Interleukin-12 is a natural chemical, or cytokine, produced by T-helper cells to activate and recruit the constituent parts of the immune system.

In test-tube experiments conducted in late 1993, researchers at the US National Cancer Institute reported that interleukin-12 improved the response of the cellular immune system to foreign organisms. In people with HIV, cellular immune responses are often diminished or lost entirely. Specifically, in vitro studies have found that IL-12 produces a proliferation of HIV-specific precursor cells.

Preliminary results in people have shown increased HIV-specific cytotoxic lymphocyte responses - that is, immune cells were more active against HIV-infected cells. However, IL-12 did not seem to boost CD4 cells numbers. Researchers have thus suggested that IL-12 does not augment the cytotoxic response through increased CD4 cell numbers.

A more recent study, which looked at the effects of IL-12 in people receiving HAART. IL-12 had no effects on CD4 count, viral load, antigen responses or lymhocyte proliferation in individuals with low CD4 counts, nor in indiviuals with relatively preserved immune systems (CD4 counts between 300 and 500 cells/mm³). A slight increase in interferon gamma production was noted at the highest doses.

IL-12 inhibits the growth of blood vessels, and is being studied as a treament for KS.

Artificial (recombinant) interleukin-12 is manufactured by the Genetics Institute Inc. in the USA.

Current use

Interleukin-12 is an unlicensed, experimental drug. In June 1995, a clinical trial testing it as a treatment for kidney cancer was stopped after ten participants were hospitalised and one died. The toxicity of IL-12 was due to the rate and frequency of the dosing. Trials of IL-12 as a treatment for cancer and HIV are now continuing using a weekly dose initially given at 100 mg/kg and gradually increased to 300mg/kg.

Key research

IL-12 is a heterodimeric cytokine encoded by two separate genes, p40 and p35. It is naturally produced by macrophages and B lymphocytes in response to antigenic stimulation. Scott reported that it stimulates the production of interferon gamma from T and natural killer (NK) cells. Seder reported that IL-12 enhances production of interferon gamma and reduces IL-4 mediated suppression of interferon gamma. Gazzinelli found that it is required for T-cell-independent triggering of NK cells by intracellular parasites such as T. gondii.

It has been proposed as a treatment for HIV disease because it stimulates the T_H1 subset of CD4 cells which may be important for preventing disease progression in HIV-infected people. In one model, Hsieh demonstrated that IL-12 induced T_H1 development in naive CD4+ T-cells undergoing primary activation.

Chehimi (1993) reported that levels of interleukin-12 in HIV-infected people are significantly lower than those seen in uninfected age-matched controls.

Clerici (1993) reported that IL-12 augments the in vitro production of cytokines associated with T_H1 responses (IL-2 and interferon alfa) in HIV-infected individuals. PBMCs were cultured from 40 HIV-positive individuals unable to produce IL-2 in response to envelope peptides of HIV-1. When these cells were Env-stimulated in the presence of IL-12, increased IL-2 production was observed in 28/40 (70%). Env-stimulated IL-2 production was not seen in PBMCs from nine HIV-negative individuals studied as a control. PHA-stimulated interferon gamma production was diminished in 8 HIV-positive people; IL-12 incubation augmented interferon gamma production in 6/8 individuals. Finally, PBMCs from HIV-positive people were stimulated in vitro with non-HIV antigens (influenza virus and HLA-disparate PBMCs); IL-12 increased the T helper cell response to these antigens. Elevated responses to these antigens were not observed in cells from HIV-negative people.

Puls administered IL-12 to 15 seronegative patients. 11 subsequently had augmented CTL responses to vaccinia-gag/pol and gp120-infected targets. Three HIV-infected patients were treated with rhIL-12 and data from one person has been presented. At 48 weeks, the persons HIV-specific immune responses were increased, their general ability (NK activity) to fight off infectious agents was also increased. However, this patient's CD4 cells did not appear to

increase in number in response to various HIV-specific proteins,

in the presence of IL-12. This suggests that the mechanism of

IL-12 augmentation of CTL response is not through increased CD4

cell numbers.

McLeod reported that in vitro IL-12 has neither a direct inhibitory nor stimulatory effect on HIV replication.

References

Chehimi J et al. IL-12 dysregulation in HIV-infected patients. 1st Natl Conf on Human Retroviruses, Washington, abstract 306, 1993.

Clerici M et al. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science 262:1720-1724, 1993.

Gazzinelli RT et al. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon-gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. PNAS 90:6115-6119, 1993.

Hsieh C-S et al. Development of T_H1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547-549, 1993.

McLeod GX et al. Effects of interleukin (IL)-12 on HIV-1 replication in vitro. First Natl Conf on Human Retroviruses, Washington, abstract 54, 1993.

Pollard R et al. Safety and activity of recombinant human interleukin-12 in HIV+ patients. First International AIDS Society Conference on HIV Pathogenesis and Treatment, Buenos Aires, abstract 106, 2001.

Puls R et al. IL-12: a life or death cytokine. Eleventh Annual Conference of the Australasian Society for HIV Medicine, Perth, abstract IN 91, 1999.

Scott PS. IL-12: Initiation cytokine for cell-mediated immunity. Science 260:496-497, 1993.

Seder RA et al. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. PNAS USA 90:10188-10192, 1993.