PI3K Delta Signaling in Rheumatoid Arthritis

PI3K Delta Signaling in Rheumatoid Arthritis

Date: September 6, 2016

Author: Andrea Tarbet, Product Marketing Associate at ALPCO

Signaling pathways dictate the differentiation, activation, and functions of immune cells.  Even the slightest problem in one cell signaling pathway can transform the immune system and turn it against the body, causing an autoimmune disease. Research has shown that proper phosphoinositide 3-kinase (PI3K) cell signaling is required to maintain a healthy immune system. Studies also suggest that aberrant PI3K delta signaling in rheumatoid arthritis (RA) individuals may influence the onset of the disease and, as a result, isoform specific PI3K delta inhibitors are potential drug candidates for RA treatment2,3.

PI3K Delta Signlaing in the Immune System

White blood cells (WBC) including B cells, T cells, basophils, dendritic cells (DC), natural killer cells (NK), macrophages, neutrophils, and mast cells rely on PI3K signaling to function2,3. While the different classes and isoforms of PI3K are involved in the immune response, the PI3Kδ isoform is of greatest interest for autoimmune diseases such as RA. Research has shown that the PI3Kδ isoform is intricately woven into the many functions and regulations of WBCs including cytokine production and cell differentiation2,3:

This chart outlines the roles of different white blood cells which are essential to understanding the role of PI3K delta signaling in rheumatoid arthritis.

An Overview of Rheumatoid Arthritis

RA develops when immune cells that have leaked into the synovial tissue work together to target and destroy joints4. The specific cause of this immune system dysfunction is still unknown. It has been theorized, however, that genetics, viruses, and environmental factors can lead to the onset of RA1. Research has shown detrimental cell-to-cell interactions between B cells, T cells, DCs, mast cells, and macrophages can lead to excess inflammatory cytokine release and RA4.

PI3K Delta Signaling in Rheumatoid Arthritis

Evidence suggests that aberrant PI3K delta signaling in rheumatoid arthritis may be linked via interleukin-6 (IL-6), a well-known pro-inflammatory cytokine. Dendritic cells produce IL-6 and PI3K delta signaling promotes the cytokine’s release. IL-6 sequentially activates B cells, macrophages, T cells, and neutrophils5. Research has already shown that levels of IL-6 in synovial tissue and fluid can correlate with RA severity, therefore demonstrating how more IL-6 equals more joint destruction5. Currently, antibodies against IL-6 are available to treat RA, although for some, an IL-6 antibody is not enough to keep the autoimmune disease at bay.

How Isoform Specific PI3K Delta Inhibitors Can Treat Rheumatoid Arthritis

Since PI3Kδ is not only involved in the regulation of IL-6 release from DC cells, but also in the functions of other WBCs, inhibiting PI3K delta signaling may be an improved method to treat RA. MEI Pharma’s isoform specific PI3K delta inhibitor ME-401 (originally Pathway Therapeutics’ PWT143) showed promising results in a mouse collagen-induced arthritis model. The experimental data showed how the PI3K delta inhibitor was able to prevent arthritis onset in the mice7. Additionally, the compound inhibited cytokine production in human T cells and TNF-alpha in human B cells, while also preventing the activation of basophils7.

ME-401 has also been shown to be a highly specific PI3K delta inhibitor that does not cross-react with other protein kinases7. This isoform specific PI3K delta inhibitor has a longer half-life and works in multiple immune cells when compared to PI3K inhibitors from the previous generation7. The data from ME-401 supports how specifically inhibiting PI3K delta signaling in rheumatoid arthritis can be used to target a pathway involved with the function of multiple immune cells. This could be extremely beneficial when treating autoimmune diseases such as RA.

The Future of PI3K Delta Inhibitors in Autoimmune Diseases

Although the current focus of ME-401 is to treat B cell malignancies, early experimental data has illustrated how inhibiting PI3K delta signaling in rheumatoid arthritis can be used to develop potentially better treatments for individuals suffering from other autoimmune diseases. Further research is still needed to determine if other isoform specific PI3K delta inhibitors are effective against autoimmune diseases.

References

  1. National Institute of Allergy and Infectious Diseases. (2005). Progress in Autoimmune Diseases Research. NIAID.
  2. Banham-Hall et al. (2012). The therapeutic potential for PI3K inhibitors in autoimmune rheumatic diseases. Open Rheumatol. J., 6, 245-58. doi: 10.2174/1874312901206010245. PMID: 23028409.
  3. Stark et al. (2015). PI3K inhibitors in inflammation, autoimmunity and cancer. Curr. Opin. Pharmacol., 23, 82-91. PMID: 26093105.
  4. Tran et al. (2005). Synovial biology and T cells in rheumatoid arthritis. Pathophysiology, 12(3), 183-9. PMID: 16112560.
  5. Srirangan et al. (2009). The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis., 2(5), 247–256. PMCID: PMC3383508.
  6. Ogilvie et al. (2003). The −174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: A multicenter study using simplex and multiplex juvenile idiopathic arthritis families. Arthritis Rheum., 48, 3202–3206. DOI: 10.1002/art.11300.
  7. Matthews et al. (2012). Discovery of PI3K delta inhibitors for the treatment of inflammatory and autoimmune disease [Poster]. Pathway Therapeutics.
  8. O’Farrell et al. (2012). Preclinical characterization of PWT143, a novel selective and potent phosphatidylinositol 3-kinase delta (PI3K delta) inhibitor with ex-vivo activity in hematologic malignancies. Blood, 120, 2907.
  9. MEI Pharma. (2016). ME-401. MEIpharma.com.
  10. Murphy et al. (2008). Janeway’s Immunobiology, Seventh Generation. Garland Sciences and Taylor & Francis Group, LLC.: New York, New York.
  11. Diabetes.co.uk. (2016). White Blood Cells. Diabetes.co.uk.
  12. Ortiz-Maldonado et al. (2015). The biology behind PI3K inhibition in chronic lymphocytic leukaemia. Ther. Adv. Hematol., 6(1), 25–36. PMCID: PMC4298491.
  13. Falcone et al. (2000). The human basophil: A new appreciation of its role in immune responses. Blood, 96(13), 4028-38. PMID:11110670.
  14. Winkler et al. (2013). PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chemistry & Biology, 20(11), 1364–1374. doi:10.1016/j.chembiol.2013.09.017.
  15. Guo et al. (2008). The p110δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J. Exp. Med., 205(10), 2419–2435. PMCID: PMC2556795.
  16. Sadhu et al. (2003). Essential role of phosphoinositide 3-kinase δ in neutrophil directional movement. J. Immunol., 170, 2647-2654. PMID: 12594293.
  17. Kim et al. (2008). The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends Immunol., 29(10), 493–501. PMCID: PMC270666.