Identification of two pathways by which intravenous immunoglobulin modulates dendritic cells
in humans in vivo
A.S.W. Tjon1, H. Jaadar1, R. van Gent1, P. M. van Hagen2, L.J.W. van der Laan3, P.A.W. te
Boekhorst4, H.J. Metselaar1, J. Kwekkeboom1
Departments of Gastroenterology and Hepatology1, Internal Medicine and Immunology2, Surgery3 and
Hematology4, Erasmus MC-University Medical Centre, Rotterdam, The Netherlands.
Background:
High-dose
intravenous
Immunoglobulin
(IVIg)
is
a
safe
and
effective
immunosuppressive therapy in autoimmune diseases. Previously, we observed that treatment with
anti-HBsAg IVIg reduces the acute rejection incidence after liver transplantation, but the mode of
action is not fully understood. Since myeloid dendritic cells (mDCs) play a crucial role in the initiation of
cell-mediated acute rejection, we studied whether and how IVIg modulates mDCs in humans in vivo.
Methods: From 28 patients treated with IVIg (indications: immunodeficiency or autoimmune disease),
blood was collected before and at 1 and 7 days after IVIg infusion. In vitro, mDCs purified from blood
of healthy subjects were cultured with IVIg or rIL-4 for 24hr. Surface receptors on mDC were
measured by flowcytometry and plasma cytokine concentrations by ELISA.
Results: Expression of the activating Fc receptor (FcR) IIa (CD32a) on circulating mDCs was
reduced at 1 and 7 days after IVIg treatment (T=0→T=1: -30%, p=0.03; T=0→T=7: -22%, p=0.02),
while expression of the inhibitory FcRIIb (CD32b) remained unchanged. In addition, 7 days after IVIg
treatment, expression of the signalling part of the IFN-γ receptor (IFNGR2) on circulating mDC was
2.5-fold diminished (p=0.002). Hence, IVIg significantly balances mDC towards an inhibitory status.
Recently it has been described that IVIg can modulate FcR expression on macrophages in mice by
stimulating the IL-33 - IL-4 cytokine axis. Remarkably, we observed in our patients a rise in plasma IL33 levels after IVIg treatment (T=0→T=1: +179%, p<0.0001; T=0→T=7: +98%, p<0.0001), which was
positively correlated with a rise in IL-4 plasma levels (r= 0.577, p<0.01). In vitro, rIL-4 inhibited CD32a
and IFNGR2 expression on mDC, like we had observed in patients. In addition, IVIg also appeared to
have direct effect on both CD32a and IFNGR2 expression on mDC (CD32a: -96%, p<0.01; IFNGR2: 57%; p=0.2 after 24 hrs culture in presence of IVIg). Functionally, IL-4- or IVIg-treated mDCs were
less responsive to immune complex stimulation.
Conclusion: IVIg treatment results in decreased CD32a and IFNGR2 expression on mDCs, which
renders them refractory to immune complexes and IFN. This modulation may occur by stimulation of
the IL-33-IL-4 cytokine axis or by a direct effect of IVIg. Hence, by modulating the most potent antigen
presenting cells via two different pathways, IVIg may be a promising candidate for immunosuppression
after organ transplantation.
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