Immune moldulatory effects of intravenous immunoglobulin in vitro and after allogeneic bone marrow transplantation

Intravenous immunoglobulin (IVIG) has been used in patients with immunodeficiencies and various autoimmune diseases. Its immune modulatory effect is well documented. In allogeneic bone marrow transplantation (BMT) IVIG has been used to reduce the incidence of infections and graft-versus-host-disease (GVHD). To investigate further the immune-modulatory effects of IVIG, we have studied now its effects on nonspecific(mitogenic) and specific Iymphocyte responses as well as immunoglobulin (Ig)-producing cells. There was a significant dose-dependent inhibition by IVIG of various mitogenic responses by peripheral blood Iymphocytes (PBL). Inhibition was the same when stimulating different T-lymphocyte subsets. The specific Iymphocyte response in mixed Iymphocyte cultures(MLC) and to Staphylococcus aureus protein A (SPA) were also inhibited by IVIG. When comparing 12 commercial IVIG preparations (2.5 g/l), inhibition varied from 0% to 66%. IgG preparations made from single donors proved more effective than commercial IVIG in inhibiting phytohemagglutinin stimulation. The use of cytomegalovirus (CMV)hyper-Ig compared to IVIG did not result in increased inhibition of the Iymphocyte response to herpes virus antigen, but CMV negative Ig resulted in less inhibition. IgG- and IgM-production from PBL and bone marrow cells, measured as plaque-forming cells (PFC) were also inhibited in a dose-dependent fashion by IVIG. Cells were stimulated by SPA, lipopolysaccharide from E. coli (LPS) or with CMV Antigen (Ag). The inhibition of spleen-PFC varied depending on the stimuli. We compared equimolar concentrations of IgG, IgG-F(ab' )2 and IgG-Fc to determine the part of the IgG molecule which mediated the inhibitory effect. Lymphocyte responses were inhibited by F(ab')2 fragments, but only by one of two Fc preparations tested. A comparison of 4 brands of IVIG fragments showed that IgG and F(ab' )2 preparations inhibited IgG and IgM production of LPS-stimulated spleen cells, but no significant inhibition was obtained with any of the purified Fc products. In an analysis of serum levels of various cytokines in sibling BMT recipients, we found a correlation between IVIG treatment and decreased serum levels of i) sIL-2r, IL-3, IL-4, IL-6 and IL-10 in patients without complications and ii) IL-lra and TNF-a levels in patients with acute GVHD.

In two clinical studies, we evaluated the effects of prophylactic IVIG treatment after BMT (0.5 g/kg once weekly until day 90). The 1st study included 98 HLA-identical sibling transplant recipients and the 2nd 107 recipients of marrow from matched unrelated donors (MUD). No beneficial effects of IVIG treatment on GVHD, various bacterial, fungal and viral infections or other transplant related complications were detected in either of the two studies. Of all 208 patients, only one IVIG-treated patient and 4 of the controls had CMV pneumonia. The overall survival rates in the two studies were similar, with an actuarial two-year survival of 59% in the IVIG group and 57% in the controls. The median follow-up (June, 1997) was 4.4 years and 4.2 years in the two groups respectively. Forty-two IVIG-treated patients (45%) and 50 controls have died (45%). Relapse caused the death of 15 treated patients and 16 controls. Fewer IVIG treated patients died of bacterial infections (2 vs. 11, P=0.03) and more of the them, died of VOD (7 vs 0, P=0.03).

Conclusions: IVIG clearly inhibits cell-mediated T and B cell responses in vitro. The inhibition seems to be mediated by the F(ab')2 part of the IgG molecule. Immune modulatory effects by IVIG may be beneficial in BMT recipients, but our retrospective study on prophylactic use after HLA identical sibling BMT did not confirm earlier results about infections and GVHD. Nor did we detect any beneficial effects of treatment in MUD-transplant recipients. We question the use of prophylactic high-dose IVIG on a regular basis in BMT recipients.