Treatment of Murine Lupus with CTLA4Ig

Finck, Barbara; Linsley, Peter S.; Wofsy, David

doi:10.1126/science.7520604

Cited by 641 publications

(369 citation statements)

References 24 publications

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“…Alternatively, it is likely that future studies will also evaluate cotreatments with specific biologic agents to interfere with T cell helper signals, such as blocking antibodies to CD40-CD40 ligand (44,45) or the use of CTLA4-Ig (46). As an alternative approach, it may be desirable to utilize agents that block the recently discovered BLyS/BAFF/ zTNF4 system (for review, see ref.…”

Section: Mechanisms Of Autoimmunity and Rituximabmentioning

confidence: 99%

Rituximab therapy and autoimmune disorders: Prospects for anti–B cell therapy

Silverman¹,

Weisman²

2003

Arthritis & Rheumatism

343

204

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Section: Mechanisms Of Autoimmunity and Rituximabmentioning

confidence: 99%

Rituximab therapy and autoimmune disorders: Prospects for anti–B cell therapy

Silverman¹,

Weisman²

2003

Arthritis & Rheumatism

343

204

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“…General immune suppression may be induced in mice by inhibiting the CD28-B7 costimulatory signals by systemic administration of a recombinant chimeric protein, CTLA4-Ig, which consists of an immunoglobulin fused to CTLA4. 32 Kay et al 33 have demonstrated, in mice, that administration of muCTLA4-Ig, consisting of murine immunoglobulin C␥2a fused to murine CTLA4, extends the duration of adenovirus-mediated gene expression in the liver. They have also recently demonstrated that constitutive expression of murine CTLA4Ig from the viral vector also prolongs transgene expression.…”

Section: U Adrl In Pbs) the Results Indicate Transduction Of Rpe Cementioning

confidence: 99%

Co-injection of adenovirus expressing CTLA4-Ig prolongs adenovirally mediated lacZ reporter gene expression in the mouse retina

et al. 1998

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There is growing interest in gene delivery to the eye in describes a strategy for prolonging gene expression by order to develop gene therapy for the many ocular disblocking the B7-CD28 interactions between antigen orders which may be amenable to this approach. To date, presenting cells (APC) and T cells in order to prevent the recombinant adenoviruses (AV) have been the main vector costimulatory signals required for T cell survival and proused for gene delivery to anterior and posterior segments liferation. This was achieved by the co-injection of AV in animal models. As with delivery to other organs, immune encoding a secreted immunomodulatory molecule (CTLA4-responses to vector and transgene limit the duration of Ig) which consists of the extra-cellular domain of mouse expression in the eye. Using an E1-deleted adenoviral vec-CTLA4 fused to the Fc region of human IgG. Subretinal cotor carrying a lacZ reporter gene, we have previously deminjection of AV encoding ␤ galactosidase with AV encoding onstrated that a T cell-mediated immune response reduces CTLA4-Ig results in prolonged expression in retinal cells the level of intra-ocular transgene expression over time compared with subretinal injection of only adenovirus and limits it to around 3 weeks in mice. This report encoding ␤ galactosidase. Keywords: gene therapy; immune response; photoreceptor; eyeThere is growing interest in gene transfer into various tissues of the eye since there are many ocular disorders which may be amenable to gene therapy. 1 Of these, there is particular interest in developing gene therapy for inherited retinal degenerations, some of which are due to single gene defects in photoreceptor-specific genes. These disorders may ultimately be treated by gene replacement strategies which require gene transfer to photoreceptors or by strategies which prevent these cells entering the apoptotic pathway. The latter might be achieved, for instance, by the delivery of genes encoding neurotrophic growth factors to the adjacent retinal pigment epithelium (RPE) cells or to cells in the anterior chamber. A number of vectors, including those based on herpes simplex virus (HSV), 2 lentivirus 3 and adeno-associated virus (AAV) [4][5][6][7] have been used for ocular gene transfer but, to date, the most widely reported system is that based on adenoviral (AV) vectors. [8][9][10][11][12][13][14][15][16][17][18][19] Studies in either the rabbit or more often the mouse, using these AV vectors carrying a lacZ reporter gene, have demonstrated that cells in the anterior segment, including the corneal endothelium, iris pigment epithelium, ciliary body, trabecular meshwork and Schlemms canal, may be efficiently transduced by intra-cameral injection. Subretinal injection is required for efficient targeting of the RPE and also results in the transduction of a small proportion of photoreceptors. Host immune responses to vector and transgene currently present a general problem for long-term gene delivery. There has been particular concern about the immunogenicity of A...

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“…Blocking CD28/B7 pathway at the time of disease induction showed efficacy in the prevention of disease in animal models of EAE, lupus and diabetes. [25][26][27] Some of these studies concurrently showed decreased proliferative ability of the auto-reactive T cells in lymph nodes, 28 suggesting decreased expansion of T cells in vivo. Other mechanisms contributing to disease suppression were immune deviation by regulating the equilibrium of Th1 and Th2 cytokines, controlling T-cell migration or inducing anergy.…”

Section: Co-stimulatory Blockade In Eae: An Animal Model Of Msmentioning

confidence: 99%

Modulating Co-Stimulation

Viglietta

Khoury

2007

Neurotherapeutics

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Summary:The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4ϩ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing autoantigen driven T-cell activation in humans with particular attention to the CD28/B7 pathway. Inhibiting co-stimulatory molecule interactions by using monoclonal antibodies seems to be an original approach to regulate autoimmune diseases in humans.

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Treatment of Murine Lupus with CTLA4Ig

Cited by 641 publications

References 24 publications

Rituximab therapy and autoimmune disorders: Prospects for anti–B cell therapy

Rituximab therapy and autoimmune disorders: Prospects for anti–B cell therapy

Co-injection of adenovirus expressing CTLA4-Ig prolongs adenovirally mediated lacZ reporter gene expression in the mouse retina

Modulating Co-Stimulation

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