Interleukin 12 Protects from a T Helper Type 1–mediated Autoimmune Disease, Experimental Autoimmune Uveitis, through a Mechanism Involving Interferon γ, Nitric Oxide, and Apoptosis

Abstract

Pathogenic effector T cells in experimental autoimmune uveitis (EAU) are T helper type 1–like, and interleukin (IL)-12 is required for their generation and function. Therefore, we expected that IL-12 administration would have disease-enhancing effects. Mice were immunized with a uveitogenic regimen of the retinal antigen interphotoreceptor retinoid-binding protein, treated with IL-12 (100 ng/d for 5 d), and EAU was assessed by histopathology. Unexpectedly, IL-12 treatment failed to enhance EAU in resistant strains and downregulated disease in susceptible strains. Only treatment during the first, but not during the second, week after immunization was consistently protective. High levels of interferon γ (IFN-γ) were present in the serum during IL-12 treatment, but subsequent antigen-specific IFN-γ production in protected mice was diminished, as were IL-5 production, lymph node cell proliferation, and serum antibody levels. Treated mice had fewer cells and evidence of enhanced apoptosis in the draining lymph nodes. Unlike wild-type mice, IFN-γ–deficient, inducible nitric oxide synthase (iNOS)-deficient, and Bcl-2lck transgenic mice were poorly protected by IL-12, whereas IL-10–deficient mice were protected. We conclude that administration of IL-12 aborts disease by curtailing development of uveitogenic effector T cells. The data are compatible with the interpretation that IL-12 induces systemic hyperinduction of IFN-γ, causing activation of iNOS and production of NO, which mediates protection at least in part by triggering Bcl-2 regulated apoptotic deletion of the antigen-specific T cells as they are being primed.

Self-Limitation of Th1-Mediated Inflammation by IFN-γ

“…That idea is supported by a report describing that administration of IL-12 is protective in an experimental autoimmune uveitis model (34). The protection involved hyperinduction of IFN-␥, which causes an up-regulation of iNOS and production of NO (34). In fact, in the present study, we were able to demonstrate that iNOS is involved in the limitation of a Th1-mediated DTH response and acts most likely as the effector molecule downstream of IFN-␥.…”

“…That idea is supported by a report describing that administration of IL-12 is protective in an experimental autoimmune uveitis model (34). The protection involved hyperinduction of IFN-␥, which causes an up-regulation of iNOS and production of NO (34).…”

Interferon‐γ limits Th1 lymphocyte adhesion to inflamed endothelium: A nitric oxide regulatory feedback mechanism

“…It has been proposed that NO represents a downstream mediator of IFN-c action and plays an important role in T cell homeostasis and ultimately the down-regulation of some Th1-mediated inflammation [17,22,25]. NO has been shown to have various immunosuppressive actions on T cells, inhibiting T cell proliferation and secretion of cytokines and increasing T cell apoptosis [28].…”

“…In fact, it has recently been shown that IFN-c likely influences the effector phase of a T cell-mediated response by limiting the expansion of T cells after antigen challenge and by the induction of T cell apoptosis [17,19,[22][23][24]. In a number of studies, nitric oxide (NO) was identified to be an effector molecule downstream of IFN-c that was responsible for control of lymphocyte apoptosis [22,25]. Thus it has been suggested that Th1 lymphocytes can limit their own effector response via the production of IFN-c [17].…”

M-1/M-2 Macrophages and the Th1/Th2 Paradigm

“…Perhaps M-1-or M-2-dominant responses evolve into dendritic cell responses that stimulate Th1 or Th2 responses, respectively. At the same time, because M-1 equates with the production of destructive molecules such as NO, overexpression of this pathway could inhibit lymphocyte responses through a suppressor macrophage effect (30,(61)(62)(63), as suggested in Fig. 6.…”