Long-term anti-CD4 treatment of MRL/Ipr mice ameliorates immunopathology and lymphoproliferation but fails to suppress rheumatoid factor production

O’Sullivan, Frank X.; Ray, Carla J.; Takeda, Yoshihiko; Sharp, Gordon C.; Walker, Sara E.

doi:10.1016/s0090-1229(05)80013-3

Cited by 15 publications

(11 citation statements)

References 32 publications

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“…Such studies have included treatment by neonatal thymectomy, anti-Thy-1.2 Ab, anti-CD4 Ab, anti-CD3 Ab, FK506, and cyclosporin A, as well as the genetic elimination of CD4 ϩ T cells via MHC class II deficiency and CD4 deficiency: all have shown an abrogation of autoantibody production and glomerulonephritis (5)(6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Autoantibody Responses and Pathology Regulated by B7-1 and B7-2 Costimulation in MRL/lprLupus

Liang

Kashgarian

Sharpe

et al. 2000

The Journal of Immunology

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The activation of T lymphocytes requires both Ag-mediated signaling through the TCR as well as costimulatory signals transmitted through B7-1 and/or B7-2 with CD28. The interference of B7-mediated costimulatory signals has been proposed as one immunotherapeutic intervention for the prevention autoimmune disease. This study has examined autoantibody responses and autoimmune pathology in a murine model of human systemic lupus erythematosus (SLE), the MRL-lpr/lpr mouse, genetically deficient in B7-1 or B7-2, or in mice treated with B7-1/B7-2 blocking Abs. In contrast to other studies of murine models of SLE, MRL-lpr/lpr mice treated with B7 blocking Abs exhibit strong anti-small nuclear ribonucleoprotein (snRNP) and anti-DNA autoantibody responses with some changes in isotype switching as compared with untreated animals. All MRL-lpr/lpr mice deficient in B7-1 or B7-2 produce anti-snRNP and anti-DNA titers with isotypes virtually identical with wild-type animals. However, the absence of B7-2 costimulation did interfere with the spontaneous activation and the accumulation of memory CD4+ or CD8+ T lymphocytes characteristic of wild-type MRL-lpr/lpr mice. IgG and C3 complement deposition was less pronounced in the kidneys of B7-2 deficient MRL-lpr/lpr mice, reflecting their lessor degree of glomerulonephritis. By comparison, B7-1-deficient MRL-lpr/lpr mice had more severe IgG and C3 deposits in glomeruli.

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confidence: 99%

Autoantibody Responses and Pathology Regulated by B7-1 and B7-2 Costimulation in MRL/lprLupus

Liang

Kashgarian

Sharpe

et al. 2000

The Journal of Immunology

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“…Therefore, the present results provide additional evidence for the crucial role of CD4 + T cells in the development of IC‐associated renal disease. In accord with this, autoimmune manifestations were improved by anti‐CD4 antibody treatment [6–10].…”

Section: Discussionmentioning

confidence: 91%

“…Since this autoimmune syndrome has many similarities to human systemic lupus erythematosus (SLE) in the development of immune complex (IC)‐associated end organ disease of the kidney and salivary glands, and the production of anti‐DNA and other autoantibodies, MRL‐ lpr mice have been widely used as an animal model for SLE [1,2]. In this model, T cells, more specifically autoreactive CD4 + αβ + T cells, have been shown to be essential for the full induction of the SLE‐like manifestations including nephritis by neonatal thymectomy [3], immunodepletion with antibodies against Thy‐1, CD3 and CD4 [4–11], and genetic deletion of CD4 + T cells by targeting class II and CD4 genes [12,13]. Fas lpr ( lpr ) is defined as the insertion of an early retrotransposon in the second intron of Fas that interferes with normal transcription of the gene [14].…”

Section: Introductionmentioning

confidence: 99%

A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Faslprcg/Faslprcgmice

Zhang¹,

Yasuda²,

Wang³

et al. 2000

Clinical and Experimental Immunology

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SUMMARYThe role of CD4 molecules in the autoimmune and lymphoproliferative syndrome caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Fas lprcg / Fas lprcg (MRL-lpr cg ) mice, in combination with the novel mutant CD4 gene producing soluble CD4 (sCD4) instead of membrane-bound CD4 (mCD4). For this purpose, various autoimmune manifestations were compared among MRL-lpr cg mice homozygous (CD4 s -lpr cg ), heterozygous (CD4 s/m -lpr cg ), and wild-type (CD4 m -lpr cg ) for the CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lymphadenopathy were significantly ameliorated in CD4 s -lpr cg compared with CD4 m -lpr cg and CD4 s/mlpr cg mice, both being comparable in these clinical characteristics. In parallel with the clinical improvement, the serum levels of immunoglobulin, anti-DNA antibodies, anti-nuclear antibodies and immune complexes, and the extent of glomerular immune deposition, were significantly lower in the former. The results indicate that mCD4 is important and can not be replaced by sCD4 in full development of SLE-like manifestations, and suggest that CD4 1 T cells may aggravate the autoimmune disease by stimulating autoreactive B cells to produce autoantibodies through their helper activity in Fas mutant models. The sCD4 levels in the serum and spleen elevated with the increased accumulation of B220 1 CD4 2 CD8 2 (double-negative (DN)) T cells in CD4 s -lpr cg mice. This, together with the significantly milder lymphadenopathy associated with lower DN T cell contents in CD4 s -lpr cg than CD4 m -lpr cg mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.

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“…It has been demonstrated that arthritis in MRL/lpr mice is an age‐related phenomenon and that young MRL/lpr mice, in spite of the presence of the lpr gene, showed no evidence of the disease 5 . Furthermore, the development of arthritis was completely suppressed in MRL/lpr mice depleted of CD4 + T cells by treatment with anti‐CD4 monoclonal antibody (mAb), because of a marked inhibition of autoimmune response 6–8 …”

mentioning

confidence: 99%

“…5 Furthermore, the development of arthritis was completely suppressed in MRL/lpr mice depleted of CD4 + T cells by treatment with anti-CD4 monoclonal antibody (mAb), because of a marked inhibition of autoimmune response. [6][7][8] Mouse IgG oligosaccharide chains consist of a series of biantennary complex-type structures of ± Galb1-4GlcNAcb1-2Mana1-6(±Galb1-4GlcNAcb1-2Mana1-3)Manb1-4GlcNAcb1-4(±Fuca1-6)GlcNAc containing zero to two sialic acid residues linked to Gal residues. 9 Structural variation of the oligosaccharide chains arises from the presence or absence of fucosylation of the proximal GlcNAc residue, and galactosylation and sialylation of the outer arms.…”

mentioning

confidence: 99%

Abnormal IgG galactosylation in MRL‐lpr/lpr mice: Pathogenic role in the development of arthritis

Kuroda¹,

Nakata

Hirose

et al. 2001

Pathology International

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MRL-lpr/lpr (MRL/lpr) mice spontaneously develop arthritis by an increase in the incidence of agalactosylated oligosaccharides in serum IgG, similar to rheumatoid arthritis patients. However, whether this association has a pathogenic significance is still unknown. In this study, we analyzed the oligosaccharide structure of serum IgG in various MRL mice with or without arthritis, to clarify the relationship between the oligosaccharide abnormality and the development of arthritis. The level of agalactosylation in serum IgG was comparable in both arthritis-free MRL/lpr and MRL-+/+ (MRL/+) mice at 6 weeks of age. In contrast, the incidence of IgG lacking galactose markedly increased in MRL/lpr mice at 6 months of age (the age at which arthritis occurred), compared with that from age-matched MRL/+ mice without arthritis. However, the proportion of agalactosylated IgG increased similarly in anti-CD4 monoclonal antibody-treated MRL/lpr mice at 6 months of age, despite the absence of the development of arthritis, because of depletion of CD4+ T cells. These results suggest that the abnormality in IgG galactosylation of MRL/lpr mice developed in an age-dependent manner, but it did so independently of CD4+ T cell-dependent B-cell activation and is not a consequence of the development of arthritis.

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Long-term anti-CD4 treatment of MRL/Ipr mice ameliorates immunopathology and lymphoproliferation but fails to suppress rheumatoid factor production

Cited by 15 publications

References 32 publications

Autoantibody Responses and Pathology Regulated by B7-1 and B7-2 Costimulation in MRL/lprLupus

Autoantibody Responses and Pathology Regulated by B7-1 and B7-2 Costimulation in MRL/lprLupus

A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Faslprcg/Faslprcgmice

Abnormal IgG galactosylation in MRL‐lpr/lpr mice: Pathogenic role in the development of arthritis

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