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

Background. Although the four human immunoglobulin G (IgG) isotypes ar e similar in structure, they exhibit significant differences in effect or function and catabolic half-life. With advent of structurally engin eered antibodies, there is the potential to design antibody constructs with desired half-lives; however, it is first necessary to discover t he structures and mechanisms that control immunoglobulin metabolism. M ethods. Radioiodinated chimeric antibodies, consisting of a mouse anti dansyl variable region and the four human IgG constant regions, were i njected intravenously into Balb/c and severe combined immunodeficiency (SCID) mice, and their half-lives were determined by whole body and w hole blood counting. Dependence of the rate of immunoglobulin cataboli sm on immunoglobulin concentration, a normal regulatory phenomenon spe cific to IgG, was evaluated by the introduction of large amounts of hu man gamma-globulin intraperitoneally. Results. Whole body and blood ha lf-lives were statistically indistinguishable. The four IgG isotypes w ere 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, alt hough this was not observed in SCID mice. Relevance of the model was c onfirmed by the demonstration of the presence of the concentration-cat abolism phenomenon, a relationship unique to normal IgG regulation. Co nclusions. 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.