Mesangial cell proliferation and matrix accumulation are considered to contribute to the development of glomerulosclerosis. To investigate the pathological role played by mesangial cell damage in progressive renal disease appropriate progressive models initiated by a mesangial cell injury should be developed. Monoclonal antibody (mAb) 1–22–3 (IgG3) recognizes a critical epitope of the Thy–1.1 molecule on the mesangial cell surface, binding of which induces more severe mesangial cell injury than in the case of OX–7, a commercially obtainable anti–Thy–1.1 mAb. The mAb 1–22–3 has enabled us to develop irreversible models of renal damage induced by two consecutive injections, by a single injection into unilaterally nephrectomized rats, or by a single simultaneous injection with another mAb, in addition to the corresponding reversible model. Detailed examinations using the combination of both types of models, all of which are initiated by an immune mechanism directed against the identical epitope on the Thy–1.1 molecule, are expected to provide new insights into mechanisms of irreversible renal injury initiated by mesangial cell damage and also to develop novel and rational therapeutic approaches to progressive, primarily mesangial diseases.