Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice

Nishimura, Hiroyuki; Okazaki, Taku; Tanaka, Yoshimasa; Nakatani, Kazuki; Hara, Masatake; Matsumori, Akira; Sasayama, Shígetake; Mizoguchi, Akira; Hayashi, Hiroshi; Minato, Nagahiro; Honjo, Tasuku

doi:10.1126/science.291.5502.319

Cited by 1,642 publications

(1,126 citation statements)

References 13 publications

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“…Indeed, B6 mice deficient in Fc␥ receptor IIB (Fc␥RIIB) spontaneously develop circulating antichromatin and anti-dsDNA autoantibodies along with immune complex GN and pulmonary vasculitis, whereas Fc␥RIIB-deficient BALB/c mice do not (56). Moreover, B6 mice deficient in programmed death 1 (PD-1) develop a clinical phenotype highlighted by arthritis and GN (57), whereas BALB/c mice deficient in PD-1 develop no signs of arthritis or GN but do develop a lethal dilated cardiomyopathy (58). Thus, discrete immune disturbances elicit SLE-like features in B6 mice, but the identical immune disturbances do not do so in BALB/c mice.…”

Section: Discussionmentioning

confidence: 99%

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

Stohl¹,

Xu²,

Kim³

et al. 2005

Arthritis & Rheumatism

104

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Objective. To determine whether overexpression of BAFF can accelerate the development of systemic lupus erythematosus-associated end-organ disease in hosts with an underlying autoimmune diathesis.Methods. We introduced a BAFF transgene (Tg) into autoimmune-prone B6.Sle1 and B6.Nba2 mice and evaluated these mice for serologic autoimmunity and renal pathology.Results Conclusion. BAFF-driven effects on glomerular pathology may be mediated, at least in part, by autoantibodies with specificities other than chromatin and/or by autoantibody-independent means. There is an uncoupling of BAFF-driven precocious glomerular pathology from concomitant development of clinically apparent renal disease, strongly suggesting that BAFF overexpression works in concert with other factors to promote overt renal disease.Renal involvement in patients with systemic lupus erythematosus (SLE) is clinically apparent in ϳ50% of cases and leads to considerable morbidity. The vast majority of SLE patients with renal involvement develop increased proteinuria, sometimes to degrees great enough to adversely affect systemic fluid balance and hemodynamics (nephrotic syndrome). Glomerular disease is widely believed to be the major contributor to this increased proteinuria. Indeed, the World Health Organization (WHO) classification of lupus nephritis focuses almost entirely on glomerular lesions, with little attention to tubular, interstitial, or vascular lesions. Accordingly, factors which promote glomerular disease in SLE may be vital to the pathogenesis of lupus nephritis.

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Section: Discussionmentioning

confidence: 99%

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

Stohl¹,

Xu²,

Kim³

et al. 2005

Arthritis & Rheumatism

104

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“…The in vivo functions of PD-1, PD-L1, and PD-L2 have been of interest because PD-1 -/-mice progressively develop autoimmune diseases [12,13]. Since previous studies have shown that PD-L2 expression may be regulated in some cell types by Th2 cytokines or Th2 cells [21], and because asthma is believed to be a Th2-driven disease [23][24][25][26][27][28][29][30][31][32], it was of interest to examine whether PD-L2 can play a role in immune regulation in this context.…”

Section: Discussionmentioning

confidence: 99%

“…PD-1 has an immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic domain [9][10][11]. Depending on background strain, PD-1 -/-mice develop increased rates of glomerulonephritis, lupus-like arthritis [12], or autoimmune cardiomyopathy [13]. This provides direct evidence for PD-1 as a negative regulator of immune responses in vivo [13].…”

Section: Introductionmentioning

confidence: 99%

“…Depending on background strain, PD-1 -/-mice develop increased rates of glomerulonephritis, lupus-like arthritis [12], or autoimmune cardiomyopathy [13]. This provides direct evidence for PD-1 as a negative regulator of immune responses in vivo [13]. PD-1 mRNA is expressed at high levels in CD4 + CD25 + regulatory T cells (Treg) and anergic T cells [14,15], suggesting the possible involvement of PD-1 in regulating Treg function and T cell tolerance.…”

Section: Introductionmentioning

confidence: 99%

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Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

et al. 2004

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Programmed death-1 ligand 2 (PD-L2) is a ligand for programmed death-1 (PD-1), a receptor that plays an inhibitory role in T cell activation. Since previous studies have shown upregulation of PD-L2 expression by Th2 cytokines, and asthma is driven by a Th2 response, we hypothesized that PD-L2 might be involved in regulation of the immune response in this disease. We have found that lungs from asthmatic mice had sustained up-regulation of PD-1 and PD-L2, with PD-L2 primarily on dendritic cells. Although addition of PD-L2-Fc in vitro led to decreased T cell proliferation and cytokine production, administration of PD-L2-Fc in vivo in a mouse asthma model resulted in elevated serum IgE levels, increased eosinophilic and lymphocytic infiltration into bronchoalveolar lavage fluid, higher number of cells in the draining lymph nodes, and production of IL-5 and IL-13 from these cells. Although PD-1 was expressed on regulatory T cells, PD-L2-Fc did not affect regulatory T cell activity in vitro. This study provides in vivo evidence of an exacerbated inflammatory response following PD-L2-Fc administration and indicates a potential role for this molecule in Th2-mediated diseases such as asthma.

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“…[7][8][9] In support, PD-1-deficient animals suffer from autoimmune disorders, including lupus-like glomerulonephritis, 10 and dilated cardiomyopathy. 11 The newest member of the B7 family, designated B7-H3, was cloned from a human dendritic cell-derived cDNA library. 12 It is widely expressed in various normal tissues, and its expression can be induced on monocytes and DCs.…”

Section: Introductionmentioning

confidence: 99%

Mouse B7-H3 induces antitumor immunity

et al. 2003

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Members of the B7 family costimulate the proliferation of lymphocytes during the initiation and maintenance of antigen-specific humoral and cell-mediated immune responses. While B7-1 and -2 are restricted to lymphoid tissues, and activate naïve T cells, recently identified members including B7-H2 and -H3 are widely expressed on nonlymphoid tissues, and regulate effector lymphocytes in the periphery. B7-H3 has properties that suggested it may display antitumor activity, including the ability to stimulate Th1 and cytotoxic T-cell responses. Here, we test this notion by determining whether intratumoral injection of an expression plasmid encoding a newly described mouse homologue of B7-H3 is able to eradicate EL-4 lymphomas. Intratumoral injection of a mouse B7-H3 pcDNA3 expression plasmid led to complete regression of 50% tumors, or otherwise significantly slowed tumor growth. Mice whose tumors completely regressed resisted a challenge with parental tumor cells, indicating systemic immunity had been generated. B7-H3-mediated antitumor immunity was mediated by CD8 + T and NK cells, with no apparent contribution from CD4 + T cells. In summary, the results indicate that B7-H3 interactions may play a role in regulating cell-mediated immune responses against cancer, and that B7-H3 is a potential therapeutic tool.

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Autoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice

Cited by 1,642 publications

References 13 publications

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

Mouse B7-H3 induces antitumor immunity

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