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Dive into the research topics where Lisa Murray-Segal is active.

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Featured researches published by Lisa Murray-Segal.


Journal of Clinical Investigation | 2004

Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation

Karen M. Dwyer; Simon C. Robson; Harshal Nandurkar; Duncan J. Campbell; Hilton Gock; Lisa Murray-Segal; Nella Fisicaro; Tharun B. Mysore; Elzbieta Kaczmarek; Peter J. Cowan; Anthony J. F. d'Apice

Extracellular nucleotides play an important role in thrombosis and inflammation, triggering a range of effects such as platelet activation and recruitment, endothelial cell activation, and vasoconstriction. CD39, the major vascular nucleoside triphosphate diphosphohydrolase (NTPDase), converts ATP and ADP to AMP, which is further degraded to the antithrombotic and anti-inflammatory mediator adenosine. Deletion of CD39 renders mice exquisitely sensitive to vascular injury, and CD39-null cardiac xenografts show reduced survival. Conversely, upregulation of CD39 by somatic gene transfer or administration of soluble NTPDases has major benefits in models of transplantation and inflammation. In this study we examined the consequences of transgenic expression of human CD39 (hCD39) in mice. Importantly, these mice displayed no overt spontaneous bleeding tendency under normal circumstances. The hCD39 transgenic mice did, however, exhibit impaired platelet aggregation, prolonged bleeding times, and resistance to systemic thromboembolism. Donor hearts transgenic for hCD39 were substantially protected from thrombosis and survived longer in a mouse cardiac transplant model of vascular rejection. These thromboregulatory manifestations in hCD39 transgenic mice suggest important therapeutic potential in clinical vascular disease and in the control of serious thrombotic events that compromise the survival of porcine xenografts in primates.


Transplantation | 1998

Anti-gal Antibody-mediated Allograft Rejection In α1,3-galactosyltransferase Gene Knockout Mice: A Model of Delayed Xenograft Rejection

Martin J. Pearse; Ewa Witort; Patricia L. Mottram; Wenruo Han; Lisa Murray-Segal; Margarita Romanella; Evelyn Salvaris; Trixie A. Shinkel; David J. Goodman; Anthony J. F. d'Apice

Background. The key role of anti-galactosea1,3-galactose (anti-aGal) xenoantibodies in initiating hyperacute xenograft rejection has been clearly demonstrated using a variety of in vitro and in vivo approaches. However, the role of anti-aGal antibodies in mediating post-hyperacute rejection mechanisms, such as antibody-dependent cellular cytoxicity, remains to be determined, primarily because of the lack of a small animal model with which to study this phenomena. Methods. Hearts from wild-type mice were transplanted heterotopically into a1,3-galactosyltransferase knockout (Gal KO) mice, which like humans develop antibodies to the disaccharide galactosea1,3-galactose (Gal). At the time of rejection, hearts were examined histologically to determine the mechanism of rejection. Results. Hearts from wild-type mice transplanted into high-titer anti-aGal recipients were rejected in 8 ‐13 days. Histological examination demonstrated a cellular infiltrate consisting of macrophages (80 ‐90%), natural killer cells (5‐10%), and T cells (1‐5%). In contrast, wild-type hearts transplanted into low anti-Gal titer recipients demonstrated prolonged (>90 day) survival. However, a significant proportion (30 ‐ 40%) of these underwent a minor rejection episode between 10 and 13 days, but then recovered (“accommodated”). Conclusions. The results of this study suggest that the Gal KO mouse is a useful small animal vascularized allograft model, in which the role of anti-aGal antibody in graft rejection can be studied in isolation from other rejection mechanisms. The titer of antiaGal antibody was found to be the critical determinant of rejection. The histopathological features of rejection in this model are very similar to other models of delayed xenograft rejection, in both the timing and composition of the cellular infiltrate. The Gal KO mouse therefore provides a new rodent model, which will aid in the identification of the distinct components involved in the pathogenesis of delayed xenograft rejection.


Microsurgery | 1999

Modified technique for kidney transplantation in mice.

Wenruo Han; Lisa Murray-Segal; Patricia L. Mottram

This study describes a new method for joining the donor ureter to the recipient bladder during mouse kidney transplantation. The donor left kidney was harvested using methods previously published, except that bladder tissue was not harvested with the end of the ureter. The recipient left kidney was removed and the donor kidney was attached using end‐to‐side anastomosis. The recipient bladder was pierced with a 21‐gauge needle allowing curved forceps to be inserted through the bladder, to pull through the ureter, and the periuretal tissue was stitched to the exterior wall of the bladder. The donor ureter was allowed to retract inside the bladder. Following a right nephrectomy, grafts were monitored by blood serum creatinine and urea. With a technical success rate of 83%, this technique reduced donor harvest time by 20 minutes and ureter attachment time by 15 minutes making it the best method available for mouse kidney transplantation.


Diabetes | 2013

The Protective Effects of CD39 Overexpression in Multiple Low-Dose Streptozotocin–Induced Diabetes in Mice

Joanne S.J. Chia; Jennifer L. McRae; Helen E. Thomas; Stacey Fynch; Lorraine Elkerbout; Prue Hill; Lisa Murray-Segal; Simon C. Robson; Chen J; Anthony J. F. D’Apice; Peter J. Cowan; Karen M. Dwyer

Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell–mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell–mediated injury.


Xenotransplantation | 2000

Hyperacute rejection of vascularized heart transplants in BALB/c Gal knockout mice

Hilton Gock; Evelyn Salvaris; Lisa Murray-Segal; Patricia Mottram; Wenruo Han; Martin J. Pearse; David J. Goodman; Peter J. Cowan; Anthony J. F. d'Apice

Abstract: Pig‐to‐primate vascularized xenografts undergo hyperacute rejection (HAR). This results from pre‐formed xenoreactive antibodies directed against galactose‐α1,3‐galactose (αGal) in the donor organ and activation of the complement cascade. We describe an in vivo murine model of HAR using a BALB/c mice system devoid of histocompatibility or complement differences between donor and recipient to investigate in isolation, the effects of αGal epitope and anti‐αGal antibody interactions in causing rejection of vascularized heart transplants. Gal KO mice were immunized with rabbit red blood cell membranes to induce high anti‐αGal antibody titers that were predominantly IgM by ELISA (enzyme‐linked immunosorbent assay). When αGal‐expressing mice hearts were transplanted heterotopically into these recipients (n = 12), 67% of grafts rejected within 24 h, the majority within 16 h with histological features of HAR. In contrast, none of the grafts in the non‐immunized Gal KO recipient control group (n = 11) underwent HAR. Interestingly, approximately 50% of the remaining grafts in both the immunized and non‐immunized Gal KO recipient group were rejected between 7 and 27 days by a rejection process characterized by a dense infiltrate of macrophage/monocytes, perivascular cuffing and tissue destruction similar to recent descriptions of delayed xenograft rejection (DXR). In addition, some grafts (21.5%) continued to survive in the immunized Gal KO recipients despite the presence of anti‐αGal antibody and normal complement activity and these showed well‐preserved myocardium when harvested whilst still functioning well at days 30 or 90. No rejection was seen when Gal KO donors were used in this system (n = 4), nor when αGal‐expressing BALB/c hearts were transplanted into αGal‐expressing BALB/c recipients (n = 5). This in vivo small animal model offers the opportunity to test a variety of strategies to overcome HAR prior to more resource intensive pig‐to‐primate studies, and may provide insights into the processes similar to DXR and accommodation.


Xenotransplantation | 2000

Naturally acquired anti-αGal antibodies in a murine allograft model similar to delayed xenograft rejection

Evelyn Salvaris; Hilton Gock; Wenruo Han; Lisa Murray-Segal; Helen Barlow; Patricia L. Mottram; Martin J. Pearse; Peter J. Cowan; David J. Goodman; Anthony J. F. d'Apice

Abstract: Antibodies directed against galactose‐α1,3‐galactose (αGal) are believed to play an important a role in the pathogenesis of delayed xenograft rejection (DXR). This study was designed to determine whether α1,3‐galactosyltransferase‐deficient (Gal KO) mice can naturally acquire a sufficient anti‐αGal titre to cause the delayed type rejection of αGal‐expressing hearts. Gal KO mice of various ages were assessed for anti‐αGal antibody levels. αGal‐expressing hearts were transplanted heterotopically into these mice and monitored daily. Rejecting and surviving hearts were evaluated histologically. Results: in Gal KO mice greater than 6‐month‐old, 64% had an anti‐αGal antibody titre above the background level. When wild‐type αGal‐expressing hearts were transplanted into this group, 45% of grafts rejected within 5 to 13 days. Histological examination of the rejected hearts displayed marked tissue damage and an inflammatory infiltrate of predominantly macrophage/monocytes. Surviving grafts showed preserved morphology. Like humans, Gal KO mice naturally develop anti‐αGal antibodies with age. The titre in these mice was sufficient to cause a “delayed‐type” rejection of a significant proportion of αGal‐expressing cardiac grafts. This model thus provides an opportunity to investigate the role of naturally acquired anti‐αGal antibodies in the pathogenesis of DXR.


Transplantation | 1997

Idarubicin-anti-CD3: a new immunoconjugate that induces alloantigen-specific tolerance in mice.

Patricia L. Mottram; Wenruo Han; Lisa Murray-Segal; Thomas E. Mandel; Geoffrey A. Pietersz; Ian F. C. McKenzie

BACKGROUND In testing new anti-CD3 agents for transplantation tolerance induction, an anti-CD3 monoclonal antibody was used as a carrier for the cytotoxic drug idarubicin (IDA). METHODS Anti-CD3 (KT3) was covalently coupled with IDA, producing the IDA-KT3 immunoconjugate, which was tested for specificity by fluorometry and for inhibition of proliferation of CD3+ E3 cells ([3H]thymidine uptake). KT3 and IDA-KT3 were used to treat CBA recipients of BALB/c vascularized cardiac allografts. Mice with hearts surviving >100 days were challenged with donor and third-party (C57BL/6) skin. RESULTS Conjugation to IDA did not reduce binding of KT3 to E3 cells, although the toxicity of IDA was reduced by conjugation. In BALB/c to CBA cardiac allografts (rejected in 12-17 days), both KT3 and IDA-KT3 (0.25-0.5 mg/20 g mouse i.p. at the time of transplantation) induced tolerance. Hearts survived >100 days and skin graft challenge showed indefinite survival of donor grafts but not third-party grafts. KT3 was less toxic, as measured by tumor necrosis factor-a release and blood glucose levels, than equivalent dosages of 145-2C11. At lower dosages (0.1 mg/20 g mouse), KT3-treated animals rejected BALB/c allografts in 15 to 19 days, but IDA-KT3 induced long survival (>100 days) and donor-specific tolerance in 5 of 6 mice. CONCLUSIONS Coupling IDA to anti-CD3 reduced the in vivo toxicity of IDA and improved the immunosuppressive performance of KT3, reducing the side effects seen with other anti-CD3 agents. IDA-KT3 is a new, effective, nontoxic tolerogen in this donor-recipient combination.


Xenotransplantation | 2004

Fate of alphaGal +/+ pancreatic islet grafts after transplantation into alphaGal knockout mice.

Abhilash P. Chandra; Evelyn Salvaris; Stacey N. Walters; Lisa Murray-Segal; Hilton Gock; Anne M. Lehnert; Jeffrey K. W. Wong; Peter J. Cowan; Anthony J. F. d'Apice; Philip J. O'Connell

Abstract:  Background:  Important phylogenetic differences between pig and human tissues prevent xenotransplantation from becoming a clinically feasible option. Humans lack the galactose‐α1,3‐galactose (αGal) epitope on endothelial cell surfaces and therefore have preformed anti‐αGal antibodies. The role of these antibodies in rejection of non‐vascular xenografts remains controversial. This study investigared the role of anti‐αGal antibodies in rejection of non‐vascularized αGal+/+ grafts in αGal −/− mice.


American Journal of Transplantation | 2012

Protective effects of transgenic human endothelial protein C receptor expression in murine models of transplantation.

K.F.E. Lee; Bo Lu; Jean Christian Roussel; Lisa Murray-Segal; Evelyn Salvaris; Suzanne J. Hodgkinson; Bruce M. Hall; Anthony J. F. d'Apice; Peter J. Cowan; Hilton Gock

Thrombosis and inflammation are major obstacles to successful pig‐to‐human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti‐inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen‐induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 μmol/L vs. 78.5 ± 10.0 μmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6‐deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant‐related thrombotic and inflammatory injury, without detrimental effects in the donor animal.


Xenotransplantation | 2008

Anti‐Gal antibody‐mediated skin graft rejection requires a threshold level of Gal expression

Lisa Murray-Segal; Hilton Gock; Peter J. Cowan; Anthony J. F. d’Apice

Abstract:  Background:  Despite overcoming xenograft hyperacute rejection (HAR), Gal (galactose‐α1,3‐galactose) expression may not be completely eliminated from the α1,3‐galactosyltransferase gene knockout (Gal KO) pig because of alternative galactosyltransferases. Whether low levels of “residual” Gal are still susceptible to either complement fixing or non‐complement fixing antibody beyond the HAR barrier remains unknown. Furthermore, it would be impossible to analyze the immune response specific to low‐level Gal in a xenograft setting given the multitude of xenoantigens that could induce a recipient response. To investigate this question, we therefore used a skin graft model in BALB/c mice where the sole difference between donor and recipient was the expression of Gal, where rejection is caused by passively administered anti‐Gal monoclonal antibody and where HAR does not occur.

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Peter J. Cowan

St. Vincent's Health System

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Hilton Gock

St. Vincent's Health System

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Evelyn Salvaris

St. Vincent's Health System

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Wenruo Han

Royal Melbourne Hospital

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David J. Goodman

St. Vincent's Health System

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Nella Fisicaro

St. Vincent's Health System

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Tharun B. Mysore

St. Vincent's Health System

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Martin J. Pearse

St. Vincent's Health System

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