Use of interleukin-15

Details Use of interleukin-15 Use of interleukin-15

1999-08-23

2002-02-05

Stucker, Jeffrey (Department: 1648)

Drug, bio-affecting and body treating compositions

Lymphokine

Interleukin

C424S085100, C435S069500, C435S069520, C435S386000, C530S351000, C930S140000, C930S141000

Reexamination Certificate

active

06344192

ABSTRACT:

RELATED APPLICATION
The present application is the U.S. national phase under 35 U.S.C §317 of International Application No. PCT/EP98/00127, filed Feb. 23, 1998.
BACKGROUND OF THE INVENTION
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.
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 162 amino acid (aa) precursor protein consisting of a 48 aa peptide and a 114 aa mature protein (Grabstein et al., 1994). Although there is no sequence homology with IL-2, analysis of the amino acid sequence predicts that IL-15, like IL-2, is a member of the four &agr; helix bundle cytokine family. Furthermore IL-15 and IL-2 exert their biological activities through binding on the IL-2R&bgr; and &ggr;chains, supplemented by a specific IL-15R&agr; and IL-2R&agr; polypeptide, respectively (Giri et al., 1995). This sharing of receptor subunits probably accounts for the similar functional activities of both cytokines observed on T, B and NK cells. IL-15 mRNA is widely distributed in fibroblasts, epithelial cells and monocytes but not in resting or activated T cells, the predominant source of IL-2.
IL-15 and IL-2 share various biological functions. IL-15, like IL-2, has been defined as a T cell growth factor. IL-15 was originally discovered as a factor that could induce proliferation of the IL-2 dependent murine cytotoxic T-cell line (CD8
+
) CTLL-2 (Grabstein et al., 1994). Proliferation upon addition with IL-15 was also observed in phytohaemagglutinin (PHA)-activated CD4
+
or CD8
+
human peripheral blood T lymphocytes (PBT), and &ggr;&dgr; subsets of T cells (Grabstein et al., 1994; Nishimura et al., 1996). Studies with phenotypically memory (CD45RO
+
) and naive (CD45RO
−
) T cells, isolated from human PET, revealed that IL-15, like IL-2, induces in memory CD4
+
and CD8
+
T cells and naive CD8
+
T cells but not in naive CD4
+
T cells the expression of the CD69 activation marker and proliferation (Kanegane et al., 1996). IL-15 was as effective as IL-2 in the in vitro generation of alloantigen-specific cytotoxic T cells in mixed lymphocyte cultures and in promoting the induction of lymphokine activated killer (LAK) cells (Grabstein et al., 1994). Additionally, in vivo studies in a murine model demonstrated the capacity of IL-15 to augment CD8
+
T-cell-mediated immunity against
Toxoplasma gondii
infection (Khan and Kasper, 1996). Here vaccination of mice with soluble parasite antigen (Ag) and IL-15 resulted in significant proliferation of splenocytes expressing the CD8
+
phenotype and protection against a lethal parasite challenge for at least 1 month postimmunization.
Natural Killer (NK) cells are considered an important target for IL-15 action. Treatment of NK cells with IL-15 results in proliferation and enhancement of cytotoxic activity and in production of Interferon &ggr; (IFN&ggr;), tumor necrosis factor &agr; (TNF&agr;) and granulocyt-macrophage colony stimulating factor (GM-CSF) (Carson et al., 1994). Furthermore IL-15 can substitute for the bone marrow microenvironment during the maturation of murine NK1.1
+
cells from nonlytic to lytic effector cells (Puzanov et al., 1996).
Apart from its activities on T and NK cells, IL-15 costimulates, in a comparable way as IL-2, proliferation of B cells activated with immobilized anti-IgM or phorbol ester (Armitage et al., 1995). Stimulation of B cells with a combination of CD40L and IL-15 efficiently induces immunoglobulin synthesis. IL-15 has no stimulatory activity on resting B cells.
IL-15 was also found to have other biological activities. Chemoattractant factors are cytokines or chemokines that regulate the migration of lymphocytes to inflammation regions.
IL-15 is described as a chemoattractant factor for human PBT, inducing polarisation, invasion of collagen gels and redistribution of adhesion receptors (Wilkinson and Liew, 1995; Nieto et al., 1996). Murine mast cells proliferate in response to IL-15, but not to IL-2, using a novel receptor/signalling pathway, not shared with IL-2 (Tagaya et al., 1996). Furthermore, it has been shown that IL-15 and IL-2 have different effects on differentiation of bipotential T/NK progenitor cells, with IL-15 predominantly promoting the development of TCR&ggr;&dgr; T cells and NK cells (Leclercq et al., 1996). The most striking difference, however, between IL-15 and IL-2 lies in their expression patterns. The presence of IL-15 mRNA in a variety of non-lymfoid tissues indicates that the secretion of the cytokine is not solely regulated by the immune system and/or that the cytokine can act outside the immune system itself. Accordingly, addition of IL-15 to a myoblast cell line affects parameters associated with skeletal muscle fiber hypertrophy, suggesting IL-15 has anabolic activities and increases skeletal muscle mass (Quinn et al., 1995).
Activated CD4
+
T lymphocytes play a key role in the development of an effective immune response against pathogens by providing the growth factors necessary for the expansion of the activated CD4
+
T lymphocytes (autocrine growth) and for the expansion of CD8
+
cytolytic cells and the differentiation of B cells into antibody-secreting plasma cells (paracrine “helper” activity).
After clearance of the pathogen, a subfraction of the generated Ag-specific T cells persist as memory cells, either in the lymphoid tissue or in the circulation. Throughout this application, “memory cells” are defined as antigen-experienced cells. These memory lymphocytes are small, resting cells which are optimally primed for the generation of a quantitatively and qualitatively superior, secondary response upon a re-encounter with the priming Ag. In order to accomplish the transition from activated CD4
+
effector cell to resting CD4
+
memory cell and to acquire long-term survival, these effectors need to acquire the following characteristics:
(i) being resistant towards, or escaping from, activation-induced cell death (AICD); AICD is responsible for attenuation of the immune reaction;
(ii) being independent from autocrine growth factors, produced during the immune response. 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;
(iii) having the capacity, in case of a renewed contact with the antigen, to expand maximally by production of the necessary autocrine- and paracrine-acting helper cytokines such as IL-2.
SUMMARY OF THE INVENTION
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.
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

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