Synergistic enhancement of cell-mediated immunity by interleukin-12 plus interleukin-2: Basis for therapy of cutaneous T cell lymphoma

Abstract

Cutaneous T cell lymphoma is a clonally derived, skin-invasive malignancy of CD4+ T lymphocytes with the phenotype of mature helper T cells. Previous work has demonstrated that the Sézary form, or typically leukemic form of cutaneous T cell lymphoma, is characterized by prominent immunologic defects, including depressed cell-mediated immunity associated with marked defects in the production of interleukin-12 and other type 1 helper T cell cytokines. Recent clinical trials with recombinant human interleukin-12 for cutaneous T cell lymphoma have demonstrated that it is a potent therapeutic agent, which induces cytotoxic T cell responses. Nevertheless, a high rate of refractoriness to recombinant human interleukin-12 occurred in these studies that may be related to the downmodulation of interleukin-12 receptor expression by chronic interleukin-12 use. In an effort to enhance the overall response rate and to overcome the refractoriness to recombinant human interleukin-12 therapy, we studied the immunologic effects in vitro of adding interleukin-2 to interleukin-12 as a model to achieve these goals. We examined the stimulation of interferon-γ production, natural killer cell activity and interleukin-12 receptor expression by T cells of cutaneous T cell lymphoma patients. The addition of interleukin-12 to cutaneous T cell lymphoma patient peripheral blood cells resulted in the production of interferon-γ (mean = 7914 pg per ml ± 2161, n = 15) as did interleukin-2 alone (mean = 7222 pg per ml ± 2228, n = 15). Importantly, the addition of interleukin-2 to the interleukin-12 synergistically enhanced the levels of interferon-γ produced (mean = 16 792 pg per ml ± 2492 n = 15) (p < 0.01). Similarly, addition of interleukin-2 to interleukin-12 synergistically enhanced both the natural killer cell activity of 15 cutaneous T cell lymphoma patients as well as T cell surface interleukin-12 receptor expression in comparison with the effects of interleukin-12 or interleukin-2 alone. Thus, interleukin-2 plus interleukin-12 unequivocally produces the synergistic enhancement of multiple parameters of cell-mediated immunity as well as upmodulating interleukin-12 receptor expression; this indicates that protocols combining these two potent immune enhancing cytokines may have added therapeutic benefit for cutaneous T cell lymphoma.