the zona pellucida, a glycoprotein-containing shell that surrounds the oocyte. Sperm receptor activity of the murine oocyte resides in the zona pellucida glycoprotein ZP3 (1). Sperm recognition of murine ZP3 depends upon Olinked oligosaccharides displayed by ZP3 (Ref. 2;. Treatment of purified egg ZP3 and ZP3-derived O-linked oligosaccharides with ␣-galactosidase eliminates sperm receptor activity (6). These observations have been taken to imply that terminal ␣-galactosides on ZP3 glycoconjugates are critical for sperm binding activity (6). This notion is supported by more recent observations demonstrating that structurally defined bi-and tetraantennary blood group I-related oligosaccharides containing terminal Gal␣133Gal moieties inhibit binding of sperm to eggs in a dose-dependent manner (7).In the mouse, at least one UDP-Gal:␤-D-Gal-␣133Gal-galactosyltransferase (␣1,3GT) 1 is responsible for the synthesis of terminal Gal␣133Gal␤134GlcNAc trisaccharides from common lactosamine-terminated glycoconjugates (8, 9). Mice and other placental mammals express the Gal␣133Gal␤134GlcNAc trisaccharide products of ␣1,3GT on a variety of glycoproteins and in a variety of tissues (10, 11). Aside from the postulated role of Gal␣133Gal moiety in murine fertilization, the function(s) of this structure are not known.By contrast, humans, apes, and Old World monkeys lack the ability to synthesize these oligosaccharide moieties, because the genetic homologues of the murine ␣1,3GT locus are pseudogenes incapable of encoding a functional ␣1,3GT (12, 13). Consequently, these latter species are reciprocally replete with immunoglobulins...

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“…According to several reports, a pronounced increase in anti-donor antibodies is correlated with the time of rejection and hamster grafts are rejected by T-cell-deficient rats as rapidly as by completely immunocompetent animals (reviewed by Thomas et a/. (31)). It seems therefore generally accepted that humoral mechanisms are mainly responsible for graft rejection in this model.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, evidence for the importance of anti-donor antibodies was demonstrated by the reports on the effect of splenectomy prior to transplantation, which, in combination with other immunosuppressive treatment, resulted in prolonged graft survival in the hamster-to-rat combination (1,4,7,21). Splenectomy seems to reduce the humoral antibody response, possibly by a simple reduction of the potential antibody-producing cell pool, but other mechanisms cannot be excluded (31).…”

mentioning

confidence: 99%

Anti‐CD4 monoclonal antibody treatment in combination with total lymphoid irradiation and cyclosporin A in hamster‐to‐rat cardiac transplantation

Nielsen

Kemp

1994

APMIS

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Significantly prolonged graft survival (GS) of hamster hearts transplanted heterotopically into rats can be achieved by different immunosuppressive treatment strategies. The exact mechanism of graft rejection is unclear, but it seems to be a primarily humoral, antibody‐mediated type of rejection. The histopathology of long‐term surviving grafts is controversial and the morphology of lymphoid tissue in spleens and lymph nodes as the possible site of anti‐donor antibody formation has not previously been investigated. This report demonstrates a significantly prolonged GS in hamster‐to‐rat cardiac transplantation after combined treatment with total lymphoid irradiation (TLI), cyclosporin A (CyA) and anti‐CD4 monoclonal antibodies (MAb), where long‐term GS (>100 days) could be achieved in a few animals. The histopathology of heart grafts showed predominantly chronic vascular changes with endothelial proliferation, intimal thickening and vessel obliteration. No substantial cellular reactivity in terms of mononuclear/lymphoid cell infiltration could be demonstrated in rejected grafts. Spleens and lymph nodes were characterized by a profound global reduction in lymphoid tissue after preoperative TLI. Although subsequent lymphoid regeneration was depressed due to postoperative immunosuppression, a significant increase in IgM‐positive plasma cells was observed, supporting evidence of an antibody‐mediated mechanism of graft rejection. The role of CD4+ cells is unclear, but anti‐donor antibody formation might involve T‐cell help.

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Immunobiology of Xenografting in Rodents

Cited by 11 publications

References 20 publications

Xenotransplantation

Xenotransplantation

Oocyte Galα1,3Gal Epitopes Implicated in Sperm Adhesion to the Zona Pellucida Glycoprotein ZP3 Are Not Required for Fertilization in the Mouse

Anti‐CD4 monoclonal antibody treatment in combination with total lymphoid irradiation and cyclosporin A in hamster‐to‐rat cardiac transplantation

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