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Simon C. Robson - One of the best experts on this subject based on the ideXlab platform.
Journal of The American Society of Nephrology, 2011Co-Authors: Akira Shimizu, Simon C. Robson, David H. Sachs, Kazuhiko Yamada, Robert B ColvinAbstract:
For xenotransplantation to become a clinical reality, we need to better understand the mechanisms of graft rejection or acceptance. We examined pathologic changes in α1,3-galactosyltransferase gene-knockout pig kidneys transplanted into baboons that were treated with a protocol designed to induce immunotolerance through thymic transplantation (n=4) or were treated with long-term immunosuppressants (n=3). Hyperacute rejection did not occur in α1,3-galactosyltransferase gene-knockout kidney Xenografts. By 34 days, acute humoral rejection led to Xenograft loss in all three Xenografts in the long-term immunosuppression group. The failing grafts exhibited thrombotic microangiopathic glomerulopathy with multiple platelet-fibrin microthrombi, focal interstitial hemorrhage, and acute cellular Xenograft rejection. Damaged glomeruli showed IgM, IgG, C4d, and C5b-9 deposition. They also demonstrated endothelial cell death, diffuse endothelial procoagulant activation with high expression of tissue factor and vWF, and low expression of the ectonucleotidase CD39. In contrast, in the immunotolerance group, two of four grafts had normal graft function and no pathologic findings of acute or chronic rejection at 56 and 83 days. One of the remaining kidneys had mild but transient graft dysfunction with reversible, mild microangiopathic glomerulopathy, probably associated with preformed antibodies. The other kidney in the immunotolerance group developed unstable graft function at 81 days and developed chronic Xenograft glomerulopathy. In summary, the success of pig-to-primate xenotransplantation may necessitate immune tolerance to inhibit acute humoral and cellular Xenograft rejection.
rejection of cardiac Xenografts transplanted from α1 3 galactosyltransferase gene knockout galt ko pigs to baboonsAmerican Journal of Transplantation, 2008Co-Authors: Yosuke Hisashi, Simon C. Robson, David H. Sachs, Kazuhiko Yamada, Kenji Kuwaki, Yaulin Tseng, Stuart L Houser, H J Schuurman, David K C Cooper, Robert B ColvinAbstract:
The use of α1,3-galactosyltransferase gene-knockout (GalT-KO) swine donors in discordant xenotransplantation has extended the survival of cardiac Xenografts in baboons following transplantation. Eight baboons received heterotopic cardiac Xenografts from GalT-KO swine and were treated with a chronic immunosuppressive regimen. The pathologic features of acute humoral Xenograft rejection (AHXR), acute cellular Xenograft rejection (ACXR) and chronic rejection were assessed in the grafts. No hyperacute rejection developed and one graft survived up to 6 months after transplantation. However, all GalT-KO heart grafts underwent graft failure with AHXR, ACXR and/or chronic rejection. AHXR was characterized by interstitial hemorrhage and multiple thrombi in vessels of various sizes. ACXR was characterized by TUNEL+ graft cell injury with the infiltration of T cells (including CD3 and TIA-1+ cytotoxic T cells), CD4+ cells, CD8+ cells, macrophages and a small number of B and NK cells. Chronic Xenograft vasculopathy, a manifestation of chronic rejection, was characterized by arterial intimal thickening with TUNEL+ dead cells, antibody and complement deposition, and/or cytotoxic T-cell infiltration. In conclusion, despite the absence of the Gal epitope, acute and chronic antibody and cell-mediated rejection developed in grafts, maintained by chronic immunosupression, presumably due to de novo responses to non-Gal antigens.
acute vascular rejection of Xenografts roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activityTransplantation, 2004Co-Authors: Bernd Gollackner, David K C Cooper, Imrana Qawi, L Buhler, C Knosalla, Soizic Daniel, Elzbieta Kaczmarek, M Awwad, Simon C. RobsonAbstract:
Hyperacute rejection of vascularized discordant Xenografts can now be effectively managed. However, acute vascular rejection (AVR) then ensues, resulting in graft destruction, coagulopathy, or both within weeks. The aim of this study was to determine associations between humoral responses to the Xenograft and the induction of AVR, coagulopathy, or both.
Annals of the New York Academy of Sciences, 1999Co-Authors: Simon C. Robson, Jan Schulte Am Esch, Fritz H. BachAbstract:
Important mechanisms underlying immediate Xenograft loss by hyperacute rejection (HAR), in the pig-to-primate combination, have been recently delineated. There are now several proposed therapies that deal with the problem of complement activation and xenoreactive natural antibody (XNA) binding to the vasculature that have been shown to prevent HAR. However, vascularized Xenografts are still lost, typically within days, by delayed Xenograft rejection (DXR), alternatively known as acute vascular rejection (AVR). This process is characterized by endothelial cell (EC) perturbation, localization of XNA within the graft vasculature, host NK cell and monocyte activation with platelet sequestration and vascular thrombosis. Alternative immunosuppressive strategies, additive anti-complement therapies with the control of any resulting EC activation processes and induction of protective responses have been proposed to ameliorate this pathological process. In addition, several potentially important molecular incompatibilities between activated human coagulation factors and the natural anticoagulants expressed on porcine EC have been noted. Such incompatibilities may be analogous to cross-species alterations in the function of complement regulatory proteins important in HAR. Disordered thromboregulation is potentially relevant to the progression of inflammatory events in DXR and the disseminated intravascular coagulation seen in primate recipients of porcine renal Xenografts. We have recently demonstrated the inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FXa by porcine EC and the failure of the porcine natural anticoagulant, thrombomodulin to bind human thrombin and hence activate human protein C. The enhanced potential of porcine von Willebrand factor to associate with human platelet GPIb has been demonstrated to be dependent upon the isolated A1 domain of von Willebrand factor. In addition, the loss of TFPI and vascular ATPDase/CD39 activity following EC activation responses would potentiate any procoagulant changes within the Xenograft. These developments could exacerbate vascular damage from whatever cause and enhance the activation of platelets and coagulation pathways within Xenografts resulting in graft infarction and loss. Analysis of these and the other putative factors underlying DXR should lead to the development and testing of genetic approaches that, in conjunction with selected pharmacological means, may further prolong Xenograft survival to a clinically relevant extent.
Immunology Today, 1996Co-Authors: Fritz H. Bach, Wayne W. Hancock, Hans Winkler, Christiane Ferran, Simon C. RobsonAbstract:
Despite considerable progress in understanding the mechanisms of discordant Xenograft rejection, and overcoming hyperacute rejection through targeting of complement or antibody, vascularized Xenografts are typically rejected within days. Here, Fritz Bach and colleagues discuss the importance of endothelial cell activation, platelet aggregation and other aspects of thrombosis, as well as the contribution of host natural killer cell and monocyte activation in overcoming this next barrier to prolonged Xenograft survival.
William H. Catherino - One of the best experts on this subject based on the ideXlab platform.
Development and Validation of Hormonal Impact of a Mouse Xenograft Model for Human Uterine LeiomyomaReproductive Sciences, 2020Co-Authors: Minnie Malik, Joy Britten, William H. CatherinoAbstract:
Multiple in vivo animal models for uterine leiomyoma do not adequately represent human disease based on etiology, molecular phenotype, or limited fixed life span. Our objective was to develop a Xenograft model with sustained growth, by transplanting a well-established actively growing three-dimensional (3D) cell culture of human leiomyoma and myometrium in NOD/SCID ovariectomized female mice. We demonstrated continued growth to at least 12 weeks and the overexpression of extracellular matrix (ECM). Further, we confirmed maintenance of hormonal response that is comparable to human disease in situ. Leiomyoma Xenografts under hormonal treatment demonstrated 8 to12-fold increase of volume over the Xenografts not treated with hormones. Estradiol-treated Xenografts were more cellular as compared to progesterone or combination milieu, at the end of 8-week time frame. There was also a non-statistically significant 2–4 mm^3 increase in volume between 8-week and 12-week Xenografts with higher matrix to cell ratio in 12-week Xenografts compared to the 8-week and placebo Xenografts. Increased expression of ECM proteins, fibronectin, versican, and collagens, indicated an actively growing cell matrix formation in the Xenografts. In conclusion, we have developed and validated a Xenograft in vivo model for uterine leiomyoma that shares the genomic and proteomic characteristics with the human surgical specimens of origin and recapitulates the most important features of the human tumors, the aberrant ECM expression that defines the leiomyoma phenotype and gonadal hormone regulation. Using this model, we demonstrated that combination of estradiol and progesterone resulted in increased cellularity and ECM production leading to growth of the Xenograft tumors.
Hong Wu - One of the best experts on this subject based on the ideXlab platform.
novel dedifferentiated liposarcoma Xenograft models reveal pten down regulation as a malignant signature and response to pi3k pathway inhibitionAmerican Journal of Pathology, 2013Co-Authors: Kathleen B Smith, Linh M Tran, Elizabeth Shurell, Yunfeng Li, Daniel Braas, Heather R Christofk, Fritz C Eilber, Hong WuAbstract:
Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several Xenograft models from surgically resected human dedifferentiated liposarcoma. All Xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, Xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between Xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all Xenografts responded with increased lipid content and a more differentiated gene expression profile. These human Xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care.
Takeshi Kurita - One of the best experts on this subject based on the ideXlab platform.
Endocrinology, 2010Co-Authors: Kazutomo Ishi, Rafael Kakazu, Vanida Ann Serna, Serdar E Bulun, Takeshi KuritaAbstract:
Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17β-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a Xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma Xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The Xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL Xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma Xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.
Iduna Fichtner - One of the best experts on this subject based on the ideXlab platform.
Treatment with 5-azacitidine delay growth of glioblastoma Xenografts: a potential new treatment approach for glioblastomasJournal of Cancer Research and Clinical Oncology, 2018Co-Authors: Tobias Kratzsch, Susanne Antje Kuhn, Andreas Joedicke, Uwe Karsten Hanisch, Peter Vajkoczy, Jens Hoffmann, Iduna FichtnerAbstract:
Purpose Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. The epigenetically active ribonucleoside analog 5-azacitidine is a new therapy option that changes tumor cell chromatin, which is frequently modified by methylation and deacetylation in malignant gliomas. Methods In vitro, we analyzed cell viability, cell apoptosis, and migration of human GBM cells. In vivo, we established subcutaneous and intracerebral GBM mouse models originating from U87MG, U373MG, and primary GBM cells as well as one patient-derived Xenograft. Xenografts were treated with 5-azacitidine as well as valproic acid, bevacizumab, temozolomide, and phosphate buffered saline. The tumor sizes and Ki67 proliferation indices were determined. Glioma angiogenesis was examined immunohistochemically by expression analysis of endothelial cells (CD31) and pericytes (PDGFRβ). Results In vitro, 5-azacitidine treatment significantly reduced human glioblastoma cell viability, increased cellular apoptosis, and reduced cellular migration. In vivo, 5-azacitidine significantly reduced growth in two intracerebral GBM models. Notably, this was also shown for a Xenograft established from a patient surgery sample; whereas, epigenetically acting valproic acid did not show any growth reduction. Highly vascularized tumors responded to treatment, whereas low-vascularized Xenografts showed no response. Furthermore, intracerebral glioblastomas treated with 5-azacitidine showed a clearly visible reduction of tumor angiogenesis and lower numbers of endothelial cells and tumor vessel pericytes. Conclusions Our data show significant growth inhibition as well as antiangiogenic effects in intracerebral as well as patient-derived GBM Xenografts. This encourages to investigate in detail the multifactorial effects of 5-azacitidine on glioblastomas.