Reviewer: S. Randhawa, M.D., Allergist/Immunologist
Source: CD4+ T cells (TH2), NKT cells, mast cells
Receptors: Type I cytokine receptor family. Signal transduction involves Jak-STAT.
The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.
Erythropoietin (Epo) is produced in the kidney in response to low oxygen tension. Epo works through a type I cytokine receptor that signals through Jak2-STAT5.
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IL-13 is homologous to IL-4. Receptor distribution more limited: endothelial cells, B-cells, mononuclear phagocytes, and basophils - NOT mast cells or T-cells.
2 cognate receptors:
- IL-13Rα1 (low affinity by itself); paired with IL-4 receptor α (high affinity, signaling)
- IL-13Rα2 ( high affinity, decoy)
IL-13–induced TGF-β–mediated fibrosis is dependent on IL-13Rα2.
IL-13 binds to a low-affinity IL-13Ra2 subunit and a high-affinity complex comprised of IL-13Ra1 and IL-4Ra. Binding to this high-affinity complex leads to the phosphorylation-dependent activation of JAK1, JAK2 and STAT6.
IL-3 effects: IL-3 promotes the growth and development of mast cells from bone marrow.
IL-3 is a basophil differentiating cytokine vs. stem cell factor (c-Kit ligand) which is a mast cell growth factor.
- B cells: isotype switching to IgE
- Epithelial cells: increased mucus production
- Fibroblasts: increased collagen synthesis
- Macrophages: increased collagen synthesis
There are 3 humanized mAbs in phase I or phase II human clinical trials.
CAT-354 well tolerated in phase I trial, phase II trial is underway.
Genentech Pipeline: Lebrikizumab is a humanized monoclonal antibody that bind specifically to IL-13.
STAT6 is the common transcription factor for both IL-4 and IL-13 signaling.
Therapeutic target via:
- a dominant-negative peptide
- anti-sense RNA-based approaches
Asthma Phenotypes and Interleukin-13 - Moving Closer to Personalized Medicine - NEJM, 2011.
Interleukin-13 Signaling and Its Role in Asthma, WAO Journal, 2011.
http://www.medimmune.com/pipeline/pipeline_phase2_detail.asp, Wynn, T. A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003).
Andrews, A. L. et al. IL-13 receptor 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts. J. Allergy Clin. Immunol. 118, 858–865 (2006).
Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).
Bree, A. et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J. Allergy Clin. Immunol. 119, 1251–1257 (2007).
McCusker, C. T. et al. Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT6 peptide. J. Immunol. 179, 2556–2564 (2007).
Popescu, F. D. Antisense- and RNA-interference-based therapeutic strategies in allergy. J. Cell Mol. Med. 9, 840–853 (2005).