Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: The future for therapy of autoimmune disease?

Coleman, Miranda A.; Steptoe, Raymond J.

doi:10.1016/j.autrev.2011.08.012

Cited by 21 publications

(29 citation statements)

References 109 publications

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“…Other recent approaches for the induction of specific immune tolerance include the use of synthetic nanoparticles containing specific proteins in combination with immunosuppressive drugs (Maldonado et al, 2014), stem cell transplantation (Coleman and Steptoe, 2012) and gene transfer (Sack et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease.We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins.We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3 + cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.

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Section: Introductionmentioning

confidence: 99%

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Puentes

Dickhaut

Hofstätter

et al. 2016

J Neuroimmune Pharmacol

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“…This approach, as currently practiced, while largely effective, relies on the use of cytotoxic agents, typically with or without T-cell depletion (38), to ablate the entire immune repertoire and achieve an immune "reset" in the absence of specific mechanisms leading to protective, antigen-specific tolerance. Some studies have tested the principle of antigen-encoding BM transfer in a primed setting using "nonmyeloablative" approaches, but these have exclusively used T-cell depletion or other immunodepleting strategies (39)(40)(41) so that while recipients are ultimately reconstituted with a "tolerant" T-cell repertoire, this is not immune preserving.…”

Section: Discussionmentioning

confidence: 99%

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

et al. 2016

Self Cite

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Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by "conventional" therapies, memory T cell-mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell-derived replacement b-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement b-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8 + T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8 + memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigenspecific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized b-cell replacement therapies using patient-derived stem cells.

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“…Other methods not discussed in detail here, such as hematopoietic stem cell gene transfer, and thymic gene transfer or thymic protein treatment, were shown to induce antigen-specific Treg in vivo [144–146]. Alternatively, antigen-specific Treg can be generated in vitro using methods such as T cell gene modifications with antigen-specific TCR or chimeric antigen receptors, as initially investigated in models of autoimmune disease and now also shown to be a promising strategy to suppress inhibitor formation in hemophilia [15, 147, 148].…”

Section: Adoptive Transfer Of Ex Vivo Induced Treg or Genetically mentioning

confidence: 99%

In vivo induction of regulatory T cells for immune tolerance in hemophilia

Wang

Terhorst

Herzog

2016

Cellular Immunology

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Current therapy for the X-linked coagulation disorder hemophilia is based on intravenous infusion of the specifically deficient coagulation factor. However, 20–30% of hemophilia A patients (factor VIII, FVIII, deficiency) generate inhibitory antibodies against FVIII. Whilst formation of inhibitors directed against factor IX, FIX, resulting from hemophilia B treatment is comparatively rare, a serious complication that is often associated with additional immunotoxicities, e.g. anaphylaxis, occurs. Current immune tolerance protocols to eradiate inhibitors are lengthy, expensive, not effective in all patients, and there are no prophylactic tolerance regimens to prevent inhibitor formation. The outcomes of recent experiments in animal models of hemophilia demonstrate that regulatory CD4+ T cells (Treg) are of paramount importance in controlling B cell responses to FVIII and FIX. This article reviews several novel strategies designed to in vivo induce coagulation factor-specific Treg cells and discusses the subsets of Treg that may promote immune tolerance in hemophilia. Among others, drug- and gene transfer-based protocols, lymphocyte transplant, and oral tolerance are reviewed.

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Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: The future for therapy of autoimmune disease?

Cited by 21 publications

References 109 publications

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

In vivo induction of regulatory T cells for immune tolerance in hemophilia

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