Specific Immunotherapy of Experimental Myasthenia Gravis in Vitro: The “Guided Missile” Strategy

Wu, Jian; Wu, Bo; Miagkov, Alexei; Adams, Robert N.; Drachman, Daniel B.

doi:10.1006/cimm.2001.1778

Cited by 17 publications

(13 citation statements)

References 62 publications

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“…First, as a convenient source of abundant and highly reproducible Ag-specific T cells, we used a well-defined model murine system, with transgenic T cells that express the ␣␤TCR for HA. Although the Ag-specific T cells used here were actually monoclonal, we have also had equally striking success with a heterogeneous Ag-specific T cell population (41). Second, for the purposes of the present experiments, we have used the VV for gene transfer.…”

Section: Vv As a Vector For Gene Transfermentioning

confidence: 98%

Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Wu¹,

Wu²,

Miagkov³

et al. 2001

The Journal of Immunology

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We tested the hypothesis that APCs genetically engineered to present an Ag and to express Fas ligand (FasL) simultaneously can target and eliminate Ag-specific T cells. Transgenic T cells specific for influenza hemagglutinin (HA) were used as targets. We prepared recombinant vaccinia virus vectors (VVV) to transfer the gene constructs individually or simultaneously into APCs. We prevented unwanted viral replication by attenuating the VVVs with psoralen-UV light treatment. For presentation of the HA Ag, APCs were transduced with cDNA for HA flanked by sequences of the lysosome-associated membrane protein that direct efficient processing and presentation of the Ag by APCs. As a “warhead” for the APCs, we transduced them with the gene for FasL, which induces apoptosis of Fas-expressing activated T cells. To protect the transduced APCs from self-destruction by FasL, we transferred cDNA for a truncated form of Fas-associated death domain, which inhibits Fas-mediated cell death. Our results show that the engineered APCs effectively expressed the genes of interest. APCs transduced with VVV carrying all three gene constructs specifically killed HA-transgenic T cells in culture. Coculture with T cells specific for an unrelated Ag (OVA) had no significant effect. Our in vitro findings show that APCs can be genetically engineered to target and kill Ag-specific T cells and represent a promising novel strategy for the specific treatment of autoimmune diseases.

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Section: Vv As a Vector For Gene Transfermentioning

confidence: 98%

Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Wu¹,

Wu²,

Miagkov³

et al. 2001

The Journal of Immunology

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“…AChR-specific CD4 + T cells can be specifically eliminated in vitro by APCs genetically engineered to express relevant portions of the AChR, Fas ligand (to eliminate the activated AChR-specific T cells with which they interact), and a portion of Fas-associated death domain, which prevents self-destruction by the Fas ligand (122). It is not known yet whether this strategy can be safely used to modulate EAMG in vivo.…”

Section: The Futurementioning

confidence: 99%

Myasthenia gravis: past, present, and future

Conti‐Fine

Milani²,

Kaminski³

2006

J. Clin. Invest.

549

496

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Pathogenesis of MG: current state of the artStructure and function of the NMJ. The terminal arborization of α-motor neuron axons from the ventral horns of the spinal cord and brainstem provides the nerve terminals that form the NMJ (Figure 1). These myelinated axons reach the muscles through peripheral nerves; then each axon divides into branches that innervate many individual muscle fibers. As it approaches its target fiber, each branch loses the myelin sheath and further subdivides into many presynaptic boutons, which contain ACh-loaded synaptic vesicles and face the surface of the muscle fiber at the NMJ ( Figure 1). The synaptic bouton and the muscle surface are separated by the synaptic cleft, a 20 nm-thick space that contains acetylcholinesterase (AChE) and other proteins and proteoglycans involved in

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“…Besides the E7 protein, the LAMP-1 sorting signal has been linked to various other antigens. Vaccinia virus vectors included cytomegalovirus pp65 [92], HIV-1 gp160 [93,94], and the acetylcholine receptor [95]. Naked DNA plasmid vaccines included dengue virus 2 premembrane-envelope [96,97] and HIV-1 p55 Gag [98].…”

Section: Endogenous Targeting Of Defined Peptidesmentioning

confidence: 99%

Genetic approaches for the induction of a CD4⁺ T cell response in cancer immunotherapy

Bonehill

Heirman

Thielemans

2005

The Journal of Gene Medicine

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Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-gamma-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development.

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Specific Immunotherapy of Experimental Myasthenia Gravis in Vitro: The “Guided Missile” Strategy

Cited by 17 publications

References 62 publications

Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Myasthenia gravis: past, present, and future

Genetic approaches for the induction of a CD4⁺ T cell response in cancer immunotherapy

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Specific Immunotherapy of Experimental Myasthenia Gravis in Vitro: The “Guided Missile” Strategy

Cited by 17 publications

References 62 publications

Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Myasthenia gravis: past, present, and future

Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapy

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Product

Resources

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Genetic approaches for the induction of a CD4⁺ T cell response in cancer immunotherapy