Transplantation of bone marrow genetically engineered to express proinsulin II protects against autoimmune insulitis in NOD mice

Chan, James; Clements, Warren; Field, Judith; Nasa, Zeyad; Lock, Peter; Yap, Felicia Y. T.; Toh, Ban‐Hock; Alderuccio, Frank

doi:10.1002/jgm.968

Cited by 33 publications

(35 citation statements)

References 48 publications

(47 reference statements)

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“…Although direct comparisons of transgene expression levels in conventional transgenesis and viral-vector mediated gene-transfer are rare, both systems can lead to high levels of gene expression and promoter choice may be more critical than the means of gene transfer. [45][46][47][48][49] Importantly, studies using virally transduced BM for induction of tolerance have replicated the outcomes of transgenic BM studies 14,21,50 but testing in viral gene-transfer settings will provide important validation of the findings reported here.…”

Section: Discussionmentioning

confidence: 54%

Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Coleman

Bridge

Lane

et al. 2013

Blood

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Section: Discussionmentioning

confidence: 54%

Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Coleman

Bridge

Lane

et al. 2013

Blood

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“…6,21 BM cells collected from donor mice were transduced with retrovirus as described, 6 with the percentage of transduction of B12%. Briefly, donor mice were treated with 5-fluorouracil (140 mg kg À1 body weight) 3.5 days before BM harvest and cultured in rmIL-6 (10 ng ml À1 , R&D Systems, Minneapolis, MN, USA) and rmSCF (50 ng ml À1 , R&D Systems).…”

Section: Retroviral Transduction Of Bm and Transfermentioning

confidence: 99%

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Hosseini

Chan

et al. 2011

Gene Ther

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Myeloablative transplantation of bone marrow (BM) engineered to express myelin oligodendrocyte glycoprotein (MOG) establishes central intrathymic tolerance and completely prevents MOG-induced experimental autoimmune encephalomyelitis (EAE) in mice. Here we asked whether non-myeloablative transplantation of MOG expressing BM (pMOG-bone marrow transplantation (BMT)) can also provide the same protection. Using stepwise reduction of irradiation doses, 275 cGy irradiation with pMOG-BMT protected 100% of mice from EAE development even with two subsequent re-challenge with MOG. Irradiation doses o275 cGy produced dose-dependent partial protection with significant disease protection still evident at 50 cGy. Splenocytes from 275 cGy recipients proliferated to MOG stimulation in vitro, indicating that MOG-reactive cells are present in the periphery but failed to induce disease. MOG-stimulated splenocytes produced little or no interleukin-17, interferon-g, granulocyte-monocyte colony stimulating factor and tumor necrosis factor-a compared with EAE control. Adoptive transfer of CD4 T cells from EAE-resistant mice into Rag2 À/À mice devoid of MOG expression resulted in MOG-induced EAE in B74% of mice. Treatment of EAE-resistant mice with anti-programmed death 1 (PD-1) monoclonal antibody-induced EAE in 67% of mice. We conclude that nonmyeloablative transplantation of self-antigen expressing BM induces robust peripheral tolerance that completely prevented EAE development. Our findings implicate clonal anergy and the PD-1 pathway in the maintenance of peripheral tolerance.

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“…Using this strategy, mice given BM transduced with retrovirus encoding the self-Ag myelin oligodendrocyte glycoprotein (MOG) are protected against induction of EAE (7). This strategy has also been shown with BM-encoding proteolipid protein and the prevention of proteolipid protein-induced EAE (25), transfer of BM-encoding proinsulin II, and reduction in insulitis in type 1 diabetes-prone NOD mice (26).…”

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confidence: 92%

Gene Therapy Delivery of Myelin Oligodendrocyte Glycoprotein (MOG) via Hematopoietic Stem Cell Transfer Induces MOG-Specific B Cell Deletion

Chung

Figgett

Fairfax

et al. 2014

The Journal of Immunology

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The various mechanisms that have been described for immune tolerance govern our ability to control self-reactivity and minimize autoimmunity. However, the capacity to genetically manipulate the immune system provides a powerful avenue to supplement this natural tolerance in an Ag-specific manner. We have previously shown in the mouse model of experimental autoimmune encephalomyelitis that transfer of bone marrow (BM) transduced with retrovirus encoding myelin oligodendrocyte glycoprotein (MOG) promotes disease resistance and CD4+ T cell deletion within the thymus. However, the consequence of this strategy on B cell tolerance is not known. Using BM from IgHMOG mice that develop MOG-specific B cell receptors, we generated mixed chimeras together with BM-encoding MOG. In these animals, the development of MOG-specific B cells was abrogated, resulting in a lack of MOG-specific B cells in all B cell compartments examined. This finding adds a further dimension to our understanding of the mechanisms of tolerance that are associated with this gene therapy approach to treating autoimmunity and may have important implications for Ab-mediated autoimmune disorders.

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Transplantation of bone marrow genetically engineered to express proinsulin II protects against autoimmune insulitis in NOD mice

Abstract: We show for the first time that ex vivo genetic manipulation of HSCs to express proinsulin II followed by transplantation to NOD mice can establish molecular chimerism and protect from destructive insulitis in an antigen-specific manner.

Cited by 33 publications

References 48 publications

Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy

Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice

Gene Therapy Delivery of Myelin Oligodendrocyte Glycoprotein (MOG) via Hematopoietic Stem Cell Transfer Induces MOG-Specific B Cell Deletion

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