Renal immunopathology in murine host-versus-graft disease

BALB/c mice neonatally injected with 1 x 10(8) (A/J x BALB/c)F1 hybrid spleen cells develop polyclonal B cell activation and autoimmune features as a consequence of a host-versus-graft (HVG) reaction. In this study, we first analyzed the time-course development of the renal lesions in HVG mice. From week 2 to week 6, linear deposits of IgG were observed by immunofluorescence along the glomerular capillary walls. From week 8 to week 12, the immunofluorescence pattern of IgG changed from linear to granular, and by immunoelectron microscopy, the IgG deposits were located on the epithelial side of the glomerular basement membrane (GBM). In addition, focal glomerulosclerosis complicated this membranous glomerulopathy in about 50% of the 12-week-old HVG mice and albuminuria was increased in most of them. Circulating antibodies to antigens of the GBM (laminin, type IV collagen) and of the renal tubular epithelial (RTE) cells (dipeptidyl peptidase IV, gp330) were already detected at week 2 and were still present at week 12. Immunoglobulins eluted from isolated glomeruli contained antibodies directed against type IV collagen, laminin, and to a lesser degree against gp330. F1 donor B cells were involved in the production of nephritogenic antibodies as indicated by (a) the presence of A/J allotypic determinants on serum anti-laminin antibodies and (b) the abrogation of the in vitro production of anti-GBM, anti-laminin and anti-RTE antibodies when spleen cells from HVG mice were depleted of F1 donor B cells. Finally, mixed lymphocyte culture experiments established that T cells from HVG mice stimulate normal B cells from F1 donor hybrids to produce anti-GBM, anti-laminin, anti-type IV collagen, anti-RTE, anti-gp330 and anti-dipeptidyl peptidase IV antibodies. We conclude that mice neonatally injected with semi-allogeneic spleen cells develop a glomerulonephritis characterized by the transition from a linear to a granular IF pattern, and that the production of nephritogenic antibodies results from the activation of donor B cells by host helper T cells.