LEO Pharma Open Innovation

Research question

The aim of this text is to describe the science behind eczema/atopic dermatitis, but without mentioning the actual disease. Machine learning will be applied in order to identify literature that has an overlapping relevance but that also expands the science further. The end goal is to discover new possible biological pathways and targets that could be relevant for treatment.

 

Key words (not to be included into text uploaded to IRIS):

“dendritic cellIDEC  “MHC-IIcostimulatory effector T-cells” “Memory T-cells” “antigen presenting cellskeratinocytes Th2 Th22IL-4” “IL-31” “IL-13dupilumab TSLPIL-25”  “IL-33” “Regulatory T-cellsFoxp3IL-10” “IL-35immunosuppression tacrolimus cyclosporine immunomodulation CD3 CD28 CD2 PDE4 crisaboroleJAK kinase” tofacitinibinnate lymphoid cellsILC2IL-22R1” “IL-10R2JAK1 Tyk2 STAT3 eosinophils basophils “mast cellsneurons itch pruritus

Text:

T-cell driven tissue inflammation is characterized by an abundant presence of activated effector T-cells in the tissue. These T-cells express cytokines which contribute to inflammation by activating other cell types.

In peripheral tissue dendritic cell populations reside, e.g. Langerhans cells (LC) or “inflammatory dendritic epidermal cells” (IDEC) or other dendritic cells (DC), which upon contact with antigen migrate to the lymph nodes. In the lymph node they present the antigen via e.g. MHC-II (“MHC class 2”) molecules to T-cells thereby activating them. Not only antigen presentation by MHC-II molecules is critical but also costimulatory signals by the following receptor pairs among others: CD28 or CTLA4 / B7, CD40 / CD40L, OX40 / OX40L, PD1 / PD1L, ICOS / ICOSL. Following activation, “naïve T-cells” proliferate and then differentiate into “effector T-cells”. These cells migrate to the peripheral tissue where they upon antigen encounter for example secrete inflammatory cytokines. After a while the activated “effector T-cells” either die or become “memory T-cells”. “Memory T-cells” can then either re-circulate, for example to different sites of the peripheral tissue (as “effector memory T-cells”, Tem) or remain at the peripheral tissue site for long times in a resting non-activated state (“tissue resident T-cells”). Upon a renewed antigen challenge in the tissue “memory T-cells” can be reactivated without the need of lymph node participation and at a lower threshold of antigen stimulation. Also, a reduced need for co-stimulation is required to elicit full effector function again. Re-activation does not even require dendritic cells any longer but can be achieved by other “antigen presenting cells” (APC) like macrophages or even activated keratinocytes. The “memory T-cells” in diseased tissue are an attractive target for therapeutic intervention in T-cell driven diseases, or at least therapeutic targeting should try to also include these cell populations. 

In certain diseases, Th2 cells and to some degree Th22 cells are regarded as main disease drivers, although some contribution has been ascribed to Th1 cells and Th17 cells in disease subsets or particular stages of the disease.

Th2 cells secrete IL-4 (interleukin 4), IL-5, IL-13 and IL-31; of these IL-4 and IL-13 are regarded as main disease drivers; IL-31 has an important role in itch / pruritus which is a strong component of the disease. An antibody against the IL-4RA (“interleukin-4 receptor alpha”), dupilumab, which has shown clinical efficacy, inhibits signaling downstream of both IL-4 as well as IL-13 because both cytokines utilize the IL-4RA. The differentiation of naïve T-cells into Th2 effector cells is triggered by cytokines like TSLP, IL-25 and IL-33 which are for example secreted by keratinocytes. The transcription factor GATA-3 plays a critical role in this differentiation as well as the expression of e.g. IL-4 and IL-13. An antibody to IL-33 has shown clinical efficacy in a pilot study.

Th22 cells secrete in particular IL-22, which promotes inflammation by stimulating epidermal cells, e.g. keratinocytes. IL-22 binds to its receptor which is composed of IL-22R1 and IL-10R2 chains. It signals via JAK1, Tyk2 and STAT3 to induce for example IL-20 and IL-24. An antibody to IL-22 has shown efficacy in a subpopulation of patients.

Regulatory T-cells (t-reg, treg, tregs) are also activated by dendritic cells, however, their role is to dampen inflammation rather than promoting it. Regulatory T-cells are induced by TGF-beta in combination with other factors by involving the transcription factor Foxp3. Tregs inhibit among others effector T-cells through cell-cell contact as well as through secretion of IL-10, TGF-beta and IL-35. Increased expression of theses cytokines might thus be beneficial. Treg cells can under certain circumstances be converted into disease promoting Th2 cells, but the reverse differentiation is also possible. Thus, methods to either induce Treg cells from naïve T-cells or to convert effector Th2 into Treg could be of interest.

Other cell populations outside the T-cell lineage which play a role in the disease are for example eosinophils, basophils and mast cells as well as neurons. Mast cells and neurons are crucially involved in itch / pruritus associated with the disease.  

Several principal strategies to limit T-cell driven inflammation can be envisioned. For example, can the activation of effector T-cells be directly inhibited leading to immunosuppression. This is for example the mechanism of tacrolimus or cyclosporin. Another possibility is to modulate dendritic cells in a way that they stimulate T-cells less efficiently (for example by blocking costimulatory signals) or to bias T-cell differentiation into other T-cell subsets than Th2 / Th22 or into effector cells (immunomodulation), for example by shifting to a preferential differentiation into Treg cells. Other compounds which have shown clinical effects in the disease but which not necessarily only target T-cells are glucocorticoids, PDE4 inhibitors (e.g. crisaborole) or JAK kinase inhibitors (e.g. tofacitinib). Approaches which target “innate lymphoid cells” (in particular ILC2 – “group 2 innate lymphoid cells”) are also of interest.