IMMUNE MODULATION WITH INTERLEUKIN-4 AND INTERLEUKIN-10 PREVENTS CRESCENT FORMATION AND GLOMERULAR INJURY IN EXPERIMENTAL GLOMERULONEPHRITIS

Crescentic glomerulonephritis (GN) demonstrates immunopathological fea tures of a T helper (Th)1-directed delayed-type hypersensitivity (DTH) response. The capacity of Th2 cytokines to attenuate crescentic glome rular injury in this disease was examined by administering interleukin (IL)-4 and IL-10, singly and in combination. GN was induced by i.v. a dministration of sheep anti-mouse glomerular basement membrane (GBM) g lobulin to mice sensitized to sheep globulin 10 days earlier. Treatmen t (2.5 mu g, i.p.) with IL-4, IL-10, or both IL-4 and IL-10 (IL-4+10), was started 1 h before sensitization and continued daily until the en d of the study (10 days after administration of anti-GBM globulin). Co ntrol mice treated with PBS developed GN with glomerular accumulation of T cells and macrophages, crescents in 42.5 +/- 4.5 % of glomeruli ( normal 0 %), proteinuria (8.3 +/- 0.9 mg/24 h, normal 0.74 +/- 0.08 mg /24 h, p < 0.001) and renal impairment (creatinine clearance [cr/cl]: 93 +/- 12 mu l/min, normal 193 +/- 10 mu l/min, p < 0.001). Treatment with either IL-4, IL-10, or IL-4+10 prevented crescent formation (cres centic glomeruli: 0.8 +/- 0.5, 1.2 +/- 0.9, and 1.4 +/- 1.0 %, respect ively, all p < 0.01 compared to control) and attenuated proteinuria (3 .6 +/- 1.0, 2.2 +/- 0.5, and 2.9 +/- 0.5 mg/24 h, respectively, all p < 0.01 compared to control). IL-4+10 prevented development of renal im pairment (cr/cl: 183 +/- 22 mu l/min); IL-10 given alone limited the d ecline in renal function (cr/cl: 150 +/- 20 mu l/min), but IL-4 alone did not provide any significant protection (cr/cl: 121 +/- 17 mu l/min ). All treatments markedly diminished glomerular T cell and macrophage accumulation, reduced interferon-gamma production by splenic T cells, prevented cutaneous DTH to the disease-initiating antigen and reduced antigen-specific immunoglobulin of the IgG2a and IgG3 isotypes. These data demonstrate that crescentic GN and renal impairment can be preve nted by administration of Th2 cytokines and that this effect is associ ated with attenuation of the Th1 response to the disease-initiating an tigen.