Low Doses Of IL-12 Research Articles

In Vivo Inverse Correlation in the Activation of Natural Killer T Cells Through Dual-Signal Stimulation via a Combination of α-Galactosylceramide–Loaded Liposomes and Interleukin-12

Alpha-galactosylceramide (GC) represents a potentially new class of adjuvant because GC strongly induces interferon (IFN) gamma production from natural killer T (NKT) cells, leading to the induction of strong antitumor immunity. Interleukin (IL)-12 is another stimulating signal that induces IFN-γ production by NKT cells. We report herein on an investigation of the effect of recombinant IL-12 on NKT cell activation, when used in combination with GC-loaded octaarginine modified liposomes (GC-Lip). IFN-γ production from splenocytes simulated with GC-Lip was dose dependently enhanced in the presence of IL-12 in vitro. In contrast, IFN-γ production in vivo was enhanced at a low dose of IL-12. Enhanced IFN-γ production was observed in the case of low doses (0.5 μg and 2.5 μg) of GC-Lip but not a high dose (5 μg), that is, the IL-12 combination enhanced NKT cell activation at a 10-fold lower GC dose. The use of the above combination also enhanced the expansion of the NKT cell population. These findings indicate that in vivo IFN-γ production is inversely correlated with the dose of IL-12 during dual signal stimulation of NKT cells via both GC-Lip and IL-12, indicating that the dose of GC-Lip can be reduced without weakening NKT cell activation.

Safety and immunogenicity of a polyvalent peptide C4-V3 HIV vaccine in conjunction with IL-12.

We examined the safety and immunogenicity of a human leukocyte antigen-based HIV envelope polyvalent synthetic peptide vaccine, C4-V3, alone and in combination with subcutaneous IL-12 in nine HIV-infected patients. Lymphocyte proliferative responses increased threefold or more to all four peptides at two consecutive post-immunization timepoints for four individuals. Three responders had received IL-12, suggesting a possible adjuvant effect of Il-12. Transient mild injection site reactions (7.9) and systemic symptoms (3/9) occurred.

MUCOSAL IL-12 INHIBITS AIRWAY REACTIVITY TO METHACHOLINE AND RESPIRATORY FAILURE IN MURINE ASTHMA

The worldwide incidence, prevalence, and fatality rates from asthma are increasing despite currently available therapeutic modalities. Systemic administration of interleukin (IL)-12 has been shown to inhibit airway reactivity in murine models of asthma, but the required dosage is high and may be toxic. This study tested the hypothesis that IL-12 administered directly into the lungs is more effective in inhibiting airway reactivity than systemically administered IL-12, allowing lower doses to be used. A low dose (10 ng) of IL-12 was delivered either intratracheally (mucosal delivery) or intraperitoneally (systemic delivery) at the time of ragweed (RW) challenge in mice sensitized to RW. Basal airway resistance and airway reactivity to methacholine were measured 3 days after RW challenge. Compared to phosphate-buffered saline (PBS) challenge of RW sensitized mice, RW challenge increased basal resistance and the slope of the methacholine dose-response curve. Methacholine challenge of RW challenged mice also induced premature respiratory failure (respiratory rate < 150/min, tidal volume < 0.15 mL) in some animals. Administration of mucosal or systemic IL-12 at the time of RW challenge decreased basal airway resistance. However, only mucosal IL-12 decreased airway reactivity and inhibited respiratory failure during methacholine challenge. These findings indicate that mucosal delivery of a low dose of IL-12 is more effective than systemic IL-12 in inhibiting airway reactivity and respiratory failure in a mouse model of asthma.

Dose and timing of interleukin (IL)-12 and timing and type of total-body irradiation: Effects on graft-vs.-host disease inhibition and toxicity of exogenous IL-12 in murine bone marrow transplant recipients

Paradoxically, a single injection of recombinant murine interleukin (IL)-12 on the day of bone marrow transplantation (BMT) inhibits graft-vs.-host disease (GVHD) while preserving graft-vs.-leukemia (GVL) effects in lethally irradiated mice receiving fully MHC-mismatched bone marrow and spleen cells. These protective effects are mediated by interferon (IFN)-gamma, whose early secretion is induced by IL-12 treatment. We investigated the relationship of IL-12 dose and timing of administration, as well as timing and type of total-body irradiation (TBI), with the ability of IL-12 to inhibit GVHD or mediate toxicity. The results show that a relatively low dose of IL-12 (as little as 50 U in a single injection) can mediate significant GVHD protection. The timing of IL-12 administration, however, is a critical factor. IL-12 administered 1 hour before BMT was most protective, but protection was still observed when it was administered 1-12 hours after BMT. Delaying IL-12 administration to 36 hours post-BMT completely obviated its protective effect. Administration of a second IL-12 injection 6 days after BMT negated the protective effect of an initial injection at the time of BMT. While IL-12 protection was evident when TBI was administered by 137Cs-irradiator in one or two fractions on day -1 or day 0, the use of an X-irradiator to deliver TBI on day -1 was associated with marked IL-12 toxicity. Whereas the protective effect of IL-12 against GVHD depended on donor-derived IFN-gamma, toxicity depended on the ability of host cells to produce IFN-gamma. Careful studies are warranted to test the effects of IL-12 in the context of BMT with various conditioning regimens in large animal preclinical models before this novel approach to GVHD protection can be applied clinically. Biol Blood Marrow Transplant 1999;5(5):277-84.

Dose-dependent effects of IL-12 treatment to immune response induced after immunization with a recombinant respiratory syncytial virus (RSV) fusion protein fragment

The amino acid (aa) sequence 190–289 of the RSV fusion (F) glycoprotein expressed in insect cells (bF 190–289) has been shown to partially protect BALB/c mice and to prime for a Th2 cell response. We evaluated the effects of IL-12 treatment during antigen priming of bF 190–289 on immune response and protective efficacy. Low doses of IL-12 (10 ng) reduced IL-4 and IL-5 secretion (but did not affect IL-10 production) and decreased inflammatory signs whereas high doses of IL-12 had no effects. In addition, IL-12 treatment did not improve resistance to RSV replication. These results suggest that IL-12 treatment attenuates Th2 response and Th2 associated pulmonary inflammatory response in a dose-dependent manner, without improving protective efficacy.

Murine interleukin‐12 prevents the development of cancer cachexia in a murine model

Murine colon 26 carcinoma causes cachexia even when the tumor burden is small. In this tumor model, murine IL-12 suppressed the induction of cancer cachexia and also inhibited tumor growth. IL-12 reduced the serum levels of IL-6, a cachexia mediator in this model, and alleviated the body weight loss and other abnormalities associated with cachexia, such as adipose tissue wasting and hypoglycemia. The anticachectic activity was observed even at low doses of IL-12, insufficient to inhibit tumor growth. IL-12 greatly increased levels of IFN-γ in the tumor tissue and, to a lesser extent, in the circulation. IFN-γ given intraperitoneally also prevented cancer cachexia, although it did not reduce IL-6 levels either in the tumor or in the circulation. In athymic mice bearing the same colon 26 tumor, IL-12 was no longer anticachectic and did not induce IFN-γ. These results indicate that the anticachectic activity of IL-12 is T-cell-dependent and results from at least 2 mechanisms, the down-regulation of IL-6 and the up-regulation of IFN-γ. © 1996 Wiley-Liss, Inc.

Murine interleukin-12 prevents the development of cancer cachexia in a murine model.

Murine colon 26 carcinoma causes cachexia even when the tumor burden is small. In this tumor model, murine IL-12 suppressed the induction of cancer cachexia and also inhibited tumor growth. IL-12 reduced the serum levels of IL-6, a cachexia mediator in this model, and alleviated the body weight loss and other abnormalities associated with cachexia, such as adipose tissue wasting and hypoglycemia. The anticachectic activity was observed even at low doses of IL-12, insufficient to inhibit tumor growth. IL-12 greatly increased levels of IFN-gamma in the tumor tissue and, to a lesser extent, in the circulation. IFN-gamma given intraperitoneally also prevented cancer cachexia, although it did not reduce IL-6 levels either in the tumor or in the circulation. In athymic mice bearing the same colon 26 tumor, IL-12 was no longer anticachectic and did not induce IFN-gamma. These results indicate that the anticachectic activity of IL-12 is T-cell-dependent and results from at least 2 mechanisms, the down-regulation of IL-6 and the up-regulation of IFN-gamma.