Objective 1. To investigate whether LECs from the skin of PsA patients, in contrast to that of PsO, are capable of inducing a homing receptor profile that favors a T-cell migratory response towards the synovial joint on skin-derived, allogenic T-…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Objective 1.
Study parameter: To establish that skin-derived and synovium-derived LECs in
PsA drive the in vivo mechanisms that coordinate the programming of dermal
pathogenic T-cells to adopt a synovial joint homing profile, ie. enhanced
expression of CD161, CCR6, CCR7, CCR2, CXCR6, and loss of skin homing receptors
such as CCR4, CCR10 and CLA(based on recent literature)
Outcome
Expected results In these experiments, we expect to find that dermal LECs from
PsA patients (in contrast to PsO and controls) are capable of imprinting
skin-derived T-cells with a synovial joint homing phenotype that promote their
egress towards synovial joint compartments.
Secondary outcome
Objective 2. To investigate whether the induction of tissue-imprinting
receptors on allogenic skin-derived T-cells, as demonstrated in Aim 1, leads to
enhanced T-cell migration into the afferent lymphatic vessels of a human dermal
sheet (crawl-in assay).
Outcome:
Should an effect of PsA-induced inflammatory changes in LECs on the homing
profile of these skin-derived T-cells be confirmed, this will most likely have
a direct impact on the T-cell migratory response as reflected by an increased
entry into afferent lymphatics in the crawl-in assay.
Objective 3. To investigate whether overlapping properties may be present in
LECs from the skin, synovial tissue and lymph nodes.
Background summary
Rationale
Psoriasis (PsO) is a common inflammatory skin disease that is characterized by
acanthosis, edema formation, immune cell infiltration, abnormal vascular
proliferation, and remodelling of the lymphatic system. Up to ~30% of PsO
patients are affected by psoriatic arthritis (PsA), a devastating form of
arthritis, which leads to disability and deterioration of quality of life. The
progression of PsO to PsA is poorly understood and deserves further
investigation.
Hypothesis: Lymphatic endothelial cells (LECs), the core components of the
dermal lymphatic vasculature, may control the transmission of pathogenic
skin-derived T-cells to other anatomical sites including synovial joints and
entheseal regions in PsA.
Study objective
Objective 1. To investigate whether LECs from the skin of PsA patients, in
contrast to that of PsO, are capable of inducing a homing receptor profile that
favors a T-cell migratory response towards the synovial joint on skin-derived,
allogenic T-cells from healthy donors.
Objective 2. To investigate whether the induction of tissue-imprinting
receptors on allogenic skin-derived T-cells, as demonstrated in Aim 1, leads to
enhanced T-cell migration into the afferent lymphatic vessels of a human dermal
sheet (crawl-in assay).
Objective 3. To investigate whether overlapping properties may be present in
LECs from the skin, synovial tissue and lymph nodes.
Study design
Study design Experimental, in vitro study.
Briefly, this study investigates whether LECs from the skin of PsA patients, in
contrast to that of PsO, are capable of inducing a homing receptor profile on
dermal T-cells that favors a T-cell migratory response towards the synovial
joint. Thus, experiments are performed, where LECs isolated from skin biopsies
of control subjects or patients with PsO and PsA are co-cultured with
skin-derived donor T-cells, followed by morphological analysis using flow
cytometry and a functional test, ie. migration (crawl-in) assay. To rule out
autologous defects (patient-specific) in the cell-cell interactions, 80 mL
blood (from all participants) and synovial fluid of an inflamed joint (knee,
wrist or ankle; from PsA only) will be drawn for isolating peripheral blood
mononuclear cells (PBMC) to study autologous effects and measuring circulating
mediators. Thus, dermal LEC and T-cells (derived from PBMC) from one patient
are co-cultured.
Study burden and risks
- The expected burden from this protocol is minimized to skin biopsies and
synovial biopsies (from knee joint of patients with PsA only) that are
performed under local anesthesia from (peri-lesional) skin at non-sun exposed
skin.
Blood collection upon insertion of a (butterfly) catheter via vein of the under
arm. Potential adverse effects include small hematomas during insertion (manual
pressure over the site of bleeding is an adequate treatment) and pain or skin
reactions at the catheter site.
- Additional samples are taken from skin tissues that are obtained from
discarded human materials (skin and synovial tissue) during surgery. Risks are
not to be expected.
- Additional samples are taken from lymph node tissues that are obtained from
patients undergoing vascular surgery. Risks are not to be expected.
Maasstadweg 21
Rotterdam 3079 DZ
NL
Maasstadweg 21
Rotterdam 3079 DZ
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria psoriasis patients:
- patients that are diagnosed with psoriasis by their dermatologist
- age * 18 years
- written informed consent by the patient;Inclusion criteria psoriatic arthritis patients:
- Psoriasis patients that are diagnosed with psoriatic arthritis by their rheumatologist (according
to the CASPAR criteria)
- age * 18 years
- written informed consent by the patient;Inclusion criteria healthy volunteer:
- age * 18 years
- WHO performance score 0
- age and sex matched (for psoriasis and psoriatic arthritis)
- written informed consent ;Inclusion criteria systemic sclerosis patients:
- Patients that are diagnosed with systemic sclerosis by their rheumatologist
- age * 18 years
- written informed consent given by the patient;Inclusion criteria systemic lupus erythematodes patients:
- Patients that are diagnosed with systemic lupus erythematodes by their rheumatologist
- age * 18 years
- written informed consent given by the patient;Inclusion criteria vasculitis patients with skin involvement:
- Patients that are diagnosed with vasculitis by their rheumatologist
- age * 18 years
- written informed consent given by the patient;Human tissues;Inclusion criteria for tissue donors, ie. skin tissue: patients undergoing eyelid surgery; mammareduction/abdominoplasty; synovial tissue: knee-replacement therapy in PsA and osteoarthritis (orthopedic surgery), synovectomy wrist (plastic surgery)
- donors will be asked for their permission to use their materials anonymously; this will be recorded in their medical file.;Inclusion criteria for tissue donors, ie. patients undergoing vascular surgery. The 3 categories of vascular surgery patients that will be included are patients undergoing crossectomy in chronic venous insufficiency; carotid endarterectomy, and surgical bypass of aortoiliac occlusive disease in patients with intermittent claudicatio without any signs of infection or critical (limb) ischemia.
- written informed consent given by the patient
Exclusion criteria
- use of corticosteroids including topical or systemic for the last 6 weeks
- use of disease-modifying antirheumatic drugs (DMARDs) or immune-suppressive drugs
for the last 6 weeks
- concomitant use of drugs affecting the lymphatic system and/or immune responses
including non-steroidal anti-inflammatory drugs (NSAIDs), drugs targeting RAAS system,
and anti-allergy medication. These agents must be discontinued at least 6 weeks before
the screening visit.
- co-existence of chronic inflammatory disorders including eczema, asthma or chronic
infection
- pregnancy
- active cancer
- any lymphatic, cardiovascular or immunodeficiency disorder
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL55149.101.15 |