Reduction in serum levels of antimitochondrial (M2) antibodies following immunoglobulin therapy in severe combined immunodeficient (SCID) mice reconstituted with lymphocytes from patients with primary biliary cirrhosis (PBC)

Abstract

The effect of gammaglobulin treatment on autoantibody production was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells (PBMC) obtained from patients with PBC. All reconstituted mice displayed the presence of human antimitochondrial antibodies (αM2Ab) of both IgG and IgM types before treatment with human immunoglobulin. Two weeks after i.p. injection of 20 ×106 PBMC into SCID mice, i.p. treatment with various preparations of human immunoglobulin was initiated. In control animals treated with saline, serum levels of human αM2Ab of the IgG type increased with time, peaking around 4 weeks after reconstitution. In contrast, human IgG autoantibodies rapidly decreased in all animals treated with human IgG. Treatment with a human IgM preparation had no effect on serum levels of αM2Ab of the IgG type. The results may suggest that the pronounced reduction of specific IgG autoantibodies was due to an increased catabolism of human IgG, including the autoantibodies, in the gammaglobulin‐treated mice. Although the production of human αM2Ab in reconstituted mice could be easily shown, PBC‐specific liver lesions or bile duct destruction were not observed, irrespective of treatment protocol.

The role of the innate immune recognition system in the pathogenesis of primary biliary cirrhosis: a conceptual view

“…Severe combined immunodeficient (SCID) mice have been described as a classical model of human PBC, because they produce significant levels of AMA after reconstitution with cells from patients with PBC. But in these experiments, AMAs have not been shown to cause bile duct lesions (18).…”

“…Furthermore, AMAs are not influenced by immunosuppressive therapy and recognize a protein that belongs to a set of evolutionary conserved self‐structures (100). SCID mice, a model of human PBC, are known to produce significant levels of AMA but do not develop bile duct lesions when injected with PBMC from patients with PBC (18).…”

“…Another aspect may also become interesting reflecting the therapeutic effect of immune globulins observed in some patients with anti‐receptor autoimmunity (108). Experiments in SCID mice reconstituted with cells from patients with PBC showed a continuous decline in serum levels of AMA after treatment with human polyclonal IgG (18). Thus, anti‐idiotypic antibodies can control disease‐associated autoantibodies and therefore may be therefore considered as another interesting option in coping with progressive courses of PBC.…”

Intravenous Immunoglobulins in Autoimmune and Inflammatory Diseases

“…Interactions between IVIg and idiotypes of antigen receptors on B cells provide the basis for the ability of IVIg to regulate autoreactive B cell clones in vivo 20 . In fact , a downregulation of specific autoreactive B cells has been demonstrated in a model where severe combined immunodeficiency mice were adoptively transferred with lymphoid cells from patients with autoimmune disease and treated with IVIg 21,22 . Reduction in the titer of autoantibodies has also been observed in several conditions in vivo following IVIg therapy 23,24 .…”

Lessons from animal models of primary biliary cirrhosis

“…We are aware of at least six animal models that have been proposed: a spontaneous model of PBC; 3 a human severe combined immunodeficient (SCID) mouse model; 4 an immunization model with intrahepatic bile duct cells; 5 an inoculation model with pyruvate dehydrogenase (PDH) 6 or other infectious agent; 7 a gene‐knockout mice model; 8 and a graft‐versus‐host disease (GVHD) model; 9 as presented here. While each model has both advantages and disadvantages, the GVHD model seems particularly useful as it may provide important information about transplant‐related immunology, especially living‐donor related transplantation where there is excellent human leucocyte antigen (HLA)‐matching.…”