Pg. Tipping et al., IMMUNE MODULATION WITH INTERLEUKIN-4 AND INTERLEUKIN-10 PREVENTS CRESCENT FORMATION AND GLOMERULAR INJURY IN EXPERIMENTAL GLOMERULONEPHRITIS, European Journal of Immunology, 27(2), 1997, pp. 530-537
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.