Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells

Wadia, Persis P.; Herrera, Nancy D.; Abécassis, Michaël; Tambur, Anat R.

doi:10.1016/j.humimm.2009.05.002

Cited by 18 publications

(18 citation statements)

References 42 publications

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“…More specifically, whereas MPA inhibits both CD25 and HLA-DR expression on B cells, it inhibits CD25 but not HLA-DR expression on T cells (8). MPA has also been shown to inhibit selectively some aspects of dendritic cell maturation and function in that MPA-treated dendritic cells fail to stimulate T cells (38). Moreover, differential effects of MPA on CD83 upregulation were noted on stimulated monocytes depending on when during the dendritic cell maturation process MPA was added.…”

Section: Discussionmentioning

confidence: 99%

Mycophenolic Acid Differentially Impacts B Cell Function Depending on the Stage of Differentiation

Karnell¹,

Karnell²,

Stephens³

et al. 2011

The Journal of Immunology

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Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs.

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Section: Discussionmentioning

confidence: 99%

Mycophenolic Acid Differentially Impacts B Cell Function Depending on the Stage of Differentiation

Karnell¹,

Karnell²,

Stephens³

et al. 2011

The Journal of Immunology

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“…Other authors found that MPA 50 µg/mL (corresponding to 150 µM) also leads to CD205 downregulation, probably contributing to antigen uptake impairment (30). LPS-stimulated and MPA-pretreated DCs show decreased phosphorylation of p38 MAPK (mitogen-activated protein kinase), necessary for DC maturation (31).…”

Section: Effects On Dendritic Cellsmentioning

confidence: 98%

“…Additionally, MPA blocks IL-2 and IL-15-induced proliferation, since it impedes IL-2-mediated downregulation of the cycline (cyc)-dependent kinase (CDK) inhibitor p27/Kip1 (4); thus, CycD/CDK6 and CycE/CDK2 complex activation fails and cells cannot transit from G1 to S phase. (12,13). In SLE patients, it diminishes the circulating autoantibody levels (14).…”

Section: Effects On Lymphocytes Proliferationmentioning

confidence: 99%

“…The block of DC maturation and tolerogenicity could be due to both IMPDH-dependent and IM-PDH-independent mechanisms: guanosine depletion may provoke surface marker mRNA synthesis impairment (30); on the other hand, inhibition of both p38 MAPK phosphorylation in DCs and allogeneic T cell proliferation in co-cultures is not reversible after guanosine addition (28,31). The great majority of studies on DCs typically considered much higher MPA concentrations (more often 100 µM) compared to experiments on other cell types (more often up to 10 µM); in fact, only 100 µM may guarantee the full down-regulation of costimulatory and adhesion markers in DCs and the induction of a specific chemokine receptor expression pattern (29).…”

Section: Effects On Dendritic Cellsmentioning

confidence: 99%

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Mycophenolic acid in Rheumatology: mechanisms of action and severe adverse events

Zizzo¹,

Santis²,

Ferraccioli³

2011

Reumatismo

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MPA is clinically administered as morfolinoethyl ester (mycophenolate mofetil, MMF) or, more recently, as a salt (enteric-coated mycophenolate sodium). It is a fermentation product of Penicillium brevicompactum and other analogue fungi, identified by Gosio in 1893 as a weak antibacterial agent; in 1969 Franklin and Cook discovered its capacity to inhibit the inosine mono phosphate dehydrogenase (IMPDH), an enzyme involved in purine nucleotide synthesis (1)..

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“…Viable splenic CD19 ϩ B cells (3ϫ10 5 cells/well) isolated by positive selection (Miltenyi Biotech, Auburn, CA) from allograft recipients or naïve mice were then added to the plates. After multiple washes, wells were exposed to goat anti-mouse IgG-Fc biotin conjugate (Cedarlane) and developed using horseradish peroxidase and substrate as described previously (70). Spot scanning and analysis were performed using a CTL Immunospot reader (Cellular Technology Ltd., Shaker Heights, OH).…”

Section: B-cell Elispot Assay For Detecting Ascsmentioning

confidence: 99%

Immunosuppression Involving Soluble CD83 Induces Tolerogenic Dendritic Cells That Prevent Cardiac Allograft Rejection

Arp

Lian

et al. 2010

Transplantation

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Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells

Cited by 18 publications

References 42 publications

Mycophenolic Acid Differentially Impacts B Cell Function Depending on the Stage of Differentiation

Mycophenolic Acid Differentially Impacts B Cell Function Depending on the Stage of Differentiation

Mycophenolic acid in Rheumatology: mechanisms of action and severe adverse events

Immunosuppression Involving Soluble CD83 Induces Tolerogenic Dendritic Cells That Prevent Cardiac Allograft Rejection

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