Delayed Xenograft Rejection of Pig-to-Babbon Cardiac Transplants After Cobra Venom Factor Therapy

Kobayashi, Takaaki; Taniguchi, Shigeki; Neethling, Francisca A.; Rose, Alan G.; Hancock, Wayne W.; Ye, Y.; Niekrasz, Marek; Kosanke, Stanley D.; Wright, Les; White, David J.; Cooper, D. K. C.

doi:10.1097/00007890-199711150-00005

Cited by 158 publications

(119 citation statements)

References 15 publications

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“…We have found cobra venom therapy to maintain the CH50 at zero, and to be without side-effects. 20 Though minor increases in D-dimer were observed, an important distinguishing feature supporting a central role of TTP was the absence of significant changes in plasma fibrinogen levels. Moreover, the pathology was most consistent with TTP or TM; the thrombotic lesions were predominantly arteriolar in distribution, platelet antigens were observed in association with vWF and fibrin deposition was minimal.…”

Section: Discussionmentioning

confidence: 95%

“…at approximately 100 units/kg/day on days −1 to 14 or 28 to deplete complement levels so that CH50 is approximately equal to 0%. 20 Groups 1, 2 and one group 4 animal also received cyclosporine (Novartis, Basel, Switzerland) (at approximately 15 mg/kg/day) by continuous i.v. infusion from days −8 to 28 to maintain a whole blood level of 1200-1400 ng/ml.…”

Section: Conditioning Regimen In Baboonsmentioning

confidence: 99%

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Porcine hematopoietic cell xenotransplantation in nonhuman primates is complicated by thrombotic microangiopathy

Bühler

Goepfert

Kitamura

et al. 2001

Bone Marrow Transplant

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Summary:Thrombotic microangiopathy (TM) is a serious complication of bone marrow transplantation (BMT) that resembles thrombotic thrombocytopenic purpura (TTP). In attempting to achieve hematopoietic cell chimerism in the pig-to-baboon model, we have observed TM following infusion of high doses (Ͼ10 10 cells/kg) of porcine peripheral blood mobilized progenitor cells (PBPC) into baboons. We performed investigations to analyze the pathobiology of this TM and to test therapeutic interventions to ameliorate it. PBPC were obtained by leukapheresis of cytokine-stimulated swine. The initial observations were made in two baboons that underwent a non-myeloablative regimen (NMR) prior to PBPC transplantation (TX) (group 1). We then studied three experimental groups. Group 2 (n = 2) received NMR without PBPC TX. Group 3 (n = 2) received PBPC TX alone. Group 4 (n = 6) received NMR + PBPC TX combined with prostacyclin, low-dose heparin, methylprednisolone, and cyclosporine was replaced by anti-CD40L mAb in five cases. Baboons in groups 1 and 3 developed severe thrombocytopenia (Ͻ10 000/mm 3 ), intravascular hemolysis with schistocytosis (Ͼ10/high powered field (hpf)), increase in plasma lactate dehydrogenase (LDH) (2500-9000 U/l), transient neurologic changes, renal insufficiency, and purpura. Autopsy on two baboons confirmed extensive platelet thrombi in the microcirculation, and, similar to clinical BMT-associated TM/TTP, no unusually large vWF multimers or changes in vWF protease activity were observed in the plasma of baboons with TM. In group 2, self-limited thrombocytopenia occurred for 10-15 days following NMR. Group 4 baboons developed thrombocytopenia (Ͻ20 000/mm 3 ) rarely requiring plat-

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Section: Discussionmentioning

confidence: 95%

Section: Conditioning Regimen In Baboonsmentioning

confidence: 99%

Porcine hematopoietic cell xenotransplantation in nonhuman primates is complicated by thrombotic microangiopathy

Bühler

Goepfert

Kitamura

et al. 2001

Bone Marrow Transplant

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“…However, cellular elements also appear to play a significant role in the development of DXR (Blakely et al, 1994;Candinas et al, 1996;Kobayashi et al, 1997;Leventhal et al, 1993). Some studies conclude that infiltrating cells consist primarily of macrophages and NK cells in rodents (Blakely et al, 1994;Candinas et al, 1996) and are T cell-independent, in view of the low number of T cells in the infiltrates in the xenografted organs .…”

Section: Shimizu Et Almentioning

confidence: 99%

“…Some studies conclude that infiltrating cells consist primarily of macrophages and NK cells in rodents (Blakely et al, 1994;Candinas et al, 1996) and are T cell-independent, in view of the low number of T cells in the infiltrates in the xenografted organs . Others have also argued a role for macrophages and NK cells (Blakely et al, 1994;Candinas et al, 1996;Fryer et al, 1997;Kobayashi et al, 1997;Seebach and Waneck, 1997).…”

Section: Shimizu Et Almentioning

confidence: 99%

Acute Humoral Xenograft Rejection: Destruction of the Microvascular Capillary Endothelium in Pig-to-Nonhuman Primate Renal Grafts

Shimizu

Meehan

Kozłowski

et al. 2000

Laboratory Investigation

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SUMMARY:The major cause of xenograft loss beyond hyperacute rejection is a form of injury, traditionally termed delayed xenograft rejection (DXR), whose pathogenesis is unknown. Here we analyze the immunologic and morphologic features of DXR that develops in pig kidney xenografts transplanted into nonhuman primates. Kidneys from miniature swine were transplanted into cynomolgus monkeys (n ϭ 14) or baboons (n ϭ 11) that received regimens aimed to induce mixed chimerism and tolerance. No kidney was rejected hyperacutely. Morphologic and immunohistochemical studies were performed on serial biopsies, and an effort was made to quantify the pathologic features seen. The early phase of DXR (Days 0 -12) was characterized by focal deposition of IgM, IgG, C3, and scanty neutrophil and macrophage infiltrates. The first abnormality recognized was glomerular and peritubular capillary endothelial cell death as defined by in situ DNA nick-end labeling (TUNEL). Damaged endothelial cells underwent apoptosis and, later, frank necrosis. The progressive phase developed around Day 6 and was characterized by progressive deposition of IgM, IgG, C3, and prominent infiltration of cytotoxic T cells and macrophages, with a small number of NK cells. Thrombotic microangiopathy developed in the glomeruli and peritubular capillaries with TUNELϩ endothelial cells, platelet aggregation, and destruction of the capillary network. Only rare damaged arterial endothelial cells and tubular epithelial cells were observed, with rare endothelialitis and tubulitis. In the advanced phase of DXR, interstitial hemorrhage and infarction occurred. During the development of DXR, the number of TUNELϩ cells increased, and this correlated with progressive deposition of antibody. The degree of platelet aggregation correlated with the number of TUNELϩ damaged endothelial cells. We conclude that peritubular and glomerular capillary endothelia are the primary targets of renal DXR rather than tubular epithelial cells or arterial endothelium and that the earliest detectable change is endothelial cell death. DXR was characterized by progressive destruction of the microvasculature (glomeruli and peritubular capillaries) and formation of fibrin-platelet thrombi. Both cytotoxic cells and antibodies potentially mediate the endothelial damage in DXR; however, in this model, DXR is largely humorally mediated and is better termed "acute humoral xenograft rejection." (Lab Invest 2000, 80:815-830).

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“…1B). Histopathologically, the rejected hearts showed features of DXR typically seen in discordant combinations when hyperacute rejection is averted by depletion of complement (46,47), or by genetic modification of donor pig organs to express human complementregulating proteins (9,48,49).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Survival of Hamster Hearts in Presensitized Rats

Lin

Soares

Sato

et al. 2000

The Journal of Immunology

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We transplanted hamster hearts into rats that had been sensitized to hamster cardiac grafts 5 days earlier as a model for discordant xenotransplantation. Sensitized rats had high serum levels of elicited anti-donor IgM and IgG that caused hyperacute rejection. Transient complement inhibition with cobra venom factor (CVF) plus daily and continuing cyclosporin A (CyA) prevented hyperacute rejection. However, grafts underwent delayed xenograft rejection (DXR). DXR involved IgG and associated Ab-dependent cell-mediated rejection, because depletion of IgG or Ab-dependent cell-mediated rejection-associated effector cells prolonged graft survival and the serum-mediated Ab-dependent cell-mediated cytotoxicity in vitro. Blood exchange in combination with CVF/CyA treatment dramatically decreased the level of preexisting Abs, but DXR still occurred in association with the return of Abs. Splenectomy and cyclophosphamide acted synergistically to delay Ab return, and when combined with blood exchange/CVF/CyA facilitated long-term survival of grafts. These grafts survived in the presence of anti-donor IgM, IgG, and complement that precipitated rejection of naive hearts, indicating that accommodation (survival in the presence of anti-graft Abs and complement) had occurred. We attribute the long-term survival to the removal of preexisting anti-donor Abs and therapy that attenuated the rate of Ab return. Under such conditions, the surviving hearts showed expression in endothelial cells and smooth muscle cells of protective genes and an intragraft Th2 immune response. Th2 responses and protective genes are associated with resistance to IgM- and IgG-mediated, complement-dependent and -independent forms of rejection.

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Delayed Xenograft Rejection of Pig-to-Babbon Cardiac Transplants After Cobra Venom Factor Therapy

Cited by 158 publications

References 15 publications

Porcine hematopoietic cell xenotransplantation in nonhuman primates is complicated by thrombotic microangiopathy

Porcine hematopoietic cell xenotransplantation in nonhuman primates is complicated by thrombotic microangiopathy

Acute Humoral Xenograft Rejection: Destruction of the Microvascular Capillary Endothelium in Pig-to-Nonhuman Primate Renal Grafts

Long-Term Survival of Hamster Hearts in Presensitized Rats

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