Use of interleukin-15

Abstract

The invention relates to the use of IL-15 or active variants thereof and / or IL-15 activity enhancing compounds for the manufacture of a pharmaceutical composition for manipulating memory cells of the immune system, such as manipulating viability and / or responsiveness of said memory cells. The IL-15 activity enhancing compound is for example lipopolysaccharide (LPS). The invention further relates to the use of IL-15 inhibiting or eliminating compounds for the manufacture of a pharmaceutical composition for manipulating memory cells of the immune system. Such inhibiting or eliminating compounds are for example anti-IL-15 antibodies, anti-IL-15Rα antibodies, fragments of these antibodies, e.g. the Fab or F(ab′)2 fragment, soluble IL-15Rα, fusion proteins consisting of soluble IL-15Rα, and Fc fragment, compounds, e.g. peptides, binding and / or inhibiting functional IL-15 receptor, IL-15 antisense oligonucleotides.

Description

RELATED APPLICATIONS [0001] The present application is a continuation of U.S. application Ser. No. 10 / 045,185, filed Oct. 18, 2001, which is a divisional application of U.S. Ser. No. 09 / 380,049, filed Aug. 23, 1999, now U.S. Pat. No. 6,344,192, which is the U.S. national phase under 35 U.S.C. § 371 of International Application No. PCT / EP98 / 00127, filed Feb. 23, 1998. All of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] The present invention relates to a new use of Interleukin-15 (IL-15). The invention further relates to pharmaceutical preparations, containing IL-15 itself, IL-15 stimulating compounds or IL-15 inhibiting and / or eliminating compounds. [0003] The cytokine interleukin-15 (IL-15) was originally identified in culture supernatants of the simian kidney epithelial cell line CV-1 / EBNA and the T cell leukemia cell line HuT-102 (Grabstein et al., 1994; Burton et al., 1994; Bamford et al., 1994). The IL-15 cDNA sequence encodes a ...

AI Technical Summary

Benefits of technology

[0014] The research that resulted in the present invention, indicated that IL-15 promotes the generation and persistence of CD4+ memory cells, by promoting antigen activated CD4+ T-lymphocytes to acquire the characteristics, mentioned above: resistance towards AICD, insensitivity towards apoptosis following growth factor withdrawal at the end of the antigen stimulus and high responsiveness towards renewed antigen challenge. Resistance towards AICD and insensitivity towards apoptosis determine the survival of the CD4+ T lymphocytes. Responsiveness is characterised by cell division, expansion of the cell number and production of helper cytokines.

[0015] Thus, treatment of antigen stimulated CD+ cells with IL-15, even at very low concentrations, turns off the program of cell death running in the absence of growth factor. Unlike with IL-2, survival of CD4+ T cells with IL-15 is not accompanied by DNA synthesis nor proliferation, demonstrating that IL-15 induces a resting phenotype in these cells. Moreover, the sensitivity towards AICD of CD4+ T lymphocytes, cultured in presence of IL-2, is reversed by IL-15. Restimulation of these IL-15 treated, resting T cells with a suitable antigen (Ag) presented by Ag presenting cells (APC) results in maximal cell expansion, driven by a renewed production of helper cytokines. This cell expansion is not attenuated by a massive cell death as a consequence of AICD. In contrast to what is observed for cells cultured in presence of IL-2, the above-mentioned activities of IL-15 provide a method to achieve survival of immuno competent CD4+ T lymphocytes, herewith strongly improving the secondary restimulation of CD4+ T lymphocytes. In other words, the formation of immunological CD4+ memory cells can be controlled in a positive sense, by an increased IL-15 activity, or in a negative sense, by a decreased IL-15 activity.

[0017] Other possible indications of this approach are individuals showing hyporesponsiveness towards pathogens or vaccins, or suffering from a chronic infection or from a generally weakened immune condition. As we assume that the action of IL-15 becomes even more important towards the end of an acute immune response, promoting the subsequent quiescent period, therapeutic doses of IL-15 should preferentially be administered when the immune response is subsiding, in this way favouring the establishment and long-term survival of CD4+ memory cells.

Problems solved by technology

Normally, the disappearance of these growth factors—a consequence of the ending of immune activity—results in growth factor depletion-induced cell death by apoptosis;

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