THE USE OF SEVERE COMBINED IMMUNODEFICIENCY MICE TO STUDY THE METABOLISM OF HUMAN-IMMUNOGLOBULIN-G

Background. Although the four human immunoglobulin G (IgG) isotypes are similar in structure, they exhibit significant differences in effector function and catabolic half-life. With advent of structurally engineered antibodies, there is the potential to design antibody constructs with desired half-lives; however, it is first necessary to discover the structures and mechanisms that control immunoglobulin metabolism. Methods. Radioiodinated chimeric antibodies, consisting of a mouse antidansyl variable region and the four human IgG constant regions, were injected intravenously into Balb/c and severe combined immunodeficiency (SCID) mice, and their half-lives were determined by whole body and whole blood counting. Dependence of the rate of immunoglobulin catabolism on immunoglobulin concentration, a normal regulatory phenomenon specific to IgG, was evaluated by the introduction of large amounts of human gamma-globulin intraperitoneally. Results. Whole body and blood half-lives were statistically indistinguishable. The four IgG isotypes were eliminated from the whole animals in a predominantly single-phasic manner, with the half-life being dependent on the isotype studied. In Balb/c mice, immune elimination frequently occurred after 6 days, although this was not observed in SCID mice. Relevance of the model was confirmed by the demonstration of the presence of the concentration-catabolism phenomenon, a relationship unique to normal IgG regulation. Conclusions. SCID mice provide an adequate initial animal model for the study of human-mouse chimeric antibodies. Further understanding of the factors governing immunoglobulin catabolism can be probed by study of recombinant human constant regions in this animal system.