Immune response includes both a cell response and a humoral response. Cell response is mostly mediated by T cells, whereas humoral response is mediated by B cells. Lymphocytes have important roles in immune response, including directing the cell death of cells infected by viruses, cytokine and antibody production, etc. Lymphocytes are also involved in acute and chronic inflammatory diseases.
Cytokines are soluble proteins mediating reactions between cells and affecting cell growth and differentiation. Cytokines exert their effects through the binding to specific receptors which leads to the activation of specific transduction signals for said cytokines.
Interleukin-10 (IL-10) is a pleiotropic cytokine produced by several cell types such as macrophages, monocytes, Th2 type and regulatory T cells and B cells. IL-10 is a cytokine with immunosuppressive and anti-inflammatory properties; it regulates a number of cellular myeloid and lymphoid activities and directly inhibits the production of several inflammatory cytokines by T cells and NK (Natural Killer) cells.
IL-10 was first described as a cytokine synthesis inhibitory factor (CSIF) produced by Th2 cells which inhibited production of proinflammatory cytokines such as interferon-gamma (IFN-γ), interleukin-1-alpha (IL-1α), interleukin-1-beta (IL-1β), interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α), by Th1 cells. In addition to inhibiting production of proinflammatory cytokines, it has been shown that IL-10 can inhibit antigen-specific Th1 cell proliferation reducing the capacity of antigen-presenting monocytes through the deregulation of the major histocompatibility complex (MHC) class II expression in these cells.
The discovery that IL-10 has a strong inhibitory effect on Th1 cell activation and on production of proinflammatory cytokines led to the hypothesis that IL-10 was a potent immunosuppressant of cell-mediated immune responses. Other authors have proposed the use of this cytokine in the treatment of acute and chronic inflammatory processes as well as in autoimmune diseases. For these reasons, this cytokine has been used in several autoimmune diseases, such as psoriasis, rheumatoid arthritis and Crohn's disease. However, in other diseases, such as in infectious processes or in cancer, it has a negative effect since it prevents the induction of Th1 responses which would favor the cure. Examples of these processes include leprosy, tuberculosis, leishmaniasis, as well as viral infections. Thus, it has been described that IL-10 is abundantly expressed in chronic infection due to the hepatitis C virus (HCV). This cytokine can be produced by Th2 cells as a result of stimulating with HCV antigens. It can also be produced by regulatory T cells (CD4 and CD8) inhibiting the development of Th1 type antiviral effector cells. Finally, infected dendritic cells (DC) or monocytes in contact with HCV proteins produce a larger amount of IL-10 than non-infected cells, which favors the development of Th2 responses and prevents the elimination of the virus.
As mentioned above, another field in which IL-10 has an important role is in antitumor response. Thus, tumor cells or tumor infiltrate cells can produce, among other molecules, IL-10, which damages the functioning of DCs. Good DC functioning inhibition in tumors would be one of the reasons for which an antitumor response does not occur. Given that the inhibition of IL-10 in vitro and in vivo results in an increase in interleukin 12 (IL-12) production and, concomitantly, an increase in Th1 response, said IL-10 inhibition would be very useful both in certain antiviral therapies, such as chronic HCV infection, and in antitumor therapies, where potent Th1 type responses are to be induced. Thus, it has been described that the combination of a non-methylated oligonucleotide (CpG) and an anti-IL-10 receptor antibody, preventing the interaction between IL-10 and its receptor, allows inducing a more effective antitumor response, greater than that reached when only CpG is used (Vicari A. P. et al. Reversal of tumor-induced dendritic cell paralysis by CpG immuno-stimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med. Aug. 19, 2002; 196(4):541-9). Other strategies that are usually used to inhibit the biological activity of IL-10 include either the use of specific neutralizing antibodies or the use of antisense oligonucleotides (oligos) of the IL-10-encoding gene which block its expression. The use of antibodies allows a total and specific blockage of this cytokine (IL-10) although certain side-effects are enhanced both due to the presence of exogenous immunoglobulins in blood and due to the effects derived from the systemic blockage of IL-10. Furthermore, the stability of immunoglobulins over time does not allow a short time period control of the blockage of the activity of this cytokine. Antisense oligos inhibit IL-10 production at the gene expression level, which can generate important deregulations in all the processes in which this cytokine is involved.
It is therefore necessary to identify new IL-10 inhibitors which are specific, have a greater efficacy and are potentially useful in human therapy.
USPTO Backgrounds
USPTO Backgrounds