Adeno-associated virus-mediated human IL-10 gene transfer suppresses the development of experimental autoimmune orchitis

Watanabe, Masahiro; Kashiwakura, Yuji; Kusumi, Norihiro; Tamayose, Kenji; Nasu, Yasutomo; Nagai, Atsushi; Shimada, Takashi; Daida, Hiroyuki; Kumon, Hiromi

doi:10.1038/sj.gt.3302463

Cited by 33 publications

(24 citation statements)

References 31 publications

(29 reference statements)

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“…IL-10 is ordinarily known to be an immunosuppressive cytokine. In EAO, adeno-associated virus-mediated human IL-10 gene transfer suppressed the development of the disease ( Watanabe et al 2005). However, it exerts the opposite effect in some autoimmune diseases including EAO (Rosenbaum & Angell 1995, Hill & Sarvertnick 2002, Kaneko et al 2003, Tokunaga et al 2008.…”

Section: Effects Of Vasectomy On Testicular Autoimmunitymentioning

confidence: 99%

Caput epididymitis but not orchitis was induced by vasectomy in a murine model of experimental autoimmune orchitis

Terayama²,

Naito³

et al. 2008

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Immunization of mice with viable syngeneic testicular germ cells (TGC) alone can induce autoimmune responses against autoantigens of both round and elongating spermatids, resulting in the development of experimental autoimmune orchitis (EAO). Histological lesions in this EAO model without an adjuvant are characterized by lymphocytic infiltration into the testes, spermatogenic disturbance, and a complete lack of epididymitis. In this study, we investigated the effects of vasectomy (Vx) on TGC-induced EAO expecting that Vx augments the severity of testicular inflammation in A/J mice. The results showed that mice receiving Vx alone exhibited no significant inflammatory cell response in either the testes or epididymides, and mice receiving shamVxCTGC immunization had EAO with no epididymitis. In sharp contrast, no EAO was found in the testes of any mice receiving VxCTGC immunization. Instead, caput epididymitis involving CD4CT cells, CD8CT cells, B cells, and macrophages were induced in them with striking elevation of the tissue levels of both IL6 and IL10 mRNA. Furthermore, serum autoantibodies induced by shamVxCTGC immunization were reactive with both round (immature) and elongating (mature) spermatids; however, those induced by VxCTGC immunization were specific to acrosomes of mature spermatids and spermatozoa. These unexpected results indicate that Vx may induce the mode by which autoreactive lymphocytes gain access to TGC autoantigens in the epididymides, leading to autoimmune responses against the autoantigens of mature rather than immature spermatids. Reproduction (2008) 135 859-866

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Section: Effects Of Vasectomy On Testicular Autoimmunitymentioning

confidence: 99%

Caput epididymitis but not orchitis was induced by vasectomy in a murine model of experimental autoimmune orchitis

Terayama²,

Naito³

et al. 2008

Reproduction

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“…93 Overexpression of IL-10 in the testis significantly reduces the levels of inflammation in EAO models. 94 Therefore, multiple immunosuppressive factors are involved in the maintenance of immune homeostasis in testicular tissue.…”

Section: Immune Privilege In the Testismentioning

confidence: 99%

Testicular defense systems: immune privilege and innate immunity

et al. 2014

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The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation.

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“…The construction and production of AAV vectors was performed as previously described (15)(16)(17). Briefly, for the rAAV vector plasmid (hTERT promoter/luciferase with the one-step, conventional TSTA and advanced TSTA system) construction, the AAV vector plasmid (SF) derivatives of psub-201 were employed.…”

Section: Construction and Production Of Adeno-associated Virus (Aav) mentioning

confidence: 99%

Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging

et al. 2011

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Abstract. The two-step transcriptional amplification (TSTA) system was previously reported to enhance the tissue-specific gene expression driven by weak promoters, but the enhancement of the gene expression is limited to use in in vitro and in vivo experimental situations. To achieve robust tissuespecific gene expression using the TSTA system, we developed an advanced TSTA system which includes polyglutamines and rat glucocorticoid receptor sequences between the GAL4 and VP16 sequences in the region of the first step of transcription. We evaluated the advanced TSTA system as a method to enhance the human telomerase reverse transcriptase (hTERT) promoter-driving cancer-specific transcription in various cancer cell lines. As a result, the advanced TSTA enhanced cancer-specific luciferase gene expression in all of the examined cancer cell lines, when compared with both the one-step and conventional TSTA systems (an ~6-and ~17-fold enhancement, respectively). Notably, the enhancement of the hTERT driven expression by the conventional TSTA system was modest and even inferior to the one-step system in several cancer cell lines. We then constructed a luciferase gene encoding the adenoassociated virus vector in which the hTERT promoter-mediated expression was driven by the advanced TSTA or control systems. In an orthotopic liver tumor model, mice were treated with the vector via tail vein injection. An optical imaging device was used to visualize the in vivo luciferase expression in the orthotopic tumor. The advanced TSTA system significantly enhanced the luciferase expression compared with the one-step and conventional TSTA systems (18.0±1.0-and 15.9±0.85-fold gain, respectively). Therefore, the advanced TSTA system significantly improves hTERT-dependent cancer-specific gene expression both in vitro and in vivo when compared with the previous systems. Since the advanced TSTA method can also be applied to other site-specific gene expression systems using tissue-specific promoters, this approach is expected to become a valuable tool enabling in vivo site-specific targeting in the field of gene therapy and molecular imaging.

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Adeno-associated virus-mediated human IL-10 gene transfer suppresses the development of experimental autoimmune orchitis

Cited by 33 publications

References 31 publications

Caput epididymitis but not orchitis was induced by vasectomy in a murine model of experimental autoimmune orchitis

Caput epididymitis but not orchitis was induced by vasectomy in a murine model of experimental autoimmune orchitis

Testicular defense systems: immune privilege and innate immunity

Advanced two-step transcriptional amplification as a novel method for cancer-specific gene expression and imaging

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