Immunomodulation by hyperimmunoglobulins after solid organ transplantation: Beyond prevention of viral infection

Hyperimmunoglobulins are pharmaceutical formulations of human IgG which contain high titers of antibodies against specific viruses. They have been successfully used in solid organ transplantation (SOT) to prevent Cytomegalovirus (CMV) and Hepatitis B Virus (HBV) infection. The introduction of effective and cheaper antiviral drugs has resulted in decreasing usage of hyperimmunoglobulins in SOT. However, it may still be attractive to combine antiviral drug therapy with hyperimmunoglobulins after SOT, as there is some evidence that hyperimmunoglobulins, similar to high doses of intravenous immunoglobulins (IVIgs), might exert anti-inflammatory activity and thereby prevent immunological graft damage and improve graft and patient survival. In this review we discuss the existing clinical evidence for beneficial anti-inflammatory effects of hyperimmunoglobulins after cardiac, lung, kidney, and liver transplantation. Only a limited number of studies have addressed this issue, and these studies often included small patient cohorts and showed considerable variations in the type, intensity and duration of treatment regimens. Due to these limitations, it is difficult to draw firm conclusions. Retrospective studies consistently demonstrated that addition of CMV hyperimmunoglobulin (CMV-Ig) to antiviral drug prophylaxis after lung transplantation is associated with reduced rates of CMV disease and bronchiolitis obliterans syndrome (BOS), and improved patient survival. The doses of CMV-Ig administered after SOT are much lower than the minimal effective dose of IVIg used for anti-inflammatory therapy in auto-immune diseases. Therefore, it is questionable whether the reduced incidence of BOS is the result of 'direct' anti-inflammatory effects of CMV-Ig or is caused by a reduction of CMV infection, which is a risk factor for BOS. No or very limited evidence for better prevention of immunological graft damage by anti-CMV combination therapy is available for heart, kidney and liver transplant patients. In liver transplantation published evidence suggests that the high-doses of Hepatitis B virus hyperimmunoglobulin (HBIg) administered to prevent HBV-infection may reduce the risk of acute rejection, while combination therapy of HBIg and antiviral drugs in HBV-infected patients is consistently associated with better graft and patient survival compared to antiviral monotherapy. Well-designed prospective randomized studies with larger patient cohorts are needed to substantiate the current limited evidence for anti-inflammatory benefits of hyperimmunoglobulins besides prevention of CMV and HBV infection after SOT.