Download Recent progress and perspective in JAK inhibitors and new targets

Recent progress and perspective in JAK inhibitors and new targets for
rheumatoid arthritis
許秉寧
台大醫學院免疫所，台大醫院內科
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by
synovial inflammation and joint destruction. However, the combined use of synthetic
disease-modifying anti-rheumatic drug (DMARD) such as methotrexate and a
biological DMARD targeting tumour necrosis factor (TNF) has revolutionized
treatment of RA. Clinical remission is a realistic target to treat and the maintenance of
remission has produced significant improvements in structural and function outcomes.
However, biological DMARDs are limited to intravenous or subcutaneous uses and
orally available small but strong products have been developed. The multiple
cytokines and cell surface molecules bind to receptors, resulting in the activation of
various signalling, including phosphorylation of kinase proteins. Among multiple
kinases, Janus kinase (JAK) plays pivotal roles in the pathological processes of RA.
Tofacitinib, a small product targeting JAK, inhibits phosphorylation of JAK1 and
JAK3, subsequent Stat1 and expression of Stat1-inducible genes, which contribute to
efficient propagation of its anti-inflammatory effects for the treatment of RA. The
primary targets of tofacitinib are dendritic cells, CD4+ T cells such as Th1 and Th17
and activated B cells which leads to multi-cytokine targeting. Six global phase 3
studies revealed that oral administration of 5 or 10 mg tofacitinib was significantly
effective than placebo with or without methotrexate in active RA patients with
methotrexate-naïve, inadequately responsive to methotrexate or TNF-inhibitors.
Therapeutic efficacy of tofacitinib was observed in a short term after administration
and was as strong as adalimumab, a TNF-inhibitor. The most commonly observed
adverse events were related to infection, hematologic, hepatic and renal disorders and
association of tofacitinib with carcinogenicity and infections remains debated. Further
investigation would help us understand the positioning of JAK inhibitors on RA.
New Therapies for IBD: From the Bench to the Bedside
翁孟慈
亞東醫院內科
After a long time of pharmacological developments and clinical trials in
inflammatory bowel disease (IBD) therapy, a great number of successful studies and
new therapy principles have been made into clinical practice. Six biologic agents are
currently approved for the treatment of IBD: four anti-TNF agents (infliximab,
adalimumab, golimumab and certolizumab pegol) and two anti-integrin agents
(natalizumab and vedolizumab).
Some initially promising therapies such as anti-integrin antibodies and small
molecule adhesion inhibitors will most likely be approved in the next years for IBD
therapy. Tofacitinib, a small molecule JAK inhibitor, is a promising candidate for the
treatment of UC. Anti-IL 12/23 (Ustekinumab ) is effective in refractory C.D and is
recruiting for phase III trial . Anti-IL6 strategies will be further evaluated and keep in
mind the caveat of a lack of CRP induction in anti-IL6 treated patients.
Lung Microbiomes and the Application of Probiotics in Allergic
Diseases
Jiu-Yao Wang (王志堯), MD, DPhil
Distinguished Professor of Pediatrics
Director, Allergy and Clinical Immunology Research (ACIR) Center
College of Medicine, National Cheng Kung University
Tainan, Taiwan
The increase in the incidence of allergic diseases over the past 20–30 years and the
dichotomy in the rate of allergic disease between industrialized and developing
countries have suggested that environmental change is a major factor in the
development of allergy and asthma. These observations have led researchers to
propose the ‘‘hygiene hypothesis’’ or “ microbiota hypothesis” for allergies and
asthma. The concept is that significant perturbations in gastrointestinal (GI)
microbiota composition in westernized living styles (due to antibiotic use, dietary
changes, and other lifestyle differences) have disrupted the mechanisms of mucosal
immunologic tolerance. According to the definition, perturbation is an alteration of
the function of a biological system, induced by external or internal mechanisms.
Beneficial effects of probiotics are long known to mankind. Research is beginning to
unravel the true nature of the human microbiome and its interaction with the immune
system. The growing prevalence of atopic diseases in the developed world led to the
proposition of the “hygiene hypothesis.” Dysbiosis is linked to atopic diseases;
probiotic supplementation is able to alter the microbiome and certain probiotic strains
have immunomodulatory effects in favor of a suppression of Th-2 and stimulation of
a Th1 profile. We expect future study results will provide solid evidences that
commensal microbiota perturbation determine the protection or exacerbation in
allergic asthma, and provide the proofs of concept values that intervention or
maintenance in our normal commensal microbiota will have clinical benefit for the
immunological tolerance in patients suffered from allergic asthma. To determine
whether daily supplementation with specific Lactobacillus gasseri A5 for 8 weeks can
improve the clinical symptoms and immunoregulatory changes in school children
suffering from asthma and allergic rhinitis (AR). We conducted a randomized,
double-blind, placebo-controlled study on school children (age, 6–12 years) with
asthma (AS) and allergic rhinitis (AR). Our results showed the pulmonary function
and PEFR increased significantly, and the clinical symptom scores for asthma and AR
decreased in the probiotic-treated patients as compared to the controls. Further, there
was a significant reduction in the TNF-a, IFN-g, IL-12, and IL-13 production by the
PBMCs following the probiotic treatment. In conclusion, probiotic supplementation
may have clinical benefits for school children suffering from allergic airway diseases
such as asthma and AR (Pediatr Pulmonol. 2010;45:1111–1120.). In the mice model
of mite-sensitive allergic asthma, oral administration with L. gasseri can attenuate
major characteristics of allergen-induced airway inflammation and IL-17
pro-inflammatory immune response in a mouse model of allergic asthma, which may
have clinical implication in the preventive or therapeutic potential in allergic asthma
(Brit J Nutr 2012; 108; 130–139.) Using probiotics as complementary treatment
options in AR and AS seems to be a promising concept although the evidence is of a
preliminary nature to date and more convincing trials are needed.
Immune Mechanism and Danger Signals in Severe Cutaneous Adverse
Drug Reactions
Wen-Hung Chung, M.D., Ph.D.
Director of Department of Dermatology& Drug hypersensitivity clinical and research
center, Chang Gung Memorial Hospital, Taipei & Linko; Taiwan
The clinical presentations of drug eruption may vary from mild maculopapular
exanthema (MPE) to severe, life-threatening Severe Cutaneous Adverse Drug
Reactions (SCAR), including Stevens-Johnson syndrome (SJS) and toxic epidermal
necrosis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).
Our previous findings of drug-specific genetic makers related to hypersensitivity
reactions (e.g. HLA-B*1502 for carbamazepine-induced SJS/TEN, and HLA-B*5801
for allopurinol-induced SJS/TEN/DRESS) is important steps for the personalized
medicine by performing genetic tests before prescribing.
It is now known that the HLA associations in drug eruption is more than just a genetic
marker and has a functional role as well. This reaction can be mediated by cytotoxic T
lymphocytes (CTLs) in an HLA-restricted fashion. The role of the drug-specific T
cells and their T-cell receptors has also been clarified. Downstream cytotoxic signals
of SJS/TEN have been elucidated with granulysin, a cytotoxic protein produced by
CTLs or natural killer cells deemed to be the key mediator in the reaction.
Though the HLA predisposition plays a critical role in drug-induced SCAR, other
factors like individual differences in drug clearance or metabolism may also
contribute to SCAR development, recovery or prognosis. Our recent study identified
that a variant of CYP2C locus is related to PHT induced SCAR. From a genome-wide
association study encompassing 105 cases with PHT-related SCAR, we identified
CYP2C9*3 which reduce CYP2C9 enzymatic activity was significantly associated
with PHT-induced SCAR. Although HLA-B*5801 is strongly associated with
allopurinol-induced SCAR, but the low positive predictive value of HLA-B*5801
suggesting that other factors are also involved in the pathogenesis of
allopurinol-induced SCAR. We recently revealed that the renal insufficiency directly
affected the excretion of plasma oxypurinol, and sustained high levels of oxypurinol
in the plasma of patients with allopurinol-induced SCAR was significantly associated
with high levels of granulysin and was correlated with poor prognosis.
The Role of Th17 and IL-17 in Immune Responses and Human
Inflammatory Diseases
林世昌
國泰綜合醫院風濕免疫科
IL-17 cytokine family consists of six members, IL-17A to IL-17F, and they
appear to exert distinct functions. IL-17A and IL-17F share high homology in the
amino acid sequence and can bind to the same receptor, suggesting that they may have
similar biological activities. IL-17A and IL-17F appear to play an important role in
contributing to immune responses for the host defense against micro-organism
infection. In addition, IL-17A and IL-17F may be also involved in the pathogenesis
of autoimmune diseases, allergic diseases, and the tumor development. The
functions of other IL-17 family members, IL-17B, IL-17C, and IL-17D, remain
largely unknown. IL-17A and IL-17F can be produced from different sources,
including immune cells and non-immune cells. The IL-17 receptor family consists
of five members, IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE, which can
form dimers to interact with different IL-17 cytokines. For example, homodimers
and heterodimers of IL-17A and IL-17F can bind IL-17RA/IL-17RC heterodimer
receptor. IL-17A is the signature cytokine of a recently identified CD4+ T cell
subset, T helper 17 (Th17) cells, which also can produce IL-17F, IL-21, IL-22 and
CCL20 in addition to IL-17A.
The development of Th17 cells can be induced by
cytokines, such as the combination of IL-6 plus TGF-, or IL-21 plus TGF-, and can
be enhanced by the presence of IL-23. Several studies have shown that IL-17 is able
to induce expression of pro-inflammatory cytokines, and IL-17 and Th17 cells were
found to play an important role in the development of several inflammatory and
autoimmune diseases in animal models. Therefore, it has been hypothesized that
Th17 cells and IL-17 cytokines also play an important role in the development of
human immune and inflammatory disease. Targeting IL-17 and Th17 cells has been
designed in the clinical trials for treating human psoriasis, and psoriatic arthritis,
ankylosing spondylitis, and rheumatoid arthritis diseases in recent years. Recently,
data from clinical trials of targeting IL-17 and IL-17RA (including secukinumab,
brodalumab and ixekizumab) in treating human immune diseases have been
published.
C-type Lectins in the Pathogenesis of Infectious and Autoimmune Diseases
Shie-Liang Hsieh
Genomics Research Center, Academia Sinica, Taipei, Taiwan
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
Institute of Immunology, National Taiwan University
Glycan binding proteins, also known as lectins, are abundantly expressed in human
immune and non-immune cells, and are involved in cell-cell contact, interaction
between host and pathogens, and immune cells recognition to both endogenous
and exogenous danger signals. Human lectins comprises several families, including
galectins (S-type), C-type lectins, P-type lectins, I-type lectins, and M-type lectins.
Among these five major lectin families, we are particularly interested in C-type
lectins because it is expanded in human genomes with diverse functions during
inflammatory reactions.
There are 91 C-type lectin receptors (CLRs) divided into 16 groups have been
identified in human genome. Due to the difficulty to identify their ligands, thus the
functions of most CLRs are not well elucidated yet. Among the CLRs, the spleen
tyrosine kinase (Syk)-coupled CLR, including Dectin-1/CLEC7A, Dectin-2/CLEC6A,
Mincle/CLEC4E, and MDL1/CLEC5A, have been shown to be involved in the
pathogenesis of human diseases. In addition, we found the novel C-type lectin 18
(CLEC18) contain three polymorphic genes located in human chromosome 21, and
the polymorphic amino acid residues in the C-type lectin domain (CTLD) determines
host response to viral infection. The potential functions of Syk-CLRs and CLEC18 in
the pathogenesis of infectious and autoimmune diseases will be addressed, and
discuss their potential as therapeutic targets for the development of novel
therapeutic agents.