Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28–CD80/86 blockade

Chavez, Houria; Beaudreuil, Séverine; Abbed, Karim; Taoufic, Y.; Kriaa, F; Charpentier, B; Dürrbach, Antoine

doi:10.1016/j.trim.2007.01.005

Cited by 55 publications

(35 citation statements)

References 18 publications

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“…There have been concerns about the detrimental effect of CD28-CD86/80 blockade on Tregs after studies showed that this co-stimulatory pathway was essential for thymic production of nTregs and peripheral homeostasis of iTregs in an in vivo mouse model (71); however, in a cohort of renal recipients who were randomly assigned to Belatacept versus CNI maintenance therapy, Bluestone et veat that all patients in that study underwent induction with Basiliximab, it was argued that the decrease was most probably due to the induction therapy; however, they and others observed no change in either the frequency or the potency of Tregs in 2 to 5 yr of follow-up (72,73).…”

Section: Belatacept (Lea29y)mentioning

confidence: 99%

Immunosuppressive Drugs and Tregs

Serres

Sayegh

Najafian

2009

Clinical Journal of the American Society of Nephrology

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To define therapeutic strategies that promote tolerance, it is of critical importance to determine the effects of immunosuppressive drugs on regulatory T cells (Tregs). This review discusses the current knowledge about the physiology of Tregs in humans, the role or Tregs in transplantation, and the impact of the different types of immunosuppressive agents on the frequency and functionality of Tregs in in vitro and in vivo systems.

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Section: Belatacept (Lea29y)mentioning

confidence: 99%

Immunosuppressive Drugs and Tregs

Serres

Sayegh

Najafian

2009

Clinical Journal of the American Society of Nephrology

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“…CTLA4-Ig impedes CD28 and CD80/86 interactions, thus preventing T cell activation through costimulatory signals (5). Moreover, CTLA4-Ig binding to CD80/86 on APC surface has been shown to negatively interfere with dendritic cells (DC) maturation (7)(8)(9), which exhibited a tolerogenic phenotype, leading to the expansion of CD4 ϩ CD25 ϩ FoxP3 ϩ regulatory T cells in rodents but not in humans (10). However, tolerogenic DC may act through various other mechanisms, which are not completely elucidated.…”

mentioning

confidence: 99%

Dendritic Cells Secrete the Immunosuppressive HLA-G Molecule upon CTLA4-Ig Treatment: Implication in Human Renal Transplant Acceptance

Bahri

Naji

Menier

et al. 2009

The Journal of Immunology

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CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 ± 14 ng/ml) than patients treated with calcineurin inhibitors (5 ± 1 ng/ml) or healthy donors (5 ± 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.

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“…Conversely, it appears recently that patients treated with Belatacept had a high concentration of soluble HLA-G. In vitro analysis has shown that dendritic cells in a context of an allogenic reaction are able to synthesize and secrete HLA-G in the presence of Belatacept [65,66]. The secretion is maintained in the presence of Belatacept indicating that HLA-G participates in the allogenic graft acceptance.…”

Section: Impact Of Immunosuppressive Molecules On Hla-g Expressionmentioning

confidence: 99%

HLA-G in organ transplantation: towards clinical applications

Deschaseaux

Delgado

Pistoia

et al. 2010

Cell. Mol. Life Sci.

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HLA-G plays a particular role during pregnancy in which its expression at the feto-maternal barrier participates into the tolerance of the allogenic foetus. HLA-G has also been demonstrated to be expressed in some transplanted patients, suggesting that it regulates the allogenic response. In vitro data indicate that HLA-G modulates NK cells, T cells, and DC maturation through its interactions with various inhibitory receptors. In this paper, we will review the data reporting the HLA-G involvement of HLA-G in human organ transplantation, then factors that can modulate HLA-G, and finally the use of HLA-G as a therapeutic tool in organ transplantation.

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Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28–CD80/86 blockade

Cited by 55 publications

References 18 publications

Immunosuppressive Drugs and Tregs

Immunosuppressive Drugs and Tregs

Dendritic Cells Secrete the Immunosuppressive HLA-G Molecule upon CTLA4-Ig Treatment: Implication in Human Renal Transplant Acceptance

HLA-G in organ transplantation: towards clinical applications

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