CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice

Miao, Carol H.; Harmeling, Benjamin R.; Ziegler, Steven F.; Yen, Benjamin; Torgerson, Troy R.; Chen, Liping; Yau, Roger J.; Peng, Bowen; Thompson, Arthur R.; Ochs, Hans D.; Rawlings, David J.

doi:10.1182/blood-2009-06-228155

Cited by 56 publications

(53 citation statements)

References 41 publications

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“…5,6,10,14,35,41 For example, induced Treg can control antibody formation against coagulation factors long-term, in part because they promote conversion of nonregulatory CD4 + T-cells to Treg, thereby amplifying the regulatory response. 42 This process is TGF-β dependent. 19 Here, we demonstrate that TGF-β blockage prevents the Treg response to hepatic AAV-hF.IX gene transfer, which is required to suppress B-and T-cell responses to hF.IX in C3H/HeJ mice.…”

Section: Discussionmentioning

confidence: 99%

Nonredundant Roles of IL-10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer

et al. 2011

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Hepatic gene transfer using adeno-associated viral (AAV) vectors has been shown to efficiently induce immunological tolerance to a variety of proteins. Regulatory T-cells (Treg) induced by this route suppress humoral and cellular immune responses against the transgene product. In this study, we examined the roles of immune suppressive cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in the development of tolerance to human coagulation factor IX (hF.IX). Interestingly, IL-10 deficient C57BL/6 mice receiving gene transfer remained tolerant to hF.IX and generated Treg that suppressed anti-hF.IX formation. Effects of TGF-β blockade were also minor in this strain. In contrast, in C3H/HeJ mice, a strain known to have stronger T-cell responses against hF.IX, IL-10 was specifically required for the suppression of CD8(+) T-cell infiltration of the liver. Furthermore, TGF-β was critical for tipping the balance toward an regulatory immune response. TGF-β was required for CD4(+)CD25(+)FoxP3(+) Treg induction, which was necessary for suppression of effector CD4(+) and CD8(+) T-cell responses as well as antibody formation. These results demonstrate the crucial, nonredundant roles of IL-10 and TGF-β in prevention of immune responses against AAV-F.IX-transduced hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Nonredundant Roles of IL-10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer

et al. 2011

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“…Studies in mice engineered to express a Foxp3 reporter demonstrated that Foxp3 expression is confined to a subset of ␣␤ T cells and correlates with suppressive activity irrespective of CD25 expression. [25][26][27] In addition, a recent study conducted with SH2 domain-containing inositol 5-phosphatasedeficient mice shows that CD25 Ϫ T cells express higher Foxp3 levels, and CD4 ϩ CD25 Ϫ Foxp3 ϩ T cells have profound immunosuppressive capacity in vitro and in vivo. 37 Moreover, there is now compelling evidence that "adaptive" Tregs may be generated from peripheral CD4 ϩ CD25 Ϫ Foxp3 Ϫ T cells under well-defined conditions (ie, the type of antigen stimulation, the nature of the APCs, and cytokine milieu).…”

Section: Discussionmentioning

confidence: 99%

“…Studies in mice engineered to express a Foxp3 reporter confirmed that Foxp3 is a lineage marker of Tregs and correlates with suppressor activity irrespective of CD25 expression. [25][26][27] In particular, in an autoimmune nonobese diabetic mouse model, anti-CD3 treatment induced adaptive CD4 ϩ CD25 low Foxp3 ϩ Tregs in the periphery that suppress T-cell immunity in a transforming growth factor-␤ (TGF-␤)-dependent manner. 28 Here we report the successful use of the anti-CD3 monoclonal antibody in modulating immune responses against FVIII after gene therapy.…”

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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“…The strength of tolerance induction to F.IX following hepatic gene transfer for hemophilia B is proportional to transgene expression levels (4, 57). Tolerance to F.VIII following gene transfer is likely also mediated by a similar Treg-dependent mechanism (253). Thus, in addition to the difficulty in achieving therapeutic correction, the low expression levels of F.VIII following gene transfer also reveal challenges from the immune system.…”

Section: Gene Therapies For Hemophlia Amentioning

confidence: 99%

Gene therapy for hemophilia

Rogers

Herzog

2015

Front Biosci

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Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors.

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CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice

Abstract: Gene transfer of a factor VIII (FVIII) plasmid

Cited by 56 publications

References 41 publications

Nonredundant Roles of IL-10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer

Nonredundant Roles of IL-10 and TGF-β in Suppression of Immune Responses to Hepatic AAV-Factor IX Gene Transfer

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

Gene therapy for hemophilia

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