Induction of Regulatory T Cells by Intravenous Immunoglobulin: A Bridge between Adaptive and Innate Immunity

Abstract

Intravenous immunoglobulin (IVIg) is a polyclonal immunoglobulin G preparation with potent immunomodulatory properties. The mode of action of IVIg has been investigated in multiple disease states, with various mechanisms described to account for its benefits. Recent data indicate that IVIg increases both the number and the suppressive capacity of regulatory T cells, a subpopulation of T cells that are essential for immune homeostasis. IVIg alters dendritic cell function, cytokine and chemokine networks, and T lymphocytes, leading to development of regulatory T cells. The ability of IVIg to influence Treg induction has been shown both in animal models and in human diseases. In this review, we discuss data on the potential mechanisms contributing to the interaction between IVIg and the regulatory T-cell compartment.

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…50 Likewise, Tfr cells were detected in peripheral blood of B-cell-deficient mice, where bTfr cells may avoid full activation bypassing B-cell areas. 136 IgG Fc-derived peptides were found to induce expansion and activation of human thymic-derived Treg cells, which was proposed as a tolerizing mechanism of IgG. These findings contrasted with the significant reduction of blood Tfh cells observed in B-cell-deficient patients.…”

“…50,133 It is established that Tfh cells predominantly respond to foreign antigens while Tfr cells respond to self-antigens. 136 The putative impact of IVIg treatment and endogenous IgG Fc regions on Tfr-cell induction and differentiation from thymic Treg cells warrants further studies. 99 Whether the absence of bystander activation by B cells (in B-cell-deficient patients) has a different impact on Tfh-and Tfr-cell expansion, or whether recirculation kinetics is distinct in these two cell populations (Tfr cells recirculating predominantly prior to B-cell interaction and Tfh cells also recirculating from follicles and GC) remains speculative.…”

Modulatory effect of intravenous immunoglobulin on Th17/Treg cell balance in women with unexplained recurrent spontaneous abortion

“…This includes the capacity of IVIg to modulate the function of antigen-presenting cells (APCs) and phagocytic cells, 35,[117][118][119][120][121] to inhibit the differentiation and expansion of effectors lymphocytes, 122-124 of B cells, 120,125 or to induce CD95 (Fas)-mediated apoptosis in human T and B cells and monocytes. 27,126,127 As discussed above, Th17/Treg balance is thought to influence the pathogenesis of numerous autoimmune and inflammatory diseases; therefore, several studies have also investigated the potential effect of IVIg on Th17/Treg ratio. 27,126,127 As discussed above, Th17/Treg balance is thought to influence the pathogenesis of numerous autoimmune and inflammatory diseases; therefore, several studies have also investigated the potential effect of IVIg on Th17/Treg ratio.…”

“…137 Several mechanisms of action have been described during the last 25 years, including (a) modulation of Fcγ receptor expression on leukocytes and endothelial cells; (b) interaction with complement proteins; (c) modulation of cytokines and chemokines synthesis and release; (d) modulation of cell proliferation and apoptosis; (e) remyelination; (f) neutralization of circulating antibodies; (g) selection of immune repertoires; and (h) interaction with other cell surface molecules on lymphocytes and monocytes 27,126,127,138,139. 137 Several mechanisms of action have been described during the last 25 years, including (a) modulation of Fcγ receptor expression on leukocytes and endothelial cells; (b) interaction with complement proteins; (c) modulation of cytokines and chemokines synthesis and release; (d) modulation of cell proliferation and apoptosis; (e) remyelination; (f) neutralization of circulating antibodies; (g) selection of immune repertoires; and (h) interaction with other cell surface molecules on lymphocytes and monocytes 27,126,127,138,139.…”

Thymoma‐associated graft‐versus‐host‐like disease treated with high‐dose i.v. immunoglobulin

“…IVIG comprises polyclonal immunoglobulin G and is effective for a wide range of autoimmune and inflammatory diseases, probably by increasing regulatory T-cell function and coordinating cytokine networks. 5 This case demonstrates that high-dose IVIG may be useful for alleviating skin conditions in those with thymomaassociated GVH-like disease.…”