Recent Advances in Immune Modulation

Miao, Carol H.

doi:10.2174/156652307782151524

Cited by 15 publications

(9 citation statements)

References 121 publications

(153 reference statements)

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“…Some of these approaches are described below. In the companion review, Carol H. Miao also discussed some immunointervention strategies, which could enable long-term transgene expression [Miao, 2007].…”

Section: Discussionmentioning

confidence: 99%

Immune Responses to Gene Product of Inducible Promoters

Guiner

Stieger²,

Snyder³

et al. 2007

CGT

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Efficient gene transfer has been achieved in several animal models using different vector systems, leading to stable transgene expression. The tight control of this expression is now an important outcome for the field of gene therapy. Such regulation is likely to be required for therapeutic applications and in some instances for safety reasons. For this purpose, several regulatable systems depending on small molecules have been developed. Among these, the tetracycline and the rapamycin dependent systems have been largely used. However, if long-term regulation of the transgene has been obtained in small animal models using these inducible systems, when translational studies were initiated in larger animals, the development of an immune response against proteins involved in transgene regulation were often observed. Such immune response was especially documented when using the TetOn tetracycline regulatable system in nonhuman primates (NHP). Humoral and destructive cellular immune responses against the transactivator involved in this regulation system were documented in a large majority of NHP leading to the complete loss of the transgene regulation and expression. This review will describe the immune responses observed in these different model systems applied for transgene regulation. Focus will be finally given on future directions in which such immune responses might be surmounted, enabling long-term transgene regulation in future clinical developments of gene transfer.

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Section: Discussionmentioning

confidence: 99%

Immune Responses to Gene Product of Inducible Promoters

Guiner

Stieger²,

Snyder³

et al. 2007

CGT

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“…Recent studies indicate that immune responses against vectors or transgene products can become major obstacles for successful application of gene therapy. [1][2][3] Hemophilia A, a congenital bleeding disorder caused by a monogenic defect of coagulation factor VIII (FVIII), is an ideal candidate for the successful application of somatic cell gene therapy. Previous preclinical and clinical trials demonstrated that viral and nonviral gene transfer of FVIII [4][5][6][7][8][9] often results in transient gene expression in the absence of immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

Anti-CD3 antibodies modulate anti–factor VIII immune responses in hemophilia A mice after factor VIII plasmid-mediated gene therapy

Peng

Rawlings

et al. 2009

Blood

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One major obstacle in gene therapy is the generation of immune responses directed against transgene product. Five consecutive anti-CD3 treatments concomitant with factor VIII (FVIII) plasmid injection prevented the formation of inhibitory antibodies against FVIII and achieved persistent, therapeutic levels of FVIII gene expression in treated hemophilia A mice. Repeated plasmid gene transfer is applicable in tolerized mice without eliciting immune responses. Anti-CD3 treatment significantly depleted both CD4+ and CD8+ T cells, whereas increased transforming growth factor-β levels in plasma and the frequency of both CD4+CD25+FoxP3+ and CD4+CD25−Foxp3+ regulatory T cells in the initial few weeks after treatment. Although prior depletion of CD4+CD25+ cells did not abrogate tolerance induction, adoptive transfer of CD4+ cells from tolerized mice at 6 weeks after treatment protected recipient mice from anti-FVIII immune responses. Anti-CD3–treated mice mounted immune responses against both T-dependent and T-independent neo-antigens, indicating that anti-CD3 did not hamper the immune systems in the long term. Concomitant FVIII plasmid + anti-CD3 treatment induced long-term tolerance specific to FVIII via a mechanism involving the increase in transforming growth factor-β levels and the generation of adaptive FVIII-specific CD4+Foxp3+ regulatory T cells at the periphery. Furthermore, anti-CD3 can reduce the titers of preexisting anti-FVIII inhibitory antibodies in hemophilia A mice.

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“…Thus, safe and effective means to induce tolerance and prevent and/or modulate the transgene-specific immune responses after gene therapy need to be developed. 22 Limited success has been achieved to induce tolerance against transgene product on prolonged exposure to antigens, including mucosal administration of FVIII-C2 domain, 23 B-cell gene therapy, 24 or hepatic gene transfer. 25 However, in most cases tolerance was established in only a fraction of the treated animals.…”

Section: Introductionmentioning

confidence: 99%