Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy

Abstract

BackgroundIntravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking.MethodsTen newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4–5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA.ResultsThe fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α.ConclusionTreg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.

GM-CSF and IL-4 are not involved in IVIG-mediated amelioration of ITP in mice: a role for IL-11 cannot be ruled out

“…A recent report that looked at cytokine/chemokine induction by IVIg, using a multiplex cytokine assay and two different strains of mice with ITP that respond to IVIg, has shown that IL-33 is produced following IVIg treatment only in BALB/cJ mice, but not in C57BL/6J mice [41]. This supports other studies which have shown that IL-33 is not involved in the mechanism of IVIg action [42]. However, high amounts of IL-4 were produced in both mouse strains upon IVIg induction.…”

Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE

“…In addition to IL-33, which is mainly produced by epithelial and endothelial cells, IL-3 secreted by activated T cells and mast cells is also known for inducing priming of basophils. 17,[33][34][35][36] We sought to confirm whether human basophil priming by IL-33 at a dose equivalent to that induced by IVIG in patients with rheumatic and neurologic autoimmune diseases 11,12 would stimulate IL-4 production, as proposed from mouse studies. IL-33 primed human basophils (based on CD69 expression) and induced IL-4, 37 but the extent of priming was only marginal when compared with IL-3mediated priming.…”

“…Unlike IL-3 (Fig 1, D-F), only a marginal increase in expression of CD69 on basophils (Fig 2, A and B) or their cytokine production (Fig 2, C) was observed after IL-33 stimulation of basophils at a dose equivalent of that induced in IVIG-treated patients. 11,12 Despite enhancement of IL-33R expression by IL-3 (see Fig E4 in this article's Online Repository at www.jacionline.org), IL-33 when used in combination with IL-3 did not exert either a synergistic or additive effect on IVIG-induced basophil activation (Fig 2, D and E). Hence these results do not support a major role for IL-33 in priming human basophils toward IVIG responsiveness.…”

Natural Antibodies: from First-Line Defense Against Pathogens to Perpetual Immune Homeostasis

“…However, translation of these findings to humans failed to recapitulate the mechanisms although requirement of sialylation has been confirmed in other experimental models [78,79,82,83,88,89,92]. Studies in humans have revealed that IVIG can directly interact with basophils to induce IL-4 secretion, and can act either directly on Tregs or on DCs to expand Tregs [46,65,[93][94][95][96].…”