Intravenous Gammaglobulin (IVIG): A Novel Approach to Improve Transplant Rates and Outcomes in Highly HLA-Sensitized Patients

S. C. Jordan; A. A. Vo; A. Peng; M. Toyoda; D. Tyan


American Journal of Transplantation. 2006;6(3):459-466. 

In This Article


IVIG products are derived from the plasma of thousands of donors. This insures that a wide diversity of antibody repertoire can be administered to patients. We also know that the Fc portion of IgG is critical for many of the beneficial effects seen in inflammatory and autoimmune disorders.[15,26,27,31] The Fc region interacts with Fcγ receptors on immune cells that can either up-regulate or dissipate an immune response. The Fc portion of IgG also has the ability to interact with complement components and regulate inflammation by absorption of active complement components and inhibition of C3 convertase activity.[15,31]

Based on our observations of the in vitro and in vivo effectiveness of IVIG in modulation of anti-HLA antibodies, our experiences in the use of IVIG in inflammatory and autoimmune disorders and the use in the treatment of severe AMR episodes in cardiac and renal allograft recipients,[10,11,12,13,14,28] we feel IVIG has an important role in the management of highly sensitized patients awaiting transplantation. These patients are unlikely to receive a transplant unless a therapeutic intervention is undertaken to reduce anti-HLA antibodies. The data briefly reviewed here suggest that IVIG offers significant benefits in reducing PRA levels and improving the chances for transplantation. The reason(s) for the beneficial effects observed in acute rejection and specific mechanism(s) of action of IVIG have remained unclear until recently. The effectiveness of IVIG in treatment of inflammatory and autoimmune disorders has prompted many studies into potential mechanisms of action. There are numerous proposed mechanisms of action that may be relevant to the modification of allosensitization. These include (a) modification of autoantibody and alloantibody levels through induction of anti-idiotypic circuits,[10,11,12,13,14,15] (b) inhibition of cytokine gene activation and anti-cytokine activity,[15] (c) anti-T-cell receptor activity,[15] (d) Fc receptor-mediated interactions with antigen presenting cells to block T-cell activation,[15,28,30] (e) anti-CD4 activity,[15] (f) stimulation of cytokine receptor antagonists[15] and (g) inhibition of complement activity.[15,27,31] Using the mixed lymphocyte culture system, we have shown that IVIG can significantly inhibit T-cell activation and reduce the expression of CD40, CD19, ICAM-1, CD86 and MHC-class II on APCs in the MLR.[28] The primary effect is on B cells and indeed, we have demonstrated that IVIG induces significant B-cell apoptosis in vitro through Fc receptor-dependent mechanisms.[28] Samuelsson et al. have recently described another unique immunoregulatory effector function for IVIG. These investigators demonstrated that IVIG induces the expression of FcγRIIB, an inhibitory receptor on B cells. This suggests that IVIG may regulate B-cell function through induction of inhibitory receptors on immune cells with subsequent inhibition of cell proliferation and/or induction of apoptosis.[26] Another interesting observation that may have relevance, especially for the treatment of AMR is from Magee et al.[27] who showed that IVIG treatment significantly prolonged the survival of pig-to-baboon xenotransplants (from 30-60 min to 10 days). This beneficial effect was through inhibition of complement-mediated endothelial cell injury by IVIG. The Fc portion of IVIG has high affinity for activated complement components (C3b and C4b) and could represent a novel mechanism for inhibition of complement-mediated injury to allografts that has been recently described for both acute rejection and chronic rejection in humans.[29,31,32]

Other investigators have recently shown that IVIG inhibits the generation of C5b-C9 MAC, thus preventing antibody-mediated injury. IVIG also inactivates C3b and accelerate C3b catabolism.[15,31] IVIG can also inhibit the activation of endothelial cells in in vitro models of inflammation. These observations may have relevance to acceptance of human solid organ transplants since Williams et al.[32] recently showed that a critical difference between xenografts that survived through accommodation versus those lost by AMR was the lack of C5b-C9 MAC in the grafts with accommodation. Data by Bayry et al.[30] suggest that IVIG inhibits the maturation and function of dendritic cells, impairing their APC activity and inducing IL-10 production. This data are in concert with data from our laboratory demonstrating similar effects on B cells.[28]

Recently, Abe et al.[33] examined gene expression in patients with Kawasaki disease (KD) before and after high-dose IVIG infusion. These investigators demonstrated that in KD, the immunomodulatory effects of IVIG were likely mediated by suppression of an array of immune activation genes in monocytes and macrophages. Another paper by Gill et al.[34] using an animal model system of ischemia-reperfusion injury demonstrated that IVIG has direct inhibitory effects on leukocyte recruitment in vitro and in vivo through inhibition of selectin and integrin functions. The relevant mechanisms of action of IVIG are summarized in Figure 3.

Figure 3.

This figure summarizes the relevant mechanisms of action known for IVIG in modification of autoimmunity, alloimmunity and inflammation. These are divided into Fab- and Fc-mediated events. Many beneficial regulatory mechanisms have been described for IVIG that have relevance to transplantation.

Regardless of the mechanism(s) involved, current data suggest that IVIG represents a novel and effective approach to the reduction of anti-HLA antibodies pre-transplant and treatment of allograft rejection episodes post-transplant, especially those resistant to other therapies or where antibody-mediated mechanisms are present.

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