Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Seppen, Jurgen; Til, Niek P. van; Rijt, Roos van der; Hiralall, Johan K.; Kunne, Cindy; Elferink, Ronald P.J. Oude

doi:10.1038/sj.gt.3302681

Cited by 39 publications

(18 citation statements)

References 38 publications

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“…40 However, therapeutic transgenes are sometimes seen as foreign antigens by the mature immune system, as XIAP is an endogenous protein, and should not cause an immune response. Because human XIAP might cause immune lesions in mice, one solution to this problem is to introduce the gene in the fetal or neonatal period, which should lead to tolerance 41 . We checked for immune reaction in the mice after human XIAP transduction.…”

Section: X-chromosome Linked Inhibitor Of Apoptosis Protein Xh Wang Ementioning

confidence: 99%

X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

Wang

et al. 2007

Gene Ther

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Loss of muscle protein is a serious complication of catabolic diseases and contributes substantially to patients' morbidity and mortality. This muscle loss is mediated largely by the activation of the ubiquitin-proteasome system; however, caspase-3 catalyzes an initial step in this process by cleaving actomyosin into small protein fragments that are rapidly degraded by the proteasome-dependent proteolytic pathway. We hypothesized that X-chromosome linked inhibitor of apoptosis protein (XIAP), an endogenous caspase-3 inhibitor, would block this first step in the cleavage of actomyosin that would make XIAP a candidate for treating muscle wasting. To determine if XIAP could attenuate muscle protein degradation, we used a recombinant lentivirus (Len-XIAP) encoding the full-length human XIAP cDNA to express XIAP in vivo. In muscle of streptozotocin-treated insulin-deficient mice, total muscle protein degradation, caspase-3 activity, and myofibril destruction were increased while XIAP was decreased. Overexpression of XIAP in these mice attenuated the excessive muscle protein degradation. Increased proteasome activity, caspase-3 activity and myofibril protein breakdown were all reduced. The ability of XIAP to prevent the loss of muscle protein suggests that XIAP could be a therapeutic reagent for muscle atrophy in catabolic diseases.

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Section: X-chromosome Linked Inhibitor Of Apoptosis Protein Xh Wang Ementioning

confidence: 99%

X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

Wang

et al. 2007

Gene Ther

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“…23 Similar findings have been reported by many groups and for a wide range of applications and vector platforms. [24][25][26][27][28] The induction of a cellular immune response against an antigen is the result of antigen presentation by professional antigenpresenting cells (APCs), such as macrophages and dendritic cells (DCs). 29 APCs can present endogenously expressed or exogenously acquired antigens on major histocompatibility complex (MHC) class I molecules, and prime naive CD8 ϩ T cells, which, in turn, target the destruction of cells expressing the antigen.…”

mentioning

confidence: 99%

In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance

Annoni

Brown

Cantore

et al. 2009

Blood

123

119

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We previously showed that incorporating target sequences for the hematopoieticspecific microRNA miR-142 into an antigen-encoding transgene prevents antigen expression in antigen-presenting cells (APCs). To determine whether this approach induces immunologic tolerance, we treated mice with a miR-142-regulated lentiviral vector encoding green fluorescent protein (GFP), and subsequently vaccinated the mice against GFP. In contrast to control mice, no anti-GFP response was observed, indicating that robust tolerance to the transgene-encoded antigen was achieved. Furthermore, injection of the miR-142-regulated vector induced a population of GFP-specific regulatory T cells. Interestingly, an anti-GFP response was observed when microRNA miR-122a was inserted into the vector IntroductionUnwanted immune responses are a major medical problem in autoimmunity and gene therapy. Existing approaches to subdue an immune response use nonspecific methods of immune suppression, including corticosteroids, and molecules that block T-cell signaling, proliferation, and function. Developing a means for inducing antigen-specific tolerance would provide a way to overcome the limitations of existing immune modulating agents. Because multiple antigens are likely to be involved in any single autoimmune disorder or cell/tissue transplant, there has been skepticism about antigen-specific therapy. 1 However, the emerging knowledge of regulatory T cells (Tregs) has caused a re-examination of this view. 2,3 Tregs play a natural role in preventing the development of autoimmunity by homing to the tissue where their cognate antigen is expressed, and suppressing local immune responses through direct inhibition of effector T cells. 4,5 The ability of antigenspecific Tregs to control a complex immune response was demonstrated by experiments showing that adoptive transfer of BDC2.5 Tregs, which are specific for a single islet antigen, into nonobese diabetic mice was able to reduce the incidence of diabetes. 6 Delivery of simple antigenic molecules, either by protein or gene vector-based administration, offers an attractive platform for tolerance induction in comparison with global immunosuppression. The most clinically advanced antigen-specific therapies involve administration of the soluble form of the antigen. Unfortunately, application of this approach to the treatment of autoimmune disease has been mostly unsuccessful in human clinical trials. [7][8][9][10][11] One of the limitations of these tolerance-inducing strategies is that they do not ensure that the antigen is targeted to pathways that can promote tolerance, and, more importantly, to pathways that induce antigen-specific Tregs. 12,13 This is partly because strategies for reliably targeting an antigen into these pathways in vivo have not been available, and these pathways are still poorly understood, making them difficult to target. 14,15 An alternative to protein-based antigen administration is to use gene delivery as a means of inducing tolerance. 16,17 Success has been achieved in animal ...

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“…However, the immune response towards UGT1A1 can result in loss of therapeutic efficacy. In neonatal Gunn rats, upon transduction with a lentiviral vector, only a transient correction of serum bilirubin levels was seen [107]. Also, in adult Gunn rats treated with an Ad5 vector with a viral promoter, the correction was only transient [108].…”

Section: The Promise Of Liver-directed Gene Therapy In Crigler-najjarmentioning

confidence: 97%

Gene Replacement Therapy for Genetic Hepatocellular Jaundice

Dijk

Beuers

Bosma

2014

Clinic Rev Allerg Immunol

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Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.

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Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats

Cited by 39 publications

References 38 publications

X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance

Gene Replacement Therapy for Genetic Hepatocellular Jaundice

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