Immunoregulation by interleukin‐12 in MB49.1 tumor‐bearing mice: Cellular and cytokine‐mediated effector mechanisms

Abstract

Administration of recombinant murine interleukin (rmIL)-12 to MB49.1 tumor-bearing mice results in dose-dependent regression of the primary tumor and the generation of protective antitumor immunity in the majority of animals. rmIL-12 administration is associated with a marked increase in lymph node cellularity that is predominantly due to the expansion of B220+ B cells as well as CD8+ T cells. Stimulation of lymph node cells from rmIL-12-treated, but not control tumor-bearing mice, with MB49.1 tumor cells in vitro was shown to enhance the secretion of interferon (IFN)-gamma. The magnitude of this in vitro response was dependent on the dose of rmIL-12 administered in vivo and mirrored the change in circulating serum IFN-gamma. Furthermore, at the height of the in vitro response to tumor stimulation, the addition of a neutralizing antibody to murine IL-12 suppressed IFN-gamma production, indicating a role for endogenous IL-12 in this antigen-specific cytokine response. Although studies in SCID mice confirmed that an appropriate T cell response was required for rmIL-12-mediated antitumor activity, in immunocompetent animals early tumor regression was not accompanied by cellular infiltration of the tumor. In contrast, a profound increase in tumor-associated inducible nitric oxide synthase (iNOS) was observed in mice receiving rmIL-12 which preceded T cell infiltration of the tumor which could be detected during the second week of IL-12 treatment. Direct tumor killing through the cytotoxic actions of NO via the iNOS pathway may serve as a way of generating tumor antigen which enables the host to mount a subsequent T cell response against the tumor.

The Anti-Tumor Effect of Interleukin-12 is Enhanced by Mild (Fever-Range) Thermal Therapy

“…Importantly, deletion of the iNOS gene (Dinapoli et al, 1996), or inhibition of NOS via arginine analogs such as L-NMA (Tsung et al, 1997) correlate with reduced tumor rejection. In addition, one report suggests that early tumor regression in some IL-12 models is due to increased tumor iNOS levels (Hunter et al, 1997). However, to better clarify a role for NO in the anti-tumor effects reported here, it will be important to demonstrate that the NOS inhibitor actually prevents NO production in our studies.…”

Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer

“…Our previous paper demonstrated that intravesical CS/IL-12 does result in measurable serum IL-12 levels [10]. It has also been established that systemic IL-12 can induce subcutaneous MB49 regression [23]. Once the treatments ceased, 3 of 5 mice exhibited exponential tumor growth and succumbed within 20 days after the last treatment.…”

IL‐1, IL‐18, and IL‐33 families of cytokines

“…However, IFN-g production in response to IL-18 was not restricted to Th1 cells. The combination of IL-18 and IL-12 acting on CD8 1 T cells, NK cells, and activated B cells also induced upregulation of the IL-18Ra chain and the production of large amounts of IFN-g (114,118,119). In addition to its effect on IFN-g production, IL-18 is also able to stimulate Th2 responses.…”