Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice.

Abstract

We have previously shown that continuous administration of anti-interleukin 10 (anti-IL-10) antibodies (Abs) to BALB/c mice modifies endogenous levels of autoantibodies, tumor necrosis factor alpha (TNF-alpha), and interferon gamma, three immune mediators known to affect the development of autoimmunity in "lupus-prone" New Zealand black/white (NZB/W)F1 mice. To explore the consequences of IL-10 neutralization in NZB/W F1 mice, animals were injected two to three times per week from birth until 8-10 mo of age with anti-IL-10 Abs or with isotype control Abs. Anti-IL-10 treatment substantially delayed onset of autoimmunity in NZB/W F1 mice as monitored either by overall survival, or by development of proteinuria, glomerulonephritis, or autoantibodies. Survival at 9 mo was increased from 10 to 80% in anti-IL-10-treated mice relative to Ig isotype-treated controls. This protection against autoimmunity appeared to be due to an anti-IL-10-induced upregulation of endogenous TNF-alpha, since anti-IL-10-protected NZB/W F1 mice rapidly developed autoimmunity when neutralizing anti-TNF-alpha Abs were introduced at 30 wk along with the anti-IL-10 treatment. Consistent with the protective role of anti-IL-10 treatment in these experiments, continuous administration of IL-10 from 4 until 38 wk of age accelerated the onset of autoimmunity in NZB/W F1 mice. The same period of continuous IL-10 administration did not appear to be toxic to, or cause development of lupus-like autoimmunity in normal BALB/c mice. These data suggest that IL-10 antagonists may be beneficial in the treatment of human systemic lupus erythematosus.

Hydrodynamics-based delivery of the viral interleukin-10 gene suppresses experimental crescentic glomerulonephritis in Wistar–Kyoto rats

“…In contrast, continuous administration of IL-10 exacerbated GN in the New Zealand black/ white mouse model of lupus, which is classified as a Th2-predominant model. 3,36 Many factors complicate the pathogenesis of kidney diseases. To test the involvement of the many recognized candidate genes quickly, the development of a gene transfer method is necessary.…”

Interleukin‐10 Response Abnormalities in Systemic Lupus Erythematosus

“…Increased levels of IL-10 and IL-6, as well as the associated cytokines TNF-a and GM-CSF, could enhance B-cell proliferation and differentiation [16][17][18][19]. Exogenous IL-6 has been shown to promote murine lupus, while specific monoclonal antibodies (MoAb) to IL-6 and IL-10 delay the development of this disease in NZB/W F 1 mice [20,21]. An intrinsic overproduction of these cytokines might also explain the pre-existing B-cell hyperactive state reported in family members of SLE patients, as well as in lupus patients themselves [22][23][24][25][26].…”

IL-12 inhibits in vitro immunoglobulin production by human lupus peripheral blood mononuclear cells (PBMC)

“…Recent advances in our understanding of the biology of cytokines have shed new light on the mechanisms underlying this inappropriate antibody production. Thus, it was demonstrated that IL-10 is overexpressed in lupus patients [1,2] and mediates, at least in part, the excessive immunoglobulin production and the autoantibody response associated with human and murine SLE [3,4]. Such results demonstrate that cytokines are closely involved in the pathogenesis of lupus and suggest that cytokine manipulation might be useful for the control of the disorder.…”