Project

Back to overview

Role of opposing cytokine signals in psoriasis

English title Role of opposing cytokine signals in psoriasis
Applicant Navarini Alexander
Number 135391
Funding scheme Project funding
Research institution Dermatologische Klinik Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.05.2011 - 30.04.2012
Approved amount 154'750.00
Show all

All Disciplines (2)

Discipline
Immunology, Immunopathology
Dermatology

Keywords (4)

Psoriasis; Cytokine; T cell; Cytokine/antibody complexes

Lay Summary (English)

Lead
Lay summary

In this project, we will examine the role of both activating T cells and suppressive T regulatory cells. To this end, we will transplant small pieces of non-lesional skin of psoriasis patients onto immunodeficient recipient mice. Upon grafting, the T cells already present inside the transplanted skin proliferate thus leading to the development of a typical psoriasis lesion within the graft. Using distinct cytokines (small messenger proteins such as interleukin 2) complexed to particular anti-cytokine antibodies, we aim to increase the fraction of different T cell subsets in this experimental system and to determine the effects on psoriasis development.

Methods and Aims:

Psoriasis is a common skin disease characterized by recurrent scaling red skin lesions and in about 20% also inflammation of the joints. Psoriasis is thought to be mediated by immune cells called T cells. There are different subsets of T cells, and they produce different messenger signals. Some subsets are supporting the development of psoriatic lesions, while others are believed to inhibit the activation of certain effector T cells. Notably, the activity of immune cells in psoriasis can be suppressed using therapeutic antibodies, however, such antibodies have to be administered continuously in order to avoid disease relapse. Therefore, it is important to know whether the immune cell population in psoriasis can be altered temporarily or even permanently as this might yield very effective treatment approaches.

Context and importance of the project:

Investigation of the effects of different immune cell subsets in the skin disease psoriasis.

Goal of the project:

Cytokine, Antibody, T cell, Psoriasis, Skin, Dermatology, Immunotherapy, Transplantation

Keywords:

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Abstract

Background. Psoriasis is a common disease characterized by recurrent scaling erythematous skin plaques and infrequently also arthritis. Psoriasis is thought to be mediated by effector T cells, including cytotoxic CD8+ cells and T helper (Th) cells. As for the latter, Th1 and Th17 cells have been implicated in disease pathogenesis through the production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-a, interferon (IFN)-? and interleukin (IL)-17, IL-22, respectively. Exaggerated responses of Th1 and Th17 cells are usually held in check by the action of T regulatory cells (Treg), which have been suggested to be less efficient in psoriasis. Thus, common treatment options of psoriasis, such as vitamin D derivates, have been shown to induce the production of Treg. Moreover, approaches targeted at skewing of the harmful Th1 immune response towards a Th2-type response by the injection of IL-4 have shown some success. However, conclusive data on the role of these different effector T cell subsets and of Treg in psoriasis is still missing. In this grant proposal, we will examine the role of human CD8+ T cells, Th1 cells, Th2 cells, and Treg in vivo in a well-established human-skin-graft-onto-AGR-mouse psoriasis model by stimulating these different skin-resident T cell subsets in a selective and potent manner using so-called cytokine/antibody complexes.Experimental system. As for the in vivo experimental system, we will be using our well-established xenotransplantation model of psoriasis, which entails the transplantation of non-lesional skin biopsies from psoriasis patients onto the backs of immunodeficient AGR mice. Due to the proliferation of resident human T cells in the epidermis and dermis, the skin grafts spontaneously develop features of psoriasis. The different T cell subsets will be stimulated using cytokine/antibody complexes, which are formed using a certain cytokine together with its specific monoclonal antibody (mAb), thus resulting in cytokine/mAb complexes. Hence, complexes of human IL-2 (hIL-2) plus MAB602 anti-hIL-2 mAb lead to the vigorous proliferation of CD8+ T cells, while complexes of hIL-2 plus 5344 anti-hIL-2 mAb induce the expansion of CD4+ Treg. IL-4/anti-IL-4 mAb complexes will serve to induce Th2 cells, IL-15/IL-15-Ra complexes will be used to stimulate CD8+ T cells, and hIL-7/anti-hIL-7 mAb complexes lead to the proliferation of all effector T cell subsets but not Treg.Specific aims. Using our above-mentioned xenotransplantation model of psoriasis, we will test whether development of a cutaneous psoriasis lesion is driven by CD8+ and Th1 (and/or Th17) cells and inhibited by Treg or skewing of the T cell response to Th2. We will focus on the following three aims. In Aim 1, we will use IL-2/mAb complexes to stimulate either preferentially CD8+ T cells (IL-2/MAB602 complexes) or selectively CD4+ Treg (IL-2/5344 complexes), or IL-7/mAb complexes to expand effector T cell subsets without affecting CD4+ Treg. Aim 2 will focus on skewing the immune response effectively from Th1/Th17 to Th2 using IL-4/mAb complexes (using MAB404). Aim 3 will evaluate phenotypic and functional properties of effector T cells in a sequential manner during development of a psoriatic lesion, including T cell cytokine profiles involved.Experimental design and methods. Cytokine/mAb complexes will be tested using the following in vitro and in vivo systems: xenotransplantation of non-lesional or lesional skin of psoriasis patients onto immunodeficient AGR mice with subsequent quantification of histological features of psoriasis; direct ex vivo flow cytometry analysis of leukocytes isolated from dispase-digested psoriasis skin grafts at different time-points following transplantation onto AGR mice, and quantification of these leukocytes using fluorescent beads as an internal calibrator; in vivo proliferation using BrdU labelling of skin-resident leukocytes located in the skin graft transplanted to AGR mice; cytokine staining of Th cells to evaluate cytokine polarization; in vitro Treg suppressor assay; isolation and assessing as above of leukocytes from skin samples or peripheral blood mononuclear cells from patients or healthy donors.Significance. Cytokine-targeted immunotherapy of psoriasis, such as anti-TNF-a and anti-p40 (IL-12/IL-23) treatment can efficiently suppress but not heal psoriasis. The herein proposed experiments hold the promise to shed light on key aspects of psoriasis and might thus allow a more adapted therapeutic approach based on Treg or Th2 skewing.
-