Cell-Based Immunotherapy with Suppressor CD8+ T Cells in Rheumatoid Arthritis

Dávila, Eduardo; Kang, Young Mo; Park, Yong Wook; Sawai, Hirokazu; He, Xing; Pryshchep, Sergey; Goronzy, Jörg J.; Weyand, Cornelia M.

doi:10.4049/jimmunol.174.11.7292

Cited by 73 publications

(64 citation statements)

References 47 publications

(47 reference statements)

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“…6A and B). CD8 + CD28 À regulatory cells have been described in different models of mice (Najafian et al 2003;MenagerMarcq et al 2006) and humans (Liu et al 1998;Davila et al 2005;Baeten et al 2006;Manavalan et al 2004). Relevant to our studies, increasing of CD8 + CD28 À T cells observed in drug-free tolerant kidney recipients (Baeten et al 2006) suggests that the appearance of CD8 + CD28 À T cells is a common feature in the prolonged graft survival.…”

Section: Discussionsupporting

confidence: 58%

A continuous infusion of a minor histocompatibility antigen–immunodominant peptide induces a delay of male skin graft rejection

Sireci¹,

Barera²,

Macaluso³

et al. 2009

Immunobiology

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We previously reported that an inhibition of antigen-specific Interferon-g release and cytotoxicity occurs after a continuous infusion of an HY immunodominant peptide although this treatment is not able to cause a significant delay of male skin grafts rejection. In vivo administration of high doses of an HY peptide, through mini-osmotic pumps, in naïve female mice was used to study the effects on the male skin grafts rejection. A continuous infusion of 1 mg of an HY peptide induces a significant delay of male skin graft rejection. In vitro HY-specific Interferon-g release was inhibited adding peptide-specific suppressor cells: the ability to inhibit Interferon-g release was evident when two HY peptides were present on the same dendritic cells indicating that the suppressor cells exert ''linked-suppression''. The phenotype of the suppressor cells is CD8 + CD28À and these cells express more CD62 ligand and FOXP3 than controls. Suppressor cells were able to cause a significant delay of rejection of male skin grafts when injected in naive female mice. The inhibitory effects of these suppressor cells seem to be due to the impairment of antigen presentation; downregulation of B7 molecules on dendritic cells occurred. Taken all together, our data demonstrate that a continuous infusion of an immunodominant HY peptide induces a T CD8 suppressor subset able to inhibit immune responses to male tissues and cells.

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Section: Discussionsupporting

confidence: 58%

A continuous infusion of a minor histocompatibility antigen–immunodominant peptide induces a delay of male skin graft rejection

Sireci¹,

Barera²,

Macaluso³

et al. 2009

Immunobiology

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“…In a recent study (49), investigators reported the isolation of CD8ϩ,CD56ϩ T cell clones from the rheumatoid synovium. In a human synovium-engrafted SCID mouse model, infusion of these cells suppressed CD4ϩ T cell-driven responses in the implanted synovial tissue.…”

Section: Discussionmentioning

confidence: 99%

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Michel

Turesson

Lemster

et al. 2007

Arthritis & Rheumatism

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Objective. T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells.Methods. Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays.Results. Chronic stimulation of CD28؉ T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56؉,CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56؉,CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56؉ T cells had skewed T cell receptor (TCR) ␣/␤-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56؉ T cells were components of cellular infiltrates in RAassociated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels.Conclusion. Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56؉ T cells in RA contributes to maladaptive immune responses and that CD56؉ T cells are potential targets for therapy.

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“…More recently, Horwitz and colleagues (24,25) demonstrated reduced production of transforming growth factor ␤ by NK cells in patients with SLE, which may in turn lead to a defect in the appearance of CD8ϩ T regulatory cells that are able to control IgG production. CD8ϩ regulatory cells may also express CD56 (26), which would classify them as NKT cells. It could thus be that a reduction in the frequency of regulatory NKT cells in patients with SLE diminishes the normal control on IgG production.…”

Section: Discussionmentioning

confidence: 99%

Natural killer T cells in families of patients with systemic lupus erythematosus: Their possible role in regulation of IGG production

Green¹,

Kennell²,

Larché³

et al. 2007

Arthritis & Rheumatism

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Objective. To determine whether there is a link between the frequency of natural killer T (NKT) cells and high levels of IgG in patients with systemic lupus erythematosus (SLE) and their relatives.Methods. Blood samples were obtained from patients with SLE, their first-degree relatives, patients with rheumatoid arthritis (RA), and healthy control subjects. The frequency of NKT cells (defined as CD56؉ T cells) was expressed as a percentage of total blood lymphocytes. Plasma levels of total IgG and IgM, and IgG antibodies to double-stranded DNA (dsDNA) were determined.Results. The frequency of NKT cells was lower in patients with SLE than in control subjects. No such decrease was observed in the relatives of patients with SLE or in patients with RA. High levels of IgG were observed in both patients with SLE and their relatives, while low levels of IgM were observed in these same groups. In relatives of patients with SLE, an inverse correlation between the frequency of NKT cells and IgG levels was observed. Moreover, raised levels of IgG in patients with SLE and their relatives and high levels of IgG anti-dsDNA in patients were associated with low frequencies of NKT cells. Conclusion.These results suggest that NKT cells have an important role in the regulation of IgG production, although NKT cells with invariant T cell receptors may not necessarily be involved. NKT cells in the setting of SLE could lack the cytokine stimulus from NK or other cells that is needed to exert control on IgG production. Enhancement of NKT cell activity may provide a novel basis for therapy in SLE.

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Cell-Based Immunotherapy with Suppressor CD8+ T Cells in Rheumatoid Arthritis

Cited by 73 publications

References 47 publications

A continuous infusion of a minor histocompatibility antigen–immunodominant peptide induces a delay of male skin graft rejection

A continuous infusion of a minor histocompatibility antigen–immunodominant peptide induces a delay of male skin graft rejection

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Natural killer T cells in families of patients with systemic lupus erythematosus: Their possible role in regulation of IGG production

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