Figure 4. Pathologic evidence that immune tolerance to ERT enhances reduction of lysosomal storage in treated dogs in kidney, synovium, and mitral valve.

Normal renal morphology from unaffected carriers is shown in the top row; arrows indicate epithelium lining distal cortical tubules. The untreated MPS I (Untr MPS I) dogs have swollen, GAG-laden cells lining distal cortical tubules and the synovium and within the mitral valve stroma. Interstitial “foam cells” (macrophages storing GAG) are common. Renal tubular cells from the nontolerant treated (Nontol 0.58 mg/kg) dogs have reduced storage, but GAG-laden interstitial macrophages persist. Synovial tissues contain modest amounts of cytoplasmic vacuolation in lining cells and reduced GAG-laden macrophages. Mitral valve storage is prominent. In tolerant dogs treated with 0.58 and 2 mg/kg, storage material is eliminated throughout renal cortical tissues. In the synovium, GAG-laden macrophages are absent and lining cell vacuolation is greatly reduced with low-dose treatment and entirely absent in the tolerant dogs treated at 2 mg/kg. Mitral valve storage is reduced in low dose–treated dogs, and cellular morphology resembles that of normal dogs in the tolerant animals treated with the higher, 2-mg/kg dose. Arrows indicate distal renal cortical tubules; proximal tubules are marked with asterisks. Arrowheads indicate accumulations of interstitial GAG-laden macrophages. All images show H&E staining. Original magnification, ×400.