Novel immunological targets in rheumatic diseases: clues from current therapies

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Drug Discovery Today � Volume 19, Number 8 �August 2014 REVIEWS

Novel immunological targets inrheumatic diseases: clues from currenttherapies

Fulvio D’Acquisto, Lorenza Rattazzi,Giuseppa Piras and Maria Letteria Galuppo

William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1 M 6BQ, UK

Many years have elapsed since the discovery of immunomodulators as effective therapeutics for the

treatment of rheumatic diseases, and we are still learning about their various mechanisms of action.

Here, we provide a concise overview of the most recent discoveries in this field of research, focusing in

particular on signaling pathways targeted by therapeutics currently used in the clinic. We highlight

areas of investigation that could potentially be explored for the development of new classes of

antirheumatic drugs.

IntroductionNow more than ever, immunology is a very exciting and fast-

evolving area of research [1]. The availability of sophisticated

technologies, together with a wide array of information obtained

from comparative biology, has provided scientists with a deeper

understanding of the complexity of adaptive and innate immune

responses. If we consider just one class of immune cells, the T

helper (Th) effector cells, it is easy to see how drastic these changes

have been. The ‘old’ and simplified Th1/Th2 duo representing the

yin and yang of the immune response has now been replaced with

spider diagrams showing naive T cells in the middle and a number

of ramifications leading to Th17, Th22, Th granulocyte macro-

phage colony-stimulating factor (GM-CSF) and Treg, to name the

latest cells reported in the literature [2]. This ever-expanding

universe of T cell subsets, as originally termed by Mosmann and

Sad [3], has served as inspiration for many scientists who have

pushed the boundaries and set themselves the task of discovering

similar subsets of B cells [4], dendritic cells [5], macrophages and

monocytes [6], to keep the list short.

Thus, it seems that the immune system has become as plastic as

the nervous system [7] and, as such, one can barely afford to focus

attention on one cell subset without considering the implications

that this might have on the others. Not surprisingly, the expansion

in so many universes has left scientists (and we the authors of this

review) with the very difficult challenge of singling out specific cell

Corresponding author: D’Acquisto, F. ([email protected])

1359-6446/06/$ - see front matter � 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.

targets or signaling pathways as the main focus for drug discovery.

Having to face this choice, we decided to focus our attention

deliberately on immunological mechanisms that are currently

targeted by clinically used therapeutics. Two reasons guided us

in this decision: (i) this would be of interest to the readers of Drug

Discovery Today; (ii) the awareness that the mechanisms of action

of long-used and well-known drugs have changed in light of these

discoveries. One such example is aspirin: born as a simple inhibitor

of prostaglandin production [8], it is now considered a transcrip-

tional regulator [9] as well as a tolerogenic agent for dendritic cells

and a modulator of T cell differentiation [10].

Proliferation and survival pathwaysThe lifespan of immune cells is governed by a wide-range of

signaling pathways that are cell-type-specific but that ultimately

lead to two main endpoints: apoptosis and/or necrosis. Whereas

apoptosis is considered an anti-inflammatory response leading to

the resolution of inflammation, necrosis initiates a cascade of

reactions that cause tissue damage and malfunction [11].

Several disease-modifying antirheumatic drugs (DMARDs) have

been shown to influence immune cell proliferation and apoptosis.

Sulfasalazine and its metabolite 5-acetyl salicylic acid have been

shown to exert a proapoptotic effect on vascular smooth muscle

cells [12] and to accelerate immunocomplex-induced neutrophil

apoptosis [13]. Both these effects occurred at concentrations

(20–100 mM), considered too low to inhibit nuclear factor (NF)kB

activation and found in serum of patients taking a standard oral

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REVIEWS Drug Discovery Today � Volume 19, Number 8 �August 2014

Legend Keys

Isolation Membranes

Cytosol &Organelles Lysosome

Hydrolases Autophagosome

Step 1 Step 2 Step 3 Step 4

Autolysosome

Proliferation Death

Homeostasis Differentiation

Drug Discovery Today

FIGURE 1

Autophagy mechanism. Autophagy, or autophagocytosis, is a catabolic process by which the cell degrades its own components through the lysosomal machinery.

It is the major mechanism used by starving cells to create energy. Autophagy plays a part in some cellular processes: proliferation, differentiation, homeostasis anddeath. A variety of autophagic processes exist but the best known involves the formation of a membrane (called isolation membrane: step 1) that isolates a part of

the cytosol including organelles and results in a vesicle (autophagasome: step 2). The autophagasome then fuses to a lysosome (step 3) creating an autolysosome

(step 4) in which the degradation of the content occurs.

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dose of the drug (3–6 g/day). Because the signaling pathways

involved in these effects are not known, it would be interesting

to investigate possible interference with the recently described

process of autophagy. This is considered as an organic and energy-

saving mechanism by which cells degrade and recycle their own

components through the lysosomal machinery (Fig. 1) [14].

The translational importance of autophagy in autoimmunity

has been supported by several recent studies, reviewed in [15].

Powerful antirheumatic drugs such as glucocorticoids have been

shown to induce lymphocyte apoptosis in a receptor-mediated

manner [16] and via the expression of a gene encoding a stress

response protein called Dig2, RTP801 or REDD1 [17]. Most inter-

estingly, the effect of glucocorticoids on autophagy does not seem

to be limited to immune cells. In fact, these drugs have been shown

to promote osteocyte autophagy – a mechanism that might ex-

plain how steroids alter bone cell fate [18].

Other drugs commonly known to modulate immune cell pro-

liferation include methotrexate (an inhibitor of folic acid metab-

olism) and leflunomide (an inhibitor of the activity of

dihydroorotate dehydrogenase, an enzyme involved in pyrimi-

dine synthesis). Intriguing studies suggest that these compounds

might have effects other than regulating immune cell survival.

Indeed, in vitro studies performed in the presence of an excess of

the substrate of the target enzyme have suggested the existence of

off-target effects and, hence, alternative mechanisms of action for

both molecules.

In the case of leflunomide, tests performed in the presence

of uridine have indicated an unexpected inhibition of Janus

kinase (JAK)1 and JAK3 activation in T cells [19] or the blockade

of cyclooxygenase-2 activity in macrophages and epithelial

cells, reviewed in [20]. Similarly, in the case of methotrexate

1156 www.drugdiscoverytoday.com

the concomitant administration of folic acid did not diminish

the anti-inflammatory properties of this drug, which have been

proposed to be caused by the release of adenosine in vitro and in

vivo [21].

Intracelllular and paracellular inflammatory pathwaysIn a paper published in 1993 by Maini et al., the authors stated: ‘In

preliminary trials in rheumatoid patients anti-TNF appears to have

an impressive effect on indices of disease activity including C-

reactive production and serum amyloid-A production. TNF alpha

appears to be a relevant therapeutic target in rheumatoid disease’

[22].

Twenty years later and anti-tumor necrosis factor (TNF)a drugs

are the treatment of choice once synthetic DMARDs start to lose

their effects or do not work [23]. Most importantly, anti-TNFa

treatment has set the scene for a new class of therapeutics, com-

monly known as biologics. These drugs are currently seen as the

Holy Grail for a wide variety of diseases including rheumatoid

arthritis and have paved the way for development of a number of

other therapeutics. Indeed, interleukin (IL)-6 and IL-1 receptor

antagonists are the next biologics that, as is the case for anti-TNFa,

block the effects of these cytokines in a wide variety of pathologies.

A great deal of research has been done on the possible mechanisms

responsible for the impressive effects of anti-TNFa drugs and

include a range of options from reduced localized inflammation

and leukocyte recruitment to decreased angiogenesis or selective

modulation of T cell subsets such as Th17 and Tregs [24].

In our view, the success behind this story lies within the

intrinsic property of the cytokine itself. It is in fact well known

that TNFa is one of the first cytokines to be produced and released

by immune cells, these being innate cells like macrophages or


LPS

TLR4

(Step 2) P

Cytoplasm c-Rel p65

(Step1)

P P P

p50 p65 26S Proteasome

c-Rel p65

26S Proteasome

p50 p65

c-Rel p65

NFκB

NFκB

NFκBNFκB

NFκB

(c) (Step 3)

(Step 4)

IκBβ

IκBβ

IκBβ

IκBβ

IκBα

IκBα

p50 p65

c-Rel p65

Nucleus TNFα

TNFα

↑↑

↑↑↑↑

κB2 site of the TNF-α promoter


FIGURE 2

Control of tumor necrosis factor (TNF)a expression by nuclear factor (NF)kB. Activation of cells by lipopolysaccharide (LPS) induces the phosphorylation of IkBa

and IkBb via two different kinetics: IkBa is the first to be phosphorylated and releases activated p50/p65 heterodimer (step 1); IkBb phosphorylation occurs withslower kinetics and leads to the activation of c-Rel/p65 (step 2). The first ‘pool’ of activated NFkB (p50/p65) translocates first to the nucleus and induces the

transcription of various genes including IkBa, IkBb and TNFa (step 3). The newly synthesized IkBa loops back and recaptures the p50/p65 heterodimer. Activated

c-Rel/p65 specifically binds the kB2 site of the TNFa promoter and forms a complex with the hypophosphorylated and newly synthesized form of IkBb (step 4). In

this way, IkBb makes c-Rel/p65 unresponsive to IkBa and contributes to the long-lasting expression of inflammatory genes such as TNFa.


members of the adaptive arm of the immune system like T and B

cells. Such a simple observation might not be so trivial if one

considers the rheumatic inflammatory cytokine cascade to be like

a domino effect where TNFa is just the first element.

A recent interesting study addressed the question of what could

be the mechanism behind the very early production of TNFa

compared with other cytokines. Using an elegant combination

of genetically modified mice and molecular tools, Rao et al. have

shown that activated NFkB complexes contribute to the initial

expression of TNFa. Then, a newly synthesized hypophosphory-

lated form of IkBb facilitates the formation of IkBb/p65/c-Rel

complexes, which selectively bind to the second of the four kB

sites (kB2) in the TNFa promoter, augmenting transcription

(Fig. 2). Consistent with these observations, IkBb-deficient mice

displayed delayed onset, lower incidence and decreased severity of

collagen-induced arthritis [25].

A deeper understanding of the mechanisms regulating IL-1

production has also been recently described. The biologic anakinra

exploits the ability of the IL-1 receptor antagonist (IL-1Ra) to

interfere with the formation of a tripartite complex composed

of IL-1, IL-1R type 1 and IL-1R accessory protein (IL-1acp) [26].

Another way to stop the activity of IL-1 could be achieved by

interfering with the process leading to the release of biologically

active IL-1b. Indeed, contrary to IL-1a, IL-1b must be proteolyti-

cally cleaved from its 31 kDa precursor form to its 17 kDa fragment

to be activated. The inflammasome is a multiprotein complex that

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Legend Key s

LRR repeats NACHTdomain

PYD domain CARD domain FIIND

Apoptoticstimuli

IL-1 β IL- 18

NALP1

Active CA SP1

K+ eff lux

Proteolytic

cleava ge

membrane

perturbation NALP3 Pro-IL-1 β

Pro-IL-18

Active CA SP1

Proteolytic

cleava ge


ASC

ASC

FIGURE 3

NACHT leucine-rich repeat protein (NALP)1 and NALP3 inflammasomes and caspase-1 signaling cascade. The oligomerization and activation of NALP1 and 3 occur

following signals (i.e. K+ efflux and membrane perturbation) triggered by apoptotic stimuli. During their activation, NALP1 and 3 inflammasomes interact with and

activate the apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) through pyrin domain (PYD)–PYD interactions. TheCARD of ASC interacts with the CARD domain of pro-caspase-1, thus giving the active form of caspase-1 by proteolytic cleavage. Caspase-1 then activates the

precursors of interleukin (IL)-1b and IL-18, thus leading to the release of IL-1b and IL-18.

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mediates the cleavage and activation of caspase-1, leading to

maturation and release of IL-1b and IL-18 [27]. Cytoplasmic

receptors of the NACHT leucine-rich repeat (LRR) and (pyrin

domain) PYD domain-containing protein (NLRP) and Nod-like

receptor (NLR) family are crucial components of the inflamma-

some and interact with the adaptor protein apoptosis-associated

speck-like protein containing a caspase recruitment domain

(CARD) (ASC), which recruits the precursor form of caspase-1

(Fig. 3).

The design of small molecules such as specific inhibitors of

inflammasome components might represent a useful alternative

to targeting of the IL-1 signaling pathway. Such an approach

would provide a number of advantages compared with current

biologic therapies. One of the most obvious pros is that synthetic

small molecules, like the DMARDs described before, are not gen-

erally immunogenic and hence not limited in their action by

counter-response of the patient’s immune system to these foreign

molecules. The increasing number of studies reporting the pres-

ence of anti-infliximab and anti-adalimumab antibodies in ‘resis-

tant rheumatoid arthritis patients’ has acted as an alarm bell,

pushing scientists and clinicians in this direction [28].


Exciting news in this regard has recently emerged. Atsttrin (an

antagonist of TNF/TNFR signaling via targeting TNF receptors) is a

small molecule including parts of three granulin domains from

progranulin (PGRN). PGRN was a receptor–orphan polyfunctional

protein until Liu and colleagues discovered that TNFR1 and TNFR2

bind to this protein (Fig. 4). Administration of human recombi-

nant PGRN to mice subjected to collagen-induced arthritis re-

duced disease progression and inhibited synovitis and cartilage

destruction [29]. In the same mouse model, atsttrin decreased

disease severity and delayed onset and progression better than

recombinant human (rh)PGRN; in a collagen–antibody-induced

arthritis mouse model, atsttrin was more effective at treating

inflammation than rhPGRN and etanercept, a soluble TNF recep-

tor. Atsttrin is well absorbed via intraperitoneal administration

and shows high stability and a long half-life (about five days). The

biological functions of PGRN go beyond inflammatory rheumatic

diseases and include other autoimmune pathologies. Patients

suffering from type 2 diabetes have higher levels of PGRN in

the serum compared with healthy subjects [30]. This is consistent

with the view of PGRN as a key adipokine mediating high-fat

diet (HFD)-induced insulin resistance, adipocyte hypertrophy and


Legend Keys

TNF-α Infliximab Prog ranulin or Atstt rin

(a) (b) (c)

TNF-α TNF-α PGRN PGRN

TNFR1 TNFR2 TNFR1 TNFR2 TNFR1 TNFR2

Pro-I nfl ammati on No signal Anti-I nfl ammati on

Rheumato id Arthritis Rh eumato id Arthritis


FIGURE 4

Modulation of tumor necrosis factor (TNF)a inflammatory pathway by progranulin. Binding of TNFa to its receptors: TNFR1 and TNFR2, causes their trimerization

and initiates a cascade of events leading to inflammation and autoimmune diseases like rheumatoid arthritis (a). Anti-TNFa therapies such as infliximab block thebinding of TNFa to its receptors and their subsequent oligomerization (b). Progranulin and its derived peptide atsttrin bind to TNFR1 and TNFR2 and act as

physiological antagonists of TNFa signaling (c).


obesity [31]. PGRN, like many other members of the adipokine

family such as leptin and adiponectin, is a representative of a new

class of mediators that are implicated in inflammation and meta-

bolic diseases [32]. This new and exciting area of research will

undoubtedly receive further attention in the future because it

remains unclear whether these mediators are harmful or protective

factors [33,34].

Cell–cell interaction and crosstalkIt takes two to tango not only in life but also in autoimmunity. The

realization of this very simple concept has prompted scientists to

investigate key molecules in the crosstalk between T cells and

antigen-presenting cells (APCs) as a potential target for therapy.

One of the best examples in this context is abatacept: a cytotoxic T

lymphocyte antigen (CTLA)-4–IgG fusion protein that modulates

CD28-mediated T cell co-stimulation and is efficacious in the

treatment of rheumatoid arthritis and many other autoimmune

diseases. Elegant recent studies have shown that abatacept sup-

presses antigen-specific T and B cell responses in vivo by suppres-

sing the acquisition of CXCR5+ICOS+ T follicular helper cell

phenotype by antigen-specific T cells despite normal B cell clonal

expansion [35]. Other studies suggested that abatacept reduced the

production of TNFa and IL-12p70 by macrophages [36].

Intriguing evidence has suggested that CTLA-4 expressed on

activated T cells can capture its ligands from opposing APCs by a

process of transendocytosis. T cells actively internalize the CTLA-

4/CD86 complexes through endocytosis and rapidly degrade

CD86 molecules in the cytoplasm thus resulting in impaired

co-stimulation via CD28 [37]. A similar ‘stealing’ mechanism

has been suggested recently for the B-cell-depleting antibody

rituximab (a chimeric anti-CD20 monoclonal antibody). The

wide therapeutic efficacy of this antibody lies in its ability to

cause B cell depletion through mechanisms such as complement-

mediated cytotoxicity and antibody-dependent cellular cytotox-

icity. However, recent studies in the cancer field have hypothe-

sized that rituximab might promote monocyte-mediated shaving

of the CD20/RTX complex from the B cell surface. This shaving

mechanism was the result of active protease activity because

EDTA and phenylmethylsulfonyl fluoride (PMSF) were able to

mediate partial inhibition [38]. Further studies are needed to

verify that such mechanisms occur in rheumatoid arthritis

patients.

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Further research is also needed to identify the mechanisms of

action of tocilizumab, a humanized antibody to IL-6-receptor-a

(IL6R-a). This biologic is supposed to block the multiple effects of

IL-6 in the crosstalk between T cells and APCs. However, despite

on-target suppression of IL-6R signaling in human monocyte-

derived dendritic cells and T cells, there are no data showing an

effect on dendritic cell maturation and/or activation, alloreactive

T cell proliferation, Treg expansion or allogeneic Th1/Th17

responses in vitro [39]. Thus, it seems that tocilizumab in analogy

to metathrexate and lefluonamide might have several other off-

target effects that are yet to be discovered.

Concluding remarks and future perspectivesThe modulation of the immune system in rheumatic disorders

has provided us with an extremely wide-range of opportunities


for drug discovery. We hope that this short review has shed some

light on the current views of the mechanism of action of effec-

tive immunotherapeutics. Whether these novel findings will

support the design of new evidence-based drugs is difficult to

say. Indeed, we firmly think that this is by no means a compre-

hensive account of the myriad of possible ways by which these

drugs continue to improve the life of many people. Conversely,

we hope that these investigations will inspire clinicians and

basic scientists to think ‘outside the box’ and look further

and further.

AcknowledgmentsWe would like to thank Dr Dianne Cooper and Professor Mauro

Perretti for carefully reading the manuscript.

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Novel immunological targets in rheumatic diseases: clues from current therapies