IMMUNOLOGICAL DETERMINANTS OF SUSCEPTIBILITY TO EXPERIMENTAL GLOMERULONEPHRITIS - ROLE OF CELLULAR-IMMUNITY

To identify the immunologic mechanisms that influence susceptibility t o GN, we compared the severity of accelerated anti-glomerular basement membrane (GBM) nephritis between Lewis (LEW) and Brown Norway (BN) ra ts and analyzed differences in their immune responses to the nephritog enic immunoglobulin. Lewis (LEW) rats preimmunized with sheep IgG deve loped proliferative GN with marked proteinuria [peak protein excretion (mean +/- SEM) = 85.3 +/- 15.3 mg/24 hr; normal = 6.4 +/- 0.8 mg/24 h r] after receiving a subnephritogenic dose of sheep anti-rat GBM antis erum. Identically treated Brown Norway (BN) rats, on the other hand, h ad minimal renal pathology and minimal proteinuria (peak protein excre tion = 22.6 +/- 3.1 mg/24 hr; normal = 13.0 +/- 0.6 mg/24 hr). Serum t iters of rat anti-sheep IgG isotypes and intraglomerular binding of sh eep IgG, rat IgG, and rat complement (C-3) were comparable in both str ains. In contrast, only LEW rats developed a strong cellular immune re sponse to sharp IgG represented by intrarenal T lymphocyte (OX19(+)) a nd monocyte (ED1(+)) accumulation [LEW vs. BN (mean +/- SEM): OX19(+) = 0.60 +/- 0.10 vs. 0.14 +/- 0.01 cells/glomerulus, control = 0.02 +/- 0.01; ED1(+) = 4.0 +/- 0.4 vs. 1.0 +/- 0.2 cells/glom., control = 0.8 +/- 0.3] and a significant cutaneous delayed-type hypersensitivity (D TH) reaction [LEW versus BN (mean I SEM): Delta ear thickness = 0.22 /- 0.02 vs. 0.05 +/- 0.03 mm; control = 0.04 +/- 0.02 mm]. Upon rechal lenge with sheep IgG in vitro, LEW splenocytes expressed a T helper 1 (Th1) cytokine pattern (IFN gamma and IL-2 mRNA, but little IL-4 mRNA) which is associated with delayed-type hypersensitivity reactions. BN splenocytes, on the other hand, expressed IL-4 in addition to IL-2 and IFN gamma mRNA that is consistent with an undifferentiated (Th0) cyto kine profile. These studies suggest that humoral immunity to heterolog ous immunoglobulin planted In the kidney is not sufficient for full ex pression of accelerated anti-GBM nephritis, and that additional cellul ar immune mechanisms are required. We conclude that susceptibility to accelerated anti-GEM nephritis is strongly influenced by the host's pr opensity to mount a Th1-type response and DTH reaction to the disease- inciting immunoglobulin.