Overexpression of heme oxygenase-1 protects allogeneic thyroid grafts from rejection in naive mice

Niimi, Masanori; Takashina, Motoi; Takami, Hiroshi; Ikeda, Yoshifumi; Shatari, Tomoo; Hamano, Kimikazu; Esato, Kensuke; Matsumoto, Kenji; Kameyama, Kaori; Kodaira, Susumu; Wood, Kathryn J.

doi:10.1067/msy.2000.109968

Cited by 15 publications

(10 citation statements)

References 22 publications

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“…Under conditions of HO activity inhibition, exogenous CO restored the beneficial effects of HO-1 (7). Moreover, HO-1 overexpression benefited liver (8), thyroid (9), and cardiac (10) allograft survival.…”

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confidence: 89%

Systemic Rather Than Local Heme Oxygenase-1 Overexpression Improves Cardiac Allograft Outcomes in a New Transgenic Mouse

Araujo¹,

Meng

Tward³

et al. 2003

The Journal of Immunology

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Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, exhibits potent antioxidant and anti-inflammatory properties. We developed HO-1 transgenic (Tg) mice using a rat HO-1 genomic transgene under the control of the endogenous promoter. Transgene expression was demonstrated by RT-PCR in all studied tissues, and a modest HO-1 overexpression was documented by Western, ELISA, and enzyme activity assays. To assess the effect of local vs systemic HO-1 in the acute rejection response, we used Tg mice as organ donors or recipients of MHC-incompatible heart grafts. In the local HO-1 overexpression model, Tg allografts survived 10.5 ± 0.7 days (n = 10), compared with 6.5 ± 0.4 days (n = 6) for wild-type donor controls (p = 0.0001). In the systemic HO-1 overexpression model, Tg recipients maintained allografts for 26.8 ± 3.4 days (n = 10), compared with 6.3 ± 0.1 days (n = 12) in wild-type controls (p = 0.00009). Inhibition of HO activity by treatment with tin protoporphyrin blunted survival advantage in Tg mice and resulted in acute graft rejection (n = 3). Increased carboxyhemoglobin levels were consistently noted in Tg mice. Comparisons of grafts at day 4 indicated that HO-1 overexpression was inversely associated with vasculitis/inflammatory cell infiltrate in both models. Hearts transplanted into Tg recipients showed decreased CD4+ lymphocyte infiltration and diminished immune activation, as judged by CD25 expression. Thus, although local and systemic HO-1 overexpression improved allograft outcomes, systemic HO-1 led to a more robust protection and resulted in a significant blunting of host immune activation. This Tg mouse provides a valuable tool to study mechanisms by which HO-1 exerts beneficial effects in organ transplantation.

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confidence: 89%

Systemic Rather Than Local Heme Oxygenase-1 Overexpression Improves Cardiac Allograft Outcomes in a New Transgenic Mouse

Araujo¹,

Meng

Tward³

et al. 2003

The Journal of Immunology

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“…Moreover, adeno-associated virusmediated overexpression of Ho-1 protected NOD mice from autoimmune diabetes by reducing the population of mature dendritic cells and autoreactive T lymphocytes, providing a successful preventive strategy for systemic Ho-1 expression in this disease [14]. Induction or overexpression of Ho-1 also successfully prolonged survival of transplanted grafts following allotransplantation of the heart [15], liver [16], thyroid [17] and islets [18]. However, it remains unclear whether HO-1 has a protective effect on pancreatic beta cells in NOD mice.…”

Section: Introductionmentioning

confidence: 99%

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Huang

Chu²,

Yu³

et al. 2010

Diabetologia

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Aims/hypothesis Haem oxygenase 1 (HO-1) has strong anti-apoptotic, anti-inflammatory and antioxidative effects that help protect cells against various forms of immune attack. We investigated whether transgenic expression of Ho-1 (also known as Hmox1) in pancreatic beta cells would protect NOD mice from autoimmune damage and prolong graft survival following islet transplantation. Methods To evaluate the protective effect of beta cellspecific HO-1 in autoimmune diabetes, we used an insulin promoter-driven murine Ho-1 construct (pIns-mHo-1) to generate a transgenic NOD mouse. Transgene expression, insulitis and the incidence of diabetes in mice were characterised. Lymphocyte composition, the development of T helper (Th)1, Th2 and T regulatory (Treg) cells, T cell proliferation and lymphocyte-mediated disease transfer were analysed. The potential effects of transgenic islets and islet transplantation on apoptosis, inflammation and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) were evaluated. Results Transgenic mice showed less severe insulitis and a lower incidence of diabetes than non-transgenic control littermates. Lymphocyte composition and functions were not affected. Islets from transgenic mice expressed lower levels of proinflammatory cytokines/chemokines, proapoptotic gene expression and amounts of ROS/RNS, and were more resistant to TNF-α-and IFN-γ-induced apoptosis. Islet grafts from transgenic mice also survived longer in diabetic recipients than control islets. Conclusions/interpretation Transgenic overexpression of Ho-1 in beta cells protected NOD mice from diabetes and delayed the autoimmune destruction of islet grafts, providing valuable insight into the development of better strategies for clinical islet transplantation in patients with type 1 diabetes.

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“…HO-1 is an inducible isoform of HO and has been shown to have potent protective effects against various stresses in diverse experimental models [2][3][4][5]. In the last decade, induction of HO-1 has been shown to be beneficial against pitfalls associated with organ transplantation, including I/R injury [6][7][8][9] and allogenic immune reactions due to histoincompatibility including graft rejection [4,[10][11][12][13] and graft-versushost disease [14]. Likewise, carbon monoxide (CO), one of the byproducts of heme degradation through HO, has a wide range of effectiveness in preventing impairment of the transplanted grafts during I/R injury [15,16], tissue injuries associated with acute rejection [17], and also mouse-to-rat xenograft rejection [18].…”

Section: Introductionmentioning

confidence: 99%

Protective effect of carbon monoxide in transplantation

Nakao¹

2006

J Cell Mol Med

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During the last decades due to the development of new immunosuppressive agents and improvements in organ preservation methods, surgical techniques, and postoperative care, organ transplantation has become an ultimate therapeutic option for irreversible organ failure. Early graft survival has significantly improved; however, the long-term outcome remains unsatisfactory. Multiple factors, both immunogenic and non-immunogenic etiologies, are involved in the deterioration of the allografts, and the recent use of expanded criteria donors to overcome the organ shortage may also contribute to the graft losses. Carbon monoxide (CO) is commonly viewed as a poison in high concentrations due to its ability to interfere with oxygen delivery. However, CO is endogenously produced in the body as a byproduct of heme degradation by the heme oxygenase (HO) and has recently received notable attention as a gaseous regulatory molecule. In fact, an augmentation of endogenous CO by induction of HO-1 or exogenously added CO is known to have potent cytoprotective effects in various disease models. Several recent reports have demonstrated that CO provides potent cytoprotective effects in the field of organ and cell transplantation. CO is able to prevent ischemia/reperfusion injury, allograft rejection, and xenograft rejection via its anti-inflammatory, anti-apoptotic and anti-proliferation effects, suggesting that CO might be a valuable therapeutic option in the field of transplantation. Based on the recent advancement of our understanding of CO as a new therapeutic molecule, this review attempts to summarize the functional roles as well as biological and molecular mechanisms of CO in transplantation and discusses potential CO application to the clinical transplant setting.

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Overexpression of heme oxygenase-1 protects allogeneic thyroid grafts from rejection in naive mice

Cited by 15 publications

References 22 publications

Systemic Rather Than Local Heme Oxygenase-1 Overexpression Improves Cardiac Allograft Outcomes in a New Transgenic Mouse

Systemic Rather Than Local Heme Oxygenase-1 Overexpression Improves Cardiac Allograft Outcomes in a New Transgenic Mouse

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Protective effect of carbon monoxide in transplantation

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