IVIg in ITP: no role for cytokines?

In this issue of Blood, Crow and colleagues demonstrate that numerous cytokines have no effect whatsoever on the acute platelet response to IVIg in a mouse model of ITP. This suggests that while IVIg may alter expression of immunomodulatory cytokines, these do not directly participate in the acute phase of the mechanism of effect. Why is this important?

Central to the immunopathology of immune thrombocytopenic purpura (ITP) is the destruction of antibody-coated platelets by FcγR-bearing phagocytic cells. The first steps towards elucidating IVIg's therapeutic mechanism came in 1982, when Fehr used chromium-labeled red cells to show that IVIg inhibited clearance of IgG-coated red cells, and inferred that opsonized platelet consumption was also decreased.¹  Four years later, specific inhibition of FcR-mediated phagocytosis with an anti-FcγRIII antibody in patients with refractory ITP simulated the dramatic but transient platelet response to IVIg.²  Until recently, and despite many speculations, the molecular mechanisms underlying the FcR-mediated response remained unclear.

The field exploded with the characterization of the FcR family and the availability of knock-out and knock-in mouse models. In 2001, Samuelsson and colleagues in Ravetch's laboratory reported that the inhibitory FcR, FcγRIIB, was a prerequisite for the platelet response to IVIg in a murine model of ITP.³  This raised new questions: what was the nature of the interactions with FcγRIIB, and which cells were involved?

Lazarus' group then dissected the mechanism of action of IVIg through an elegant series of preclinical studies, including the current report. They confirmed that FcγRIIB is a prerequisite for the IVIg effect in the passive-sensitization ITP model. Surprisingly, signal transduction molecules (eg, SHIP) did not abrogate the IVIg effect when mutated. Recently, they showed that dendritic cells preincubated with IVIg in vitro could recapitulate the therapeutic effect of IVIg and ameliorate murine ITP. These IVIg-primed leukocytes had effect only when the recipient mouse expressed FcγRIIB, whereas FcγRIIB was not required on the “initiator” dendritic cells; thus, FcγRIIB is not the direct target of IVIg, but is important downstream.⁴  Moreover, the effect of IVIg was a consequence of IVIg driving activating FcγR chain signaling, although the FcγR itself was not required.

Nearly simultaneously, Ravetch's group demonstrated that the FcγRIIB-mediated effect of IVIg depended entirely on sialylated IVIg. Sialylated-enriched IVIg was 10-fold more efficacious than normal IVIg.⁵  As nonsialylated IgG is unable to bind FcγR, this is consistent with Lazarus' demonstration of FcγR signaling on dendritic cells as necessary for the IVIg effect.

The current study explores the role of multiple cytokines and complement pathway components in IVIg-induced dendritic cell FcγR signaling activation. None appears to influence the IVIg effect, including, specifically, interleukin-1 receptor antagonist (IL-1Ra).

Lazarus and colleagues' (and Ravetch and colleagues') studies lay the foundation for development of modified IVIg or other novel agents to replace IVIg. One important caveat is that in human ITP, cytokines triggered by infusion of IVIg may affect secretion of antiplatelet antibody or, via FcRn interaction, accelerate its elimination.⁶  Furthermore, cytokine modulation may be more important in the later phases of the therapeutic response, and these effects are not captured in the acute murine disease model.

Unraveling the mechanism of the effect of IVIg in autoimmune disease, in particular on antibody-mediated platelet clearance, promises to lead to further therapeutic advances in the near future.