ANIMAL-MODELS OF IGA NEPHROPATHY - FORMULATING THERAPEUTIC STRATEGIES

This review seeks to highlight those aspects of ongoing research with animal models that may facilitate development of effective and perhaps specific therapy of IgAN. Oral immunization is typically accompanied by a predominantly Th2 response; defects in the evolution of this typi cal response, instigated by cyclophosphamide and/or oestradiol, elicit IgAN in mice. The Th2 cytokines that predominate in orally immunized mice, and in patients with IgAN, promote abnormally glycosylated IgA, similar to the IgA in patients. Immune complexes prepared with IgA ant ibody bearing altered glycosyl residues show enhanced rates of glomeru lar uptake and altered rates of clearance from the circulation. When i mmune responses to infectious pathogens are localized to sites remote from a new infection with a serologically related organism, 'misdirect ed' responses permit pathogen replication and antigen production conco mitant with strong host antibody responses. The resultant immune compl exes elicit IgAN in mice. Similar 'misdirected' immune responses may a rise in J chain-deficient subjects. Improved pharmacologic control of B cell trafficking and/or function could rectify these defects. Correc tion of deficiency in clearance of IgA immune complexes could benefit patients with secondary IgAN. Finally, manipulation of glomerular haem odynamics and/or production or response to intraglomerular cytokines a nd growth factors might ameliorate disease or forestall progression to glomerulosclerosis. Animal models have served as a conceptual springb oard for a wide variety of clinical investigations, and in turn clinic al information has guided the design and goal of experimental investig ation. Hopefully, this synergy can continue, ultimately resulting in e ffective and specific therapy.