1. Pathogénie du psoriasis
• Une des affections humaines les plus
fréquentes
– 25 millions de personnes Europe et Amérique
du Nord
• Croissance et différenciation anormale
des kératinocytes
• Réversible après thérapeutique
appropriée
• Génétique et immunologique
– Activation du système immunitaire
2. 2012
• Nature Outlook
– After decades of modest advances, psoriasis
research has caught fire. The drug pipeline is
full of novel agents. Research into the role of
the immune system in this skin disease is
bearing fruit. Genetic studies hint at the
condition's starting point. And now psoriasis is
a proof-of-principle disease for other chronic
inflammatory conditions.
4. Psoriasis
• Maladie auto-immune spécifique d’organe
– Déclenchée par activation du système immunitaire
– Analogue à
• Maladie de Crohn, RCH (MICI)
• Polyarthrite rhumatoïde,
• Sclérose en Plaques,
• Diabète de type I
– #syndrome clinique causé par activation des cellules
T et/ou B, en l’absence d’une infection ou d’une autre
cause connue
• Davidson,A N Engl J Med; 2001:345:340
6. Clinique du psoriasis
• Psoriasis vulgaire
– Plaques rouges, surélevées, pseudocicatricielles
– Apparition à l’adolescence, ou chez le jeune adulte
– et dure toute la vie
– Localisations: coudes, genoux, cuir chevelu
– Localisé ou généralisé
• Psoriasis en gouttes
• Variants: plaques épaisses, ou fines, larges ou
petites
• Arthrite psoriasique
8. Psoriasis: un modèle?
• Accessibilité de l’organe
lésé
• + disponibilité de
thérapeutiques
immunologiquement
actives facilement testées
in vivo
• http://dermatlas.med.jhmi
.edu/
10. Figure 2 Schematic representation of keratinocyte phenotypes in acute (A) and chronic (B) woundsFigure 2 Schematic representation of keratinocyte phenotypes in acute (A) and chronic (B) wounds
Biology of the Cell www.biolcell.org Biol. Cell (2006) 97, 173-183Biology of the Cell www.biolcell.org Biol. Cell (2006) 97, 173-183
11. Histologie
• Epaississement de l’épiderme
– prolifération des kératinocytes dans l’épiderme
interfolliculaire
– Allongement des « rete » épidermiques
• Différenciation terminale aberrante des
kératinocytes # maturation régénérative,
exprimée pendant la cicatrisation
– Réduction majeure de la couche granuleuse de
l’épiderme
– Formation de stratum corneum à partir de kératinocytes
incomplétement différenciés et gardant leur
noyau(parakératose)
– Desquamation et fragilité de la barrière cutanée :
• due à l’échec de l’accumulation des kératinocytes, de
secrétion des lipides extracellulaires et d’adhésion
12. Autres caractéristiques de la peau
psoriasique
• Présence de neutrophiles en petits foyers dans
le stratum corneum
• Infiltrat mononucléé dans l’épiderme
• Infiltrat marqué de cellules mononucléées
(lymphos T et DCs) dans le derme et les
vaisseaux du derme papillaire
• Dilatation des vaisseaux… rougeur
• Adhérence des L,M,P aux cellules endothéliales
des vx HEV-like
• Activation des cellules endothéliales (CD54
ICAM-1, CD106 VCAM-1, CD62E
14. En résumé
• Peau normale
• Beaucoup de lymphocytes T
• Populations résidentes de DCs
– site potentiel de réponses immunitaires
• Peau psoriasique
– Tissu lymphoïde organisé
– Autoentretien
17. Yin et Yang des interactions
cellulaires du psoriasis
• Deux acteurs principaux
– Keratinocytes épidermiques
– Leucocytes mononucléés
• Évolution d’une théorie
– où les kératinocytes sont des victimes passives de
l’activation immunitaire
– vers celle où ils sont des participants actifs dans le
recrutement et l’activation des leucocytes dans les
lésions psoriasiques
• Equilibre
– Immunité innée et acquise
– Interactions kératinocytes et leucocytes
19. Cellules effectrices de l’immunité
innée
• Cellules dendritiques plasmacytoïdes
• Cellules dendritiques CD11c+
• Neutrophiles
– Courte durée de vie
– Besoin de recrutement régulier depuis le sang
– Rôles de chemokines IL-8, GRO-α (CXCL1)
20. Cellules dendritiques
• Cellules de Langerhans,
– et DC dermiques
• Cellules dendritiques plasmacytoïdes
– BDCA-2, CD123+,
– produisant taux élevés d’interféron-α
– Rôle déclenchant majeur
– Autant que de cellules T
21. Autres DC
• Cellules dendritiques myéloïdes (CD11C+)
interstitielles
– Taux élevé de TNF, et iNOS
• (équivalent des TIP-DCs qui sont les cellules effectrices pour
l ’élimination des infections bactériennes chez la souris)
– IL-23, IL-20 activatrices respectives des T et des
kératinocytes
– Une fraction porte des marqueurs de maturation DC-
LAMP ou CD83, présentatrices d’Ags
– Agrégats dermiques avec chemokines d’organisation
du tissu lymphoïde (CCL19, CCL21, CXCL12,
CCL18)
22. T cells
• Polarisées
– TH1 (CD4+) TC1 (CD8+)
– TH17 (induites par l’IL-23)
– CD8 spécialisées pour le
homing dans l’épiderme
(αE(CD103)β7)
– CD161: rôle des cellules NKT
• NKR-P1A, is a C-type lectin
membrane glycoprotein
26. Inflammation: voies moléculaires
• Interactions cytokiniques =
type 1
– Inducteurs proximaux IL-23, IL-
12
– Production d’IFN-γ et TNF par
cellules T Th1
– Activation de gènes sensibles à
l’IFN-γ, par transduction du signal
STAT1
– IL-23 induit une hyperplasie des
kératinocytes chez la souris, effet
médié par IL-22 produite par
TH17
• Modèle utile,
– Mais fraction des 1300 gènes
uprégulés dans le psoriasis!!
28. IL-23
• Schéma
• Modèle dermatologique
• In addition to the IMQ-induced
psoriasis model launched last
year, the most recent model to be
validated is the IL-23 induced
model of psoriasisform
inflammation.
• The IL-23 psoriasis model is 21
days long and involves the
injection of IL-23 into the ear of
C57Bl/6, which produces
psoriasis-like inflammation that is
dependent on IL-22. IL-22 induces
keratinocyte proliferation and
epidermal hyperplasia contributing
to epidermal thickening.
• MD Biosciences
30. Schéma = modèle interactif
• STAT1, STAT3 et NF-kB sont activés
• Activateurs en amont
– STAT1: interféron
– NFkB: IL-1 ou TNF
– Mais aussi IL-20 et IL-22
• Cytokines dérivées des kératinocytes
PDGF
• VEGF
– Induisent croissance des kératinocytes
31. Interactions
• Cellules stromales produisent KGF (keratinocyte
growth factor) 1ou 2?
• Cytokines régulent prolifération kératinocytaires
– (+) IL-1, 6, 17, 19, 20, 22, TNF, IFNs
– (-) /blocage TNF, IL-12, ou IL-23
– TGF bêta? Surexprimé de façon focale dans la peau
du psoriasis (Journal of Investigative Dermatology (2001) 117, 569–
575)
32. Animal model/mutated mice
Nature asia 2012
• Xiaoxia Li and colleagues report that the dysregulation of IL-17
signaling in TH17 cells contributes to disease.
• They use a disease model of psoriasis in mice harboring a specific
mutation in Act1, protein that interacts with the IL-17 receptor and
for which there is known mutation that is also associated with
human disease.
• Normally IL-17 signaling triggers a self-limiting inflammatory
response, but Act1 mutant mice spontaneously develop chronic skin
inflammation.
• The authors find mutant Act1 fails to associate with a chaperone
protein hsp90, which would cease the inflammatory response. As a
result, TH17 cells cannot turn off production of IL-22.
• The authors found that blocking IL-22 with neutralizing antibodies
alleviated skin disease in the mutant mice. These findings suggest
that anti-IL-22 therapies might be beneficial to those patients that
express defective Act1.
34. Facteurs génétiques
• Maladie des caucasiens (1-2%), vs asiatiques
(0.1%), africains (rares)
• Maladie multigénique
– 10-20 régions chromosomiques ?
– Peu de gènes candidats
– Peu de familles étudiées
• MHC classe I
– Pénétrance faible (10%)
– Gène de susceptibilité PSORS1?
– Association avec Cw6, > 25 years
– Corneodesmosin?, HCR a-helical coil-coil rod
35. Autres gènes
• Du système immunitaire ou des kératinocytes
– Immune synapse
• SLC9A3R1/NAT9 region… RUNX binding site
• Lymphoid phosphatase
• Associations IL-12, IL-19/20, IRF2
– EDC epidermal differenciation complex…
– Mendelien: 17q25
• Autosomal dominant
• Zinc finger protein ZNF750 keratinocytes, pas fibroblastes ni
CD4 T cells
36. Nature Genetics 2012
metaanalysis
• 15 new susceptibility loci, increasing to 36 the number
associated with psoriasis in European individuals.
• also identified, using conditional analyses, five
independent signals within previously known loci.
• The newly identified loci shared with other autoimmune
diseases include candidate genes with roles in regulating
T-cell function (such as RUNX3, TAGAP and STAT3).
• Notably, they included candidate genes whose products
are involved in innate host defense, including interferon-
mediated antiviral responses (DDX58), macrophage
activation (ZC3H12C) and nuclear factor (NF)-κB
signaling (CARD14 and CARM1).
37. Modèles animaux??
• Homme différent des animaux à fourrure!
– Plus d’épiderme interfolliculaire (entre
follicules pileux)… psoriasis, eczéma atopique
• Pas de modèle spontané
• Engineering cutané
• Xénotransplantation
39. Microbiome
• 2012
• 2013
• … psoriasis induces
physiological changes both at
the lesion site and at the
systemic level, which select for
specific differential microbiota
among the assayed clinical
skin types. These differences
in microbial community
structure in psoriasis patients
are potentially of
pathophysiologic and
diagnostic significance.
42. Etudes cliniques, preuve de
concept
• Biothérapies approuvées au cours des 3
dernières années! Pour le psoriasis sévère
• Protéines ou anticorps ciblant des molécules
spécifiques essentielles pour la pathogénie de la
maladie
• Deux cibles
– Médiateurs de l’inflammation
– Cellules T
• Risque d’immunosuppression,
– infections, cancers
• Bien tolérées mais …? recul
43. Classification 4 groupes
• Produits (approuvés dans d’autres indications)
utilisés dans des études antérieures utiles pour
établir le substrat immunologique du psoriasis
• Immunosuppresseurs systémiques classiques
• Nouvelles biothérapies récemment approuvées
USA, Europe
• Thérapeutiques prometteuses encore en
développement
47. Biothérapies récemment
approuvées
• Cible TNF, lymphotoxin
– Infliximab (Remicade) FDA, EMEA
• Anticorps monoclonal chimérique humain liant TNF libre et
lié
– Etanercept (Enbrel) FDA, EMEA
• TNF receptor et Ig fusion liant TNF et lymphotoxinalpha
– Efficacité impressionnante mais variable selon
traitement
– Hospira's Inflectra? (infliximab) the first biosimilar
monoclonal antibody to receive positive opinion
from EMA's CHMP for rheumatoid arthritis,
inflammatory bowel disease and
plaque psoriasis - Appli
48. Biothérapies en investigations et
cibles
• Calcineurin
– Pimecrolimus (Elidel-topique eczéma)
• TNF
– Adalimumab (FDA arthrite psoriasique) HUMIRA
– Premier anticorps recombinant humain
théoriquement semblable à l’infliximab
– Protocole suivi Researchers observed antidrug
antibody in 49% of patients during the extension
study, with 90% of them displaying ADA
formation by week 24.
– Hospira's Inflectra? (infliximab) the first
biosimilar monoclonal antibody to receive
positive opinion from EMA's CHMP for
rheumatoid arthritis, inflammatory bowel
disease and plaque psoriasis - Appli
49. ADA
• Antidrug antibodies (ADAs) against biological agents may be clinically significant and potentially
alter a biological drug's treatment efficacy.
• This systematic review aims to
– (i) determine the prevalence of ADAs against infliximab, etanercept, adalimumab and ustekinumab in
patients with psoriasis;
– (ii) ascertain whether ADAs are associated with changes in drug efficacy; and (iii) explore the use of
concomitant methotrexate to prevent ADA formation.
• Through a systematic search using Medline and Embase from 29 January 1950 to 29 March
2013, we identified 25 studies that met the inclusion criteria.
• Of 7969 patients with psoriasis, 950 tested positive for ADAs. Antibodies against infliximab,
etanercept, adalimumab and ustekinumab were reported in 5·4–43·6%, 0–18·3%, 6–45% and
3·8–6% of patients, respectively.
• Anti-infliximab antibodies were associated with lower serum infliximab concentrations in three
studies, and decreased treatment response in five studies.
• ADAs against etanercept were non-neutralizing and not associated with any apparent effects on
clinical response.
• Antiadalimumab antibodies were associated with lower serum adalimumab concentrations in
three of five studies, and reduced clinical efficacy in four studies.
• Two of six studies reported that antiustekinumab antibodies were associated with lower Psoriasis
Area and Severity Index responses, and three ustekinumab studies noted that most of these
antibodies were neutralizing.
• Although the use of concomitant methotrexate with biological agents to prevent ADA formation in
other immune-mediated diseases is promising, their use in psoriasis is sparse.
• ADA development remains a challenge with biological therapies and therefore should be
considered in patients with psoriasis who experience diminished treatment response.
• British Journal of Dermatology
• Volume 170, Issue 2, pages 261–273, February 2014
51. Cible CD11a
• Cible CD11a (LFA-1)
– Efalizumab (Raptiva) FDA, EMEA
– Ciblé adhésion et costimulation
– Actif dans sous groupe de psoriasis sévère, mais
nécessite traitement au long cours
– Anticorps monoclonal murin humanisé ciblant CD11a
– CD11a:CD18 lien ICAM-1 et -2
– Génération initiale de la réponse immune dans les
ganglions et dans la peau entre migration cellules T,
activation et entrée dans épiderme
– Entraîne leucocytose sanguine CD8 mémoire, par
blocage interaction LFA-1 ICAM-1
– diminution des CD11c+ TIP DCs
52. CD2
• Cible CD2
– Alefacept (Amevive) FDA
– Protéine de fusion contenant le domaine
extracellulaire de CD58 (LFA-3)
– Cible cellules T, NK, qq DC CD14+
– Mécanisme, diminution des T, apoptose des
cellules T?
– Diminution des DCs CD11C et CD83
– Diminution de gènes IFN, STAT1, iNOS, IL-8,
IL-23, IL-20
53. CD4
• Tregalizumab (BT-061):
• Tregalizumab enhances a natural mechanism of
down regulating excessive immune responses
and is therefore developed to treat disease
conditions that originate from an overreaction of
the immune system.
• “Tregalizumab is a humanized, agonistic
monoclonal antibody which binds to a unique
epitope of CD4, and induces Treg-specific
activation and suppresses CD4 and CD8
effector cell proliferation and activity in vitro.”
54. CD6
• Itlizumab, premier anticorps humanisé
(BIOCON)
• Itolizumab, the first humanized anti CD-6
monoclonal antibody, successfully met the pre-
specified primary endpoint of significant
improvement in PASI-75 (Psoriasis Area and
Severity Index) score after 12 weeks of
treatment in patients with moderate to severe
psoriasis compared to placebo. It also met
multiple secondary endpoints after 12 and 28
weeks of treatment.
55. Cell therapies: anti-peptide
• There are several compelling lines of evidence for T
cell involvement in psoriasis, including the initiation
of psoriatic lesions in immunodeficient mice after
transfer of superantigen or IL-2 activated peripheral
blood leukocytes from psoriasis patients. In
addition, intra-epidermal CD8+ T cells isolated from
plaque regions were found to be oligoclonal,
expressing BV3 and BV13S1 genes in their TCRs
• Zorcell Psoriasis Phase II Vaccine Multicenter Study
Double Blind Placebo and Adjuvant-Controlled Trial of
TCR Peptide Vaccination in Psoriasis Vulgaris
Using a Combination of BV3 and BV13S1 20 mer or 40
mer CDR2 peptides (Gottlieb et al. in Preparation)
56. BTLA
• How BTLA is regulated
• Using a combination of human cells and a mouse
model of psoriasis, the research team described
a new pathway that regulates BTLA expression.
Ware's research showed that the "retinoid-related
orphan receptor gamma-t" (ROR gamma-t)
nuclear transcription factor works with interleukin
(IL)-7, to coordinate the expression of BTLA,
which in turn regulates gamma-delta T cell
responses to inflammatory stimuli.
• The study found that ROR gamma-t works to
inhibit BTLA transcription, thereby limiting its
availability in gamma-delta T-cells. This allows
the expansion of T-cell numbers and their
production of inflammatory cytokines, including
IL-17 and TNF.
57. Antagonistes immunologiques
ciblés
• Intérêt avec analyse cellulaire, moléculaire des
voies d’activation
– Exemple:
• Etanercept effets… suggèrent que TNF régule IL-1 et IL-8
mais plus complexe sur voies d’activation
• JAK inhibitors
• Bone Marrow transplantation?
– J Am Acad Dermatol. 2013 Mar;68(3):489-92. doi:
10.1016/j.jaad.2012.08.021. Epub 2012 Sep 12.
– Remission of psoriasis after allogeneic, but not
autologous, hematopoietic stem-cell
transplantation.
58. JAK inhibitors
• Janssen has acquired immunology rights to Astellas'
oral Janus Kinase (JAK) inhibitor ASP015K, which has
completed phase IIa trials for plaque psoriasis and is currently
in phase IIb for rheumatoid arthritis.
• But the agreement only covers ASP015K as an oral treatment for
immune-mediated inflammatory diseases.
• Meanwhile, Pfizer's tofacitinib is on-track to become the first JAK
inhibitor to reach the market for rheumatoid arthritis.
• Tyrosine kinase 2 (Tyk2), a member of the Jak kinase family,
mediates signals triggered by various cytokines, which are related
to the pathogenesis of psoriasis. Int. Immunol. (2013) doi:
10.1093/intimm/dxt062
60. IL-17
• Ixekizumab (Eli Lilly)
• New England 2012:
– At 12 weeks, the percentage of patients with a reduction in the PASI
score by at least 75% was significantly greater with ixekizumab (except
with the lowest, 10-mg dose) — 150 mg (82.1%), 75 mg (82.8%), and
25 mg (76.7%) — than with placebo (7.7%, P<0.001 for each
comparison), as was the percentage of patients with a reduction in the
PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25
mg (50.0%) versus placebo (0%, P<0.001 for each comparison).
– Similarly, a 100% reduction in the PASI score was achieved in
significantly more patients in the 150-mg group (39.3%) and the 75-mg
group (37.9%) than in the placebo group (0%) (P<0.001 for both
comparisons).
– Significant differences occurred at as early as 1 week and were
sustained through 20 weeks. Adverse events occurred in 63% of
patients in both the combined ixekizumab groups and in the placebo
group. No serious adverse events or major cardiovascular events were
observed.
62. IL-22
• Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease
has been revolutionized by targeting inflammatory cytokines as key drivers of disease
pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the
clinic.
• We developed an integrative biology approach combining human disease transcriptome data sets
with clinically relevant in vivo models in an attempt to bridge this translational gap.
• We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important
proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts
produced marked inflammatory skin changes resembling human psoriasis. Injection of anti–IL-22
monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test
potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis
integrating both the IL-22 and anti–IL-22 cytokine transcriptomes and mapping them onto a
psoriasis disease gene coexpression network identified key cytokine-dependent hub genes.
• Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so
far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation
and potential future therapeutic target in psoriasis.
• Using in silico integration of human data sets and biological models, we were able to identify a
new target in the treatment of psoriasis.
• Sci Transl Med 12 February 2014:
Vol. 6, Issue 223, p. 223ra22
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007217
63. Ciblage IL-23
• Guzelkumab
• X-PLORE, a Phase 2b, randomized, placebo-
and active comparator-controlled, parallel-group,
multicenter dose-ranging study, investigated
subcutaneous injections of five doses of
guselkumab compared with placebo and
adalimumab in patients with moderate to severe
plaque psoriasis, defined by a PASI greater than
or equal to 12, PGA greater than or equal to 3
and body surface area (BSA) involvement of at
least 10 percent who are candidates for
systemic or phototherapy
64. p40IL-12/IL-23!
• Ustekinumab (STELARA)
– Efficacy and safety of ustekinumab in patients with active
psoriatic arthritis: 1 year results of the phase 3, multicentre,
double-blind, placebo-controlled PSUMMIT 1 trial. Lancet
– But
– Inhibition progression articulaire, mais discuté approuvé FDA,
refusé NICE (cost effectiveness)
– Psoriasis patients experienced arthritis flares following
ustekinumab treatment
• Briakinumab anti-p40
– Briakinumab showed higher efficacy than methotrexate in
patients with moderate-to-severe psoriasis. Serious infections
and cancers occurred more frequently with briakinumab, NEJM
2011
65. microRNA
• The anti-miR-21 molecules are tiny strands of
nucleotides that specifically glom onto miR-21 and
prevent it from functioning.
• Wagner and his colleagues injected this treatment
into the skin of mice bearing grafts of diseased tissue
from human patients with psoriasis.
• The anti-miR-21 reduced the thickness of the human
skin lesions by about half, a response similar to that
obtained using the antibody-based psoriasis therapy
etanercept (commercially available from California-
based Amgen as Enbrel).
66. Topical treatments
• Thermalisme
• Phototherapy UV
• Alternative, complementary therapies,
ayurvedic!
• To
• Il-8 cream
• a topical formulation of a gene-regulating
nanoparticle (Dual-F-NALP) carrying two nucleic
acids, which controls the skin cells from developing
psoriatic plaques and suppresses inflammation.
67. Nature video sur Youtube
http://www.youtube.com/watch?v=_VhcZTGv0CU#t=412
7’29• The skin is the body's main barrier against physical
insults and microbial pathogens. Diverse and functionally
specialized subsets of immune cells in the skin sense
and respond to infection or various barrier breaches to
activate an immune response and eventually, return to
homeostasis. However, deregulated immune responses
can also cause skin disorders, such as psoriasis.
This Nature Video introduces the environment and key
participants in skin immunity during steady-state and
disease.