|
|
|
|
Review Article
|
|
Tumor Necrosis Factor as Mediator of Inflammatory Diseases and its Therapeutic Targeting: A Review |
|
Kuldeep Dhama,
Shyma K. Latheef,
Hari Abdul Samad,
Sandip Chakraborty,
Ruchi Tiwari,
Amit Kumar
and
Anu Rahal
|
|
|
ABSTRACT
|
Signaling molecules of immune system are cytokines that may either stimulate or suppress the responses of various cells involved in host immune mechanisms and Tumor Necrosis Factor (TNF) is one of the leading members of the group of cytokines. TNF-α from activated macrophages and LT-α/TNF-Β from T cells have now become representatives of a distinctive superfamily of cytokine ligands (TNF ligand superfamily) along with their corresponding receptors (TNF receptor superfamily); altogether constituting the TNF Superfamily. These are highly conserved proteins, found in all mammals having important ligand members which interact with the either of the two receptors, TNFR1 and TNFR2, that initiate varied signaling cascades leading to diverse cellular responses. It has been established that the appropriate regulation of TNF ligand and receptor interactions and functions are crucial for the proper immune system activity. Excessive production of various TNF cytokines has been attributed with the development of an array of autoimmune as well as inflammatory conditions. TNF cytokines help to reduce mortality due to cardiovascular diseases. Therapeutic TNF blockers include:monoclonal antibodies to TNF (Infliximab and Adalumimab) and TNF receptor fusion proteins (Etanercept and Lenercept) and are effective against rheumatoid arthritis; ankylosing spondylitis; psoriasis and asthma. Preclinical studies conducted in murine models and the pivotal role played by the TNF superfamily in cytokine mediator system will make it easier for researchers as well as scientists to develop novel drugs in near future. This review has covered all these aspects concerning TNF as mediator of inflammatory diseases and its therapeutic targeting.
|
|
|
|
|
Received: January 01, 2013;
Accepted: February 19, 2013;
Published: May 21, 2013
|
|
INTRODUCTION
Signaling molecules of immune system are cytokine that may either stimulate
or suppress the responses of various cells involved in host immune mechanisms
and interact or convey the essential messages for the proper functioning of
defense systems against numerous pathogens or disease conditions (Chauhan
and Dhama, 2008; Dhama et al., 2011). They
trigger signal-transduction pathways by binding to receptors on a target cell
(that ultimately alter gene expression in these cells). They are involved in
both innate and adaptive immunity play important role as adjunctive immunomodulators
in a variety of infectious diseases (Darnell Jr., 1997;
Bach et al., 1997; Chang
et al., 2004; Tizard, 2004). Tumor Necrosis
Factor (TNF) is one among the most studied and central pro-inflammatory cytokines
(Gillett et al., 2010). It was first identified
in 1984, in which the two forms, TNF-β and LT-α (otherwise called
lymphotoxin or TNF-α), were isolated; TNF-β from activated macrophages
and LT-α from T cells. These proteins have now become representatives of
a distinctive superfamily of cytokine ligands (TNF ligand superfamily) along
with their corresponding receptors (TNF receptor superfamily); altogether constituting
the TNF Superfamily (Croft et al., 2012). Most
of the members are expressed by immune cells or can target immune cells and
thereby exert a wide range of actions including the production of inflammatory
chemokines and cytokines, promoting cellular growth, differentiation and survival
etc. TNF-β induces the expression of selectin which bind to mucins expressed
by circulating neutrophils and this binding mediates the attachment or wandering
neutrophils to the vascular endothelium (Gabay and Kushner,
1999; Dhama and Chauhan, 2008). Cytokine like TNF-β
also induces coagulation; increases the vascular permeability and induces increased
expression of adhesion molecules on vascular endothelial cells along with playing
a central role in chronic inflammation as well as autoimmunity and malignant
diseases like cancer. For maintaining the homeostasis of the immune system;
inflammation as well as host defence, TNF plays a major role but there exists
a dark side to this powerful cytokine (especially clear in middle aged and old
aged people) (Balkwill, 2006; Dhama
et al., 2008).
Tumor Necrosis Factor (TNF) which was described as a key cytokine for inflicting
necrosis of tumors has now been recognized as a key regulator of the inflammatory
responses. Many scientific researches have concluded that TNFSF ligand-receptor
interactions and signaling pathways are active in mediating several of the inflammatory
and autoimmune diseases (Watkins et al., 1995).
TNF ligands were identified to have central role in a variety of inflammatory
conditions viz., rheumatoid arthritis, inflammatory bowel disease, ankylosing
spondylitis, psoriasis, graves disease, SLE, multiple sclerosis, diabetes,
asthma etc. (Croft et al., 2012). Moreover various
genetic polymorphisms in the proteins of this superfamily have been associated
with the susceptibility to developing disease (Haritunians
et al., 2010; Jung et al., 2010).
As the involvement of the TNF superfamily ligand and receptor molecules in
the incidence of the above pathological conditions has been established, it
is clear that the inhibition of these communications can prevent the downstream
signaling pathways, leading to the suppression of inflammatory immune cells
and thereby diminishing the pathology of autoimmune and inflammatory diseases
(Locksley et al., 2001). Several TNF blocking
drugs have been presented with therapeutic success and based on the success
of these therapies, attention is put for further developments (Thompson
et al., 2011; Dhama et al., 2013).
TNF SUPER FAMILY
The Tumor Necrosis Factor (TNF) superfamily consists of approximately 50 membrane-bound
and soluble proteins. About 350-450 million years ago there was evolution of
ligand and receptor molecules along with adaptive immune system (Croft,
2009). These are highly conserved proteins, found in all mammals (Croft,
2003a). Important ligand members of this family include TNFα, LT-α,
LT-β, OX40L, TRAIL, CD40L, CD27L, CD30L, FASL, 4-1BBL, OPGL, LIGHT, APRIL,
DR3, DR4, DR5, RANK and TALL-1 etc. (Ashkenazi and Dixit,
1998; Shu et al., 1999; Croft,
2003b; Kodama et al., 2005). With the exception
of LT-α all ligand members are type-II membrane proteins forming the hallmark
of ligand family with C-terminal extracellular domain having conserved region
of 150-amino acids that folds into homotrimers formed by β-pleated sheet.
It can generate a soluble functional form when released by proteiolytic degradation.
But unlike other protein families of notable homology, these proteins display
only about 20±25% homology at the protein level (Gillett
et al., 2010; Croft et al., 2012).
Type I transmembrane proteins constituting a variety of cysteine-rich motifs
in their extracellular domains (disulphide bridge-based structural modules)
are the members of receptor superfamily. There are two distinct types of TNF
receptors; type I and type II with molecular sizes 55 kD and 75, respectively.
A pre-ligand assembly domain (PLAD) has been described recently for a subset
of receptors, including Fas, TNF-receptor I (TNF-RI) and CD40 which is thought
to facilitate homotypic association between monomeric receptor subunits, by
which the receptor complexes are capable of responding rapidly to environmental
cues. With the emergence of adaptive immunity, an extended family gives rise
to this core family of ligand-receptors through en-bloc gene duplication events
(partially from single ancestral genes). They include the TNF superfamily homologue
Eiger and the TNF-RSF homologue Wengen (Clark et al.,
2005). Regarding the expression, different molecules of TNF ligand-receptor
family are not ubiquitously expressed. The expression of several of these molecules
is increased following immune-cell activation and this suggests that they have
a central role in modulating immune responses. Studies of TNFRs expressed by
conventional T cells and their ligands expressed by antigen-presenting cells
(ApCs) has led to the hypothesis that antigen recognition by T cells engages
and bidirectionally activates TNF-TNFR pair that contribute to the immune cells
(including T lymphocytes) effector responses (Croft, 2003a,
2009; Fang et al., 2008).
Cytokine binding to some TNF receptor family members, such as TNF-RI, TNF-RII
and CD40 favour the recruitment of TNF receptor-associated factors (TRAFs) to
the cytoplasmic domains of the receptors. The TRAFs activate transcription factors
like nuclear factor KB (NF-KB) and activation protein-I (API). Cytokine binding
to other family members, such as TNF-RI, leads to recruitment of an adapter
protein that activates caspases and triggers apoptosis. Thus, different members
of the TNF receptor family can induce gene expression and cell death and some
can do both. TNFRI knockout mice show more impaired host defense than do TNF-RII
knockout mice, suggesting that TNF-RI is more important for the function of
the cytokine. Then within 10-20 min, on ligation with TNF-β, TNFR I get
trimerized and recruits various adapter molecules. This will activate NF-κB,
inducing several anti-apoptotic genes (Complex I formation) and survival signal
(Lee et al., 2002). This is followed by (more
than 2-3 h) by an endocytosis of receptor complex resulting in the dissociation
of certain adapter proteins (TRAF-2, RIP) and recruitment of Fas-associated
Death Domain (FADD) and procasepase-8 to form Death-inducing Signaling Complex
(DISC). In the DISC, caspase-8 is activated and released into the cytoplasm
where it activates effector caspases to induce apoptosis (Croft,
2003a).
ACTION AS MEDIATORS OF INFLAMMATORY PROCESS
TNF ligands interacts with the either of the two receptors, TNFR1 and TNFR2,
that are differentially expressed on cells and initiate varied signalling cascades,
leading to diverse cellular responses viz., cell death, proliferation, differentiation
and migration (Bradley, 2008). Various pro-inflammatory
changes are the outcomes of TNF responses of vascular endothelial cells that
lead to adhesion and trans-endothelial migration of leukocytes along with vascular
leak. TNF also induces the expression of certain pro-coagulant proteins and
down-regulate anticoagulant protein, thereby inducing intravascular thrombosis
(Mark et al., 2001; Croft,
2003a). Another major role of TNF is as a modulator of host defense mechanism
against infectious agents; especially gram negative bacterial organisms. This
role has been confirmed by studies conducted in mice deficient in TNF receptor.
Those mice had severely reduced clearance of the bacterium Listeria monocytogenes
and immediately yielded to this infection (Pfeffer
et al., 1993; Rothe et al., 1993;
Bradley, 2008). There are also evidences that increased
serum TNF levels were found in the cases of uncomplicated Plasmodium falciparum
malaria and markedly increased in cases of fatal cerebral malaria (Bradley,
2008). This indicates that TNF is physiologically an important factor for
the normal defense against infections, but can be harmful if the production
is inappropriate or extreme. In hepatic diseases there will be reduced TNF production
and accompanying incapacity to fight infection (Gillett
et al., 2010).
In order to develop and modulate immune system, majority of members of ligand
family play important roles as lymphoid-enriched tissues are their main expression
sites (Khare et al., 2000). TNF, which is predominantly
from the macrophages, is a key mediator of inflammatory responses and defenses
(Tracey and Cerami, 1994; Khare
et al., 2000). Fas ligand mainly synthesized by activated T cells,
modulates thymocyte apoptosis mediated by T cell receptor (Castro
et al., 1996). CD40L, which is also expressed by activated T cells,
signals for B cell survival and proliferation as well as immunoglobulin isotype
switching (Khare et al., 2000; Gillett
et al., 2010).
Many members of the TNFSF were recognized to modulate some non-lymphoid cells
also. TNF which was initially described as a circulating factor, causing necrosis
of tumour, has since been identified as a key regulator of the inflammatory
responses. TNF ligands were identified to have central role in a variety of
inflammatory conditions viz., rheumatoid arthritis, inflammatory bowel disease,
ankylosing spondylitis, psoriasis, graves disease, SLE, multiple sclerosis,
diabetes, asthma etc (Croft et al., 2012).
In approximately 1% of population Rheumatoid Arthritis (RA) develops most commonly.
The condition is characterized by persistent synovitis resulting in progressive
damage, erosion of adjacent bone and cartilage and systemic inflammation, leading
to chronic disability. Synovial hyperplasia accompanied by angiogenesis is a
prominent feature of the condition (Geiler et al.,
2011). Predisposing causes to the condition include genetic causes, autoantibodies
and environmental factors etc. Several pro-inflammatory cytokines viz., TNF,
IL-1, GM-CSF, IL-6, are produced within the inflamed joint cavity. Because of
their predicament in the inflammatory reaction cascade, tumor necrosis factor
ligands proven to be the most important cytokines involved in rheumatoid arthritis
(Geiler et al., 2011).
Crohns disease-like inflammatory bowel disease and ulcerative colitis
are inflammatory conditions inflicting the lamina propria of intestine and an
over-expression and increased immunoreactivity of various TNF family members
have been demonstrated to be involved with the development of these inflammatory
conditions (Sands et al., 2004). Patients affected
with Crohns disease are more prone to another autoimmune condition called
Ankylosing spondylitis, which is an inflammatory arthritis, particularly affecting
the spine along with sacroiliac joints. In those patients with this condition,
elevated serum levels of various TNF proteins were identified that correlates
the role of TNF in the disease incidence (Lange et al.,
2000; Francois et al., 2006).
Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which there
will be production of autoantibodies that are specific for the DNA, RNA or various
proteins associated with nucleic acids. This will lead to the formation of immune
complexes in small blood vessels, especially in the kidneys (Yang
et al., 2009). The affected patients with SLE usually found to have
abnormal B- and T-cell function (Croft, 2009; Croft
et al., 2012). Psoriasis, an autoimmune and inflammatory disorder
affecting the skin, is characterized by the presence of psoriatic plaques, formed
by inflammatory cell infiltration and hyperkeratotic lesions. A study conducted
in patients with psoriasis has shown an upregulated expression of TNF receptors
in blood vessels associated with dermal layers (Chaudhari
et al., 2001; Gottlieb et al., 2004;
Bradley, 2008).
TNF exerts its action in the central nervous system also, where its main sources
are microglia and astrocytes, in response to infections, inflammations, ischaemic
as well as traumatic injuries. But it has been shown to have both detrimental
and favorable effects in brain, depending upon the conditions (Arnett
et al., 2001; Bradley, 2008). In murine
model, blockage of TNF during ischaemic injury to the brain resulted in amelioration
of the condition (Nawashiro et al., 1997) but
in case of experimental autoimmune encephalomyelitis, those with lack of TNF
were highly susceptible to the condition and treatment using TNF supplementation
reduced the condition. SLE is a multiple organ system related autoimmune disease
with exceptionally diverse clinical manifestations. Various studies have shown
that TNF ligand-receptor pair has been implicated in this autoimmune condition
also (Croft, 2009).
TNF has its role in cardiovascular diseases also, in which the disease pathology
has been found to be associated with the exacerbated level of various TNF cytokines.
Variety of pathological conditions of cardiovascular system viz. atherosclerosis
and myocardial infarction; myocarditis, heart failure and cardiac allograft
rejection and vascular endothelial cell responses have been implicated with
TNF. Several studies point out that certain chronic inflammatory and autoimmune
conditions such as rheumatoid arthritis have predisposition towards cardiovascular
diseases. This predisposition of increased cardiovascular risk has been found
to be in association with elevated serum level of inflammatory mediators, mainly
TNF and there also evidences for amelioration of these conditions on anti-TNF
therapy (Wolfe and Michaud, 2004; Croft,
2009).
The key role of TNF is connected with the incidence of several inflammatory
conditions in respiratory system also and some of those conditions include asthma,
chronic obstructive pulmonary disease, acute respiratory distress syndrome,
chronic bronchitis etc (Mukhopadhyay et al., 2006).
In the case of asthma, leukocytes collected from bronchiolar lavage of the patients
were to have augmented release of TNF and it was shown to play role in bronchial
hyper-responsiveness by inflicting inflammation and remodeling. TNF is associated
with the pathogenesis of various renal diseases like glomerulonephritis, renal
transplant rejection, renal ischaemia etc. (Al-Lamki et
al., 2005). It has been found that in case of diseases associated with
renal inflammation, difference in the signalling of TNF receptor subtypes leads
to difference in the efficacy and adverse effects of various blocking agents
(Al-Lamki et al., 2010).
DIFFERENT TNF LIGAND RECEPTOR INTERACTIONS IN MEDIATING INFLAMMATORY AND AUTOIMMUNE DISEASES
OX40-OX40L: One among the TNF receptor-ligand pair is OX40-OX40L which
is proinflammatory in function. Various knockout studies have proven that they
play major role in the development of autoimmune disease like Rheumatoid Arthritis
(RA), inflammatory colitis, diabetes, Multiple Sclerosis (MS), asthma and atherosclerosis
in murine models (Croft, 2009; 2010).
Compared to healthy individuals, in case of individuals with mild asthma there
is upregulation of expressed OX40 and OX40L in the submucosa of bronchi (Siddiqui
et al., 2010). Mice deficient in OX40L suffer from polymicrobial
sepsis showing improved survivality and reduction in production of cytokine
and damage of organ. Ocular inflammation is also found to have diminished in
murine autoimmune uveitis thereby widening the scope of disease control by OX40
and OX40L interaction (Zhang et al., 2010).
In a model of coxsackie virus B3 driven myocarditis, heart inflammation shown
to be ameliorated by the blockade of OX40L, thereby leading to increased survivability
(Fousteri et al., 2011). This indicates the
connection of this ligand-recceptor interaction with atherosclerosis development
(Croft, 2009; 2010). This
interaction has also been proven in correlation with the risk of development
of Systemic Lupus Erythematosus (SLE). OX40 has been found to be associated
with lupus nephritis condition by demonstrating its increased expression on
Th17 cells which infiltrate kidney parenchyma (Dolff et
al., 2010).
CD30: CD30, known for its increased expression on malignant tumors like
Hodgkins lymphoma, has been proven for its role in autoimmune diabetes
and asthma. Blockage of CD30-CD30L interaction was found to reduce the development
of these diseasevin the NOD mouse models (Oflazoglu et
al., 2009). In case of colitis, the blocking of CD30L interactions lead
to the suppression of trinitrobenzene sulfonic acid (TNBS)-induced colitis (Sun
et al., 2008; 2010). CD40-CD40L interaction,
which was described to modulate B cell activity and isotype switching has now
been identified to promote various inflammatory and autoimmune conditions in
murine models. These conditions include Graves disease, SLE, RA, MS, diabetes,
asthma, psoriasis, inflammatory bowel disease etc. (Peters
et al., 2009). CD40L is also expressed by platelets which indicate
that it may be involved in the development of atherosclerosis (Lievens
et al., 2010). This is supported by the finding that platelets from
CD40L-deficient mice were fail to adhere on vascular endothelium in vivo
and unable to form aggregates of platelet and leukocyte atherosclerotic lesions
(Lievens et al., 2010; Croft
et al., 2012).
4-1BB: 4-1BB, another important member of this superfamily, was identified
as a stimulatory molecule of activated T cells, has now been shown to express
on activated antigen presenting cells and other cell types. Various cancer studies
conducted in murine tumor models have shown that they contributes for the augmented
activity of T cytotoxic cells and NK cells (Tansey and
Szymkowski, 2009). 4-1BB may also control sepsis and biliary cirrhosis.
This ligand has shown to exert its effect on sepsis in which the ligand deficient
mice exhibited reduced mortality in a sepsis model. In case of primary biliary
cirrhosis, the expression of 4-1BBL has shown a positive correlation with the
disease markers of serum viz., interleukin (IL)-18, bilirubin, glutamyltransferase
etc. (Nguyen et al., 2009; Croft
et al., 2012).
CD70-CD27 l: CD70-CD27 ligand-receptor interaction has been found to
be between a range of immune cells and also between immune and some nonimmune
cell types. This interaction is implicated in several autoimmune diseases especially
in the case of Experimental Autoimmune Encephalomyelitis (EAE), ie mouse models
of multiple sclerosis and also in SLE of humans and murine models (Nolte
et al., 2009; Croft et al., 2012).
Recent studies with collagen-induced murine models of rheumatoid arthritis shown
to had diminished disease symptoms upon anti-CD70 antibody therapy. Expression
of CD70 is reported to be Th1 cell-specific which correlates with the finding
that therapies involving CD70 blockade had its ameliorating effects on Th1-driven
hypersensitivity reactions and contact hypersensitivity reactions, however no
effect on the extent of pathology of Th2-type disease models as in the case
of Th2-driven asthma and experimental allergic conjunctivitis (Sumi
et al., 2008; Behrendt and Hansen, 2010).
DR3-TL1A: Death receptor 3 (DR3) and TNF-like factor 1A (TL1A) interactions
are associated with Th1 co-stimulation and these molecules are now been implicated
in the pathology of gut inflammatory conditions (Croft,
2009) such as IBD, ulcerative colitis and Crohns disease (Tremelling
et al., 2008; Haritunians et al., 2010).
There is also evidence of increased TL1A expression in connection with the development
of T cell-dependent inflammatory small bowel pathology. In addition to Th1 cells
the expression of DR3 is found on Th17 cells (Meylan et
al., 2011; Croft et al., 2012). The
TL1A-DR3 interaction is not restricted only to those diseases which are regulated
by Th1- or Th17 cells, but also by Th2 cells. In anti-TL1A therapy to Th2-driven
murine models of asthma, it displayed impaired expression of Th2 cytokines,
leading to the suppression of airway inflammation and mucus production (Zhang
et al., 2009). Glucocorticoid-induced TNF receptor-related protein
(GITR) and its ligand (GITRL): The GITR-GITRL interaction pathway has reported
to be active in the development of type 1 diabetes and pancreatitis. This has
been proven by the study in NOD mice using agonist anti-GITR antibody therapy,
leading to a higher incidence of diabetes (Galuppo et
al., 2011; Croft et al., 2012).
THERAPEUTIC TARGETING OF TNF
It has been established that the appropriate regulation of TNF ligand and receptor
interactions and functions are crucial for the proper immune system activity.
Excessive production of various TNF cytokines has been attributed with the development
of an array of autoimmune as well as inflammatory conditions, some of which
are discussed above. In order to suppress the immunopathology and disease progression
of these conditions, therapies should be aimed mainly against the responses
of immune cells like T cells, APCs, NK cells and NKT cells. It is ideal that
this approach be accompanied by the maintenance of Treg cells, thereby facilitating
the control of disease for long-term (Croft, 2009).
As per these findings several successful endeavors have been made to target
these ligand-receptor interactions for the therapeutic management of inflammatory/autoimmune
conditions (Gillett et al., 2010). Cytokine
therapy is an emerging and promising treatment regimen as are the other ones
like monoclonal antibodies, avian egg antibodies, gene silencing, gene therapy,
apoptins, herbal and panchgavya elements (Mahima et
al., 2012; Deb et al., 2013; Dhama
et al., 2005a, b; 2013).
Certain catabolic effects on fat cells and whole animals are exerted by TNF-β
and have been proven by TNF-α messenger RNA expression profiling in rodent
models (obese fa/fa rats) wherein an increase in the uptake of glucose in response
to insulin peripherally has been observed significantly (Hotamisligil
et al., 1993). As TNF-α bears a neuro-inflammatory domain in
the nervous system it plays a pivotal role in drug development in the treatment
of neuropathic pain originating both centrally and peripherally. It has been
proven by various studies conducted in animal models of neuropathic pains based
on various types of nerve injuries viz. peripheral versus spinal nerve as well
as ligation versus chronic constrictive injury (Leung and
Cahill, 2010).
Preclinical studies have analyzed the activity of neutralizing antibodies that
are targeting specifically for TNF ligand proteins, or of Fc fusion proteins
with a TNFR that binds to the ligand and thereby blocks the endogenous interaction.
The effects of blocking the TNF ligand-receptor interactions discuss have been
assessed in models of inflammatory disease (viz., allergy, bronchial asthma,
organ transplantation, graft-versus-host disease (GvHD) and atherosclerosis)
and autoimmune disease (including experimental autoimmune encephalomyelitis
(EAE), diabetes, colitis, adjuvant- or collagen-induced arthritis and systemic
lupus erythematosus (Taylor et al., 2002). These
studies have shown that neutralizing any one of these TNF-TNFR interactions
can result in overpowering of conditions, which in most of the cases, is precisely
linked to decline in CD4+ or CD8+T cells activity, or in other cases results
in the impairment of NK- and NKT-cell function (Zimmerer
et al., 2012).
TNF-β is a tumor promoter helping to produce the toxic effects involved
in conventional cancer therapy viz. cytokine release syndrome as well as nephrotoxicity
induced by cisplastin. TNF-β antagonists have been developed effectively
against rheumatoid arthritis and inflammatory bowel disease due to the central
role played by TNF-β in inflammation (Szlosarek and
Balkwill, 2003). Inhibition of TNF has also been proven to be an effective
therapy for inflammatory diseases viz. psoriasis and psoriatic arthritis; ankylosing
spondylitis but the efficacy of preventing septic shock and acquired immunodeficiency
syndrome (AIDS) have been questioned. Certolizumab pegol is a novel TNF inhibitor
(Esposito and Cuzzocrea, 2009). Different therapeutic
agents are now in market under the label of TNF blockers. This includes monoclonal
antibodies to TNF and TNF receptor fusion proteins. Drugs named Infliximab and
Adalumimab are among the monoclonal antibodies to TNF whereas Etanercept and
Lenercept are the TNFR fusion proteins (Gillett et al.,
2010; Croft, 2009; Croft et
al., 2012). Etanercept comes under a human recombinant protein which
is soluble in nature. It is a fusion protein in which TNFR2 has been coupled
with the Fc portion of immunoglobulin G. Infliximab is a chimera of human and
murine immunoglobulin G1 monoclonal anti-TNF antibody. Adalibumab is produced
by the phage display and is a human anti-human TNF antibody (Bradley,
2008; Gillett et al., 2010). In case of
rheumatoid arthritis condition all the above drugs have shown to be effective.
For patients with Crohns disease, infliximab is shown to be effective
in inducing remission but not etanercept (Tracey et
al., 2008; Bradley, 2008). In ankylosing spondylitis
condition, both etanercept and infliximab are proven to be effective. Various
clinical trials have shown that infliximab, etanercept and adalimumab are operative
for treating all the manifestations in case of psoriasis. In case of patients
affected with refractory asthma has shown evidence for beneficial effects of
the drug etanercept on markers of asthma to control the condition (Tyring
et al., 2007; Tracey et al., 2008;
Bradley, 2008; Gillett et al.,
2010; Croft et al., 2012).
CONCLUSION An array of TNFR and TNFL pairs of this superfamily are correlated with their actions in augmenting the ongoing inflammatory function and autoimmune conditions. These interactions were found to exert several properties on conventional CD4 T cells, CD8 T cells, NK cells and NKT cells, including the stimulation of division, proliferation, survival, differentiation and regulating of cytokine production. Along with this, these interactions furthermore modulate the differentiation, proliferation and activity of regulatory T cells. They target intracellular signaling mediators that control canonical and non-canonical various transcription factors like NF-κB, PI3K/Akt and also calcium/NFAT pathways. They can also promote signals in APCs and non-lymphoid cells that are not yet defined but likely control production of pro-inflammatory cytokines. There are still inordinate gaps in our understanding and scientific facts concerning the activity, expression, downstream signaling pathway and participation of different molecules of TNF superfamily at various platforms of the immune response and over the progression of autoimmune as well as inflammatory diseases. Essentially it is to be resolved that upto what extent these receptors exhibit similarity or dissimilarity among one another in relation to their signalling complexes, difference in cellular responses and disease progression. Upon focusing to the therapy, it is still not well established that which ligand-receptor pair will be the best target for each particular disease conditions. In addition to this, various successful preclinical studies have been conducted in murine models which need their translation to corresponding human conditions. By playing a pivotal role in the cytokine mediator system both peripherally and centrally TNF superfamily certainly has become titan in researches concerning neurological disorders and will make it easier for researchers and scientists to develop various kinds of novel drugs in near future.
|
REFERENCES |
1: Al-Lamki, R.S., J. Wang, P. Vandenabeele, J.A. Bradley and S. Thiru et al., 2005. TNFR1-and TNFR2- mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J., 19: 1637-1645. CrossRef | Direct Link |
2: Al-Lamki, R.S., T.J. Sadler, J. Wang, M.J. Reid and A.Y. Warren et al., 2010. Tumor necrosis factor receptor expression and signaling in renal cell carcinoma. Am. J. Pathol., 177: 943-954. CrossRef | PubMed | Direct Link |
3: Arnett, H.A., J. Mason, M. Marino, K. Suzuki, G.K. Matsushima and J.P. Ting, 2001. TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci., 4: 1116-1122. CrossRef | PubMed | Direct Link |
4: Ashkenazi, A. and V.M. Dixit, 1998. Death receptors: Signaling and modulation. Science, 281: 1305-1308. Direct Link |
5: Bach, E.A., M. Aguet and R.D. Schreiber, 1997. The IFN-γ receptor: A paradigm for cytokine receptor signaling. Annu. Rev. Immunol., 15: 563-591. PubMed | Direct Link |
6: Balkwill, F., 2006. TNF-α in promotion and progression of cancer. Cancer Metastasis Rev., 25: 409-416. CrossRef | PubMed | Direct Link |
7: Behrendt, A.K. and G. Hansen, 2010. CD27 costimulation is not critical for the development of asthma and respiratory tolerance in a murine model. Immunol. Lett., 133: 19-27. CrossRef | Direct Link |
8: Bradley, J.R., 2008. TNF-mediated inflammatory disease. J. Pathol., 214: 149-160. CrossRef | PubMed | Direct Link |
9: Castro, J.E., J.A. Listman, B.A. Jacobson, Y. Wang and P.A. Lopez et al., 1996. Fas modulation of apoptosis during negative selection of thymocytes. Immunity, 5: 617-627. CrossRef | Direct Link |
10: Chang, J.H., Y.S. Ryang, T. Morio, S.K. Lee and E.J. Chang, 2004. Trichomonas vaginalis inhibits proinflammatory cytokine production in macrophages by suppressing NF-kappaB activation. Mol. Cells, 18: 177-185. PubMed |
11: Chaudhari, U., P. Romano, L.D. Mulcahy, L.T. Dooley, D.G. Baker and A.B. Gottlieb, 2001. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomized trial. Lancet, 357: 1842-1847. CrossRef | PubMed |
12: Chauhan, R.S. and K. Dhama, 2008. Cowpathy in induction of cytokines and its importance in control of human and animal diseases. Ibid, Souvenir, pp: 117-121
13: Clark, J., P. Vagenas, M. Panesar and A.P. Cope, 2005. Structural and functional footprints of the tnf/tnf-r superfamily. Ann. Rheum. Dis., 64: iv70-iv76.
14: Croft, M., 2003. Co-stimulatory members of the TNFR family: Keys to effective T-cell immunity? Nat. Rev. Immunol., 3: 609-620. CrossRef | PubMed | Direct Link |
15: Croft, M., 2003. Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine Growth Factor Rev., 14: 265-273. CrossRef | Direct Link |
16: Croft, M., 2009. The role of TNF superfamily members in T-cell function and diseases. Nat. Rev. Immunol., 9: 271-285. CrossRef | PubMed | Direct Link |
17: Croft, M., 2010. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol., 28: 57-78. CrossRef | PubMed | Direct Link |
18: Croft, M., W. Duan, H. Choi, S. Eun, S. Madireddi and A. Mehta, 2012. TNF superfamily in inflammatory disease: Translating basic insights. Trends Immunol., 33: 144-153. CrossRef | Direct Link |
19: Darnell, J.E.Jr., 1997. STATs and gene regulation. Science, 332: 1630-1633. PubMed | Direct Link |
20: Deb, R., S. Chakraborty, B.M. Veeregowda, A.K. Verma, R. Tiwari and K. Dhama, 2013. Monoclonal antibody and its use in the diagnosis of livestock diseases. Adv. Biosci. Biotechnol.
21: Dhama, K., R. Rathore, R.S. Chauhan and T. Simmi, 2005. Panchgavya: An overview. Int. J. Cow Sci., 1: 1-15.
22: Dhama, K., R.S. Chauhan and L. Singhal, 2005. Anti-cancer activity of cow urine: Current status and future directions. Int. J. Cow Sci., 1: 1-25.
23: Dhama, K. and R.S. Chauhan, 2008. Cytokines and the inflammatory responses: An overview. Proceedings of the Compendium of Training cum Workshop on Cytokine, February 26-27, 2008, Mathura, UP., India, pp: 17-33
24: Dhama, K., M. Mahendran, R.S. Chauhan and S. Tomar, 2008. Cytokines-Their functional roles and prospective applications in Veterinary practice: A review. J. Immunol. Immunopathol., 10: 79-89. Direct Link |
25: Dhama, K., A. Hansa and Anjaneya, 2011. Cytokine therapy for animal diseases: The perspectives. Livestock Line, Vol. 4.
26: Dhama, K., S. Chakraborty, Mahima, M.Y. Wani and A.K. Verma et al., 2013. Novel and emerging therapies safeguarding health of humans and their companion animals: A review. Pak. J. Biol. Sci., 16: 101-111. CrossRef | Direct Link |
27: Dolff, S., D. Quandt, B. Wilde, T. Feldkamp and F. Hua et al., 2010. Increased expression of costimulatory markers CD134 and CD80 on interleukin-17 producing T cells in patients with systemic lupus erythematosus. Arthritis Res. Ther., Vol. 12. CrossRef | Direct Link |
28: Esposito, E. and S. Cuzzocrea, 2009. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Curr. Med. Chem., 16: 3152-3167. PubMed | Direct Link |
29: Fang, L., B. Adkins, V. Deyev and E.R. Podack, 2008. Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J. Exp. Med., 205: 1037-1048. CrossRef | PubMed | Direct Link |
30: Fousteri, G., A. Dave, B. Morin, S. Omid, M. Croft and M.G. Von Herrath, 2011. Nasal cardiac myosin peptide treatment and OX40 blockade protect mice from acute and chronic virally-induced myocarditis. J. Autoimmun., 36: 210-220. CrossRef | PubMed | Direct Link |
31: Francois, R.J., L. Neure, J. Sieper and J. Braun, 2006. Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: detection of tumour necrosis factor alpha in two patients with early disease and transforming growth factor beta in three more advanced cases. Ann. Rheumat. Dis., 65: 713-720. PubMed | Direct Link |
32: Gabay, C. and I. Kushner, 1999. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med., 340: 448-454. CrossRef | PubMed | Direct Link |
33: Galuppo, M., G. Nocentini, E. Mazzon, S. Ronchetti and E. Esposito et al., 2011. The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice. Br. J. Pharmacol., 162: 1186-1201. CrossRef | PubMed | Direct Link |
34: Geiler, J., M. Buch and M.F. McDermott, 2011. Anti-TNF treatment in rheumatoid arthritis. Curr. Pharm. Des., 17: 3141-3154. PubMed | Direct Link |
35: Gillett, A., M. Marta, T. Jin, J. Tuncel and P. Leclerc et al., 2010. TNF production in macrophages is genetically determined and regulates inflammatory disease in rats. J. Immunol., 185: 442-450. CrossRef | PubMed | Direct Link |
36: Gottlieb, A.B., R. Evans, S. Li, L.M.T. Dooley and C.A. Guzzo et al., 2004. Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo controlled trial. J. Am. Acad. Dermatol., 51: 534-542. CrossRef | PubMed | Direct Link |
37: Haritunians, T., K.D. Taylor, S.R. Targan, M.D.M. Dubinsky and M.D.A. Ippoliti et al., 2010. Genetic predictors of medically refractory ulcerative colitis. Inflamm. Bowel Dis., 16: 1830-1840. CrossRef | PubMed | Direct Link |
38: Hotamisligil, G.S., N.S. Shargill and B.M. Spiegelman, 1993. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science, 259: 87-91. Direct Link |
39: Jung, J.H., Y.S. Chae, J.H. Moon, B.W. Kang and J.G. Kim et al., 2010. TNF superfamily gene polymorphism as prognostic factor in early breast cancer. J. Cancer Res. Clin. Oncol., 136: 685-694. CrossRef | PubMed | Direct Link |
40: Khare, S.D., I. Sarosi, X. Xia, S. McCabe and K. Miner et al., 2000. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc. Natl. Acad. Sci., 97: 3370-3375. PubMed | Direct Link |
41: Kodama, S., M. Davis and D.L. Faustmana, 2005. The therapeutic potential of tumor necrosis factor for autoimmune disease: A mechanistically based hypothesis. Cell. Mol. Life Sci., 62: 1850-1862. CrossRef | PubMed | Direct Link |
42: Lange, U., J. Teichmann and H. Stracke, 2000. Correlation between plasma TNFα, IGF-1, biochemical markers of bone metabolism, markers of inflammation/disease activity and clinical manifestations in ankylosing spondylitis. Eur. J. Med. Res., 5: 507-511. PubMed | Direct Link |
43: Lee, B.H., S.Y. Park, K.B. Kang, R.W. Park and I.S. Kim, 2002. NF-kappaB activates fibronectin gene expression in rat hepatocytes. Biochem. Biophys. Res. Commun., 297: 1218-1224. CrossRef | PubMed | Direct Link |
44: Leung, L. and C.M. Cahill, 2010. TNF-α and neuropathic pain: A review. J. Neuroinflammation, Vol. 7. CrossRef | Direct Link |
45: Lievens, D., A. Zernecke, T. Seijkens, O. Soehnlein and L. Beckers et al., 2010. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood, 116: 4317-4327. CrossRef | PubMed | Direct Link |
46: Locksley, R.M., N. Killeen and M.J. Lenardo, 2001. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell, 104: 487-501. CrossRef | PubMed | Direct Link |
47: Mahima, A. Rahal, R. Deb, S.K. Latheef and H.A. Samad et al., 2012. Immunomodulatory and therapeutic potentials of herbal, traditional/indigenous and ethnoveterinary medicines. Pak. J. Biol. Sci., 15: 754-774. CrossRef | Direct Link |
48: Mark, K.S., W.J. Trickler and D.W. Miller, 2001. Tumor necrosis factor-α induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J. Pharmacol. Exp. Ther., 297: 1051-1058. Direct Link |
49: Meylan, F., Y.J. Song, I. Fuss, S. Villarreal and E. Kahle et al., 2011. The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol., 4: 172-185. CrossRef |
50: Mukhopadhyay, S., J.R. Hoidal and T.K. Mukherjee, 2006. Role of TNFα in pulmonary pathophysiology. Respir. Res., Vol. 7. CrossRef | Direct Link |
51: Nawashiro, H., D. Martin and J.M. Hallenbeck, 1997. Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res., 778: 265-271. CrossRef |
52: Nguyen, Q.T., S.A. Ju, S.M. Park, S.C. Lee, H. Yagita, I.H. Lee and B.S. Kim, 2009. Blockade of CD137 signaling counteracts polymicrobial sepsis induced by cecal ligation and puncture. Infect. Immunity, 77: 3932-3938. CrossRef | Direct Link |
53: Nolte, M.A., R.W. van Olffen, K.P.J.M. van Gisbergen and R.A.W. van Lier, 2009. Timing and tuning of CD27-CD70 interactions: The impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol. Rev., 229: 216-231. CrossRef |
54: Oflazoglu, E., I.S. Grewal and H. Gerber, 2009. Targeting CD30/CD30L in Oncology and Autoimmune and Inflammatory Diseases. In: Therapeutic Targets of the TNF Superfamily, Grewal, I.S. (Ed.). Springer, New York, USA., ISBN-13: 9780387895192, pp: 174-185
55: Peters, A.L., L.L. Stunz and G.A. Bishop, 2009. CD40 and autoimmunity: The dark side of a great activator. Semin. Immunol., 21: 293-300. CrossRef | Direct Link |
56: Pfeffer, K., T. Matsuyama, T.M. Kundig, A. Wakeham and K. Kishihara et al., 1993. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell, 73: 457-467. CrossRef | Direct Link |
57: Rothe, J., W. Lesslauer, H. Lotscher, Y. Lang and P. Koebel et al., 1993. Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature, 364: 798-802. CrossRef |
58: Sands, B.E., F.H. Anderson, C.N. Bernstein, W.Y. Chey and B.G. Feagan et al., 2004. Infliximab maintenance therapy for fistulizing Crohn's disease. N. Engl. J. Med., 350: 876-885. CrossRef |
59: Shu, H.B., W.H. Hu and H. Johnson, 1999. TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J. Leukocyte Biol., 65: 680-683. Direct Link |
60: Siddiqui, S., V. Mistry, C. Doe, S. Stinson, M. Foster and C. Brightling, 2010. Airway wall expression of OX40/OX40L and interleukin-4 in asthma. Chest, 137: 797-804. CrossRef |
61: Sumi, T., W. Ishida, A. Ojima, M. Kajisako, T. Sakanishi, H. Yagita and A. Fukushima, 2008. CD27 and CD70 do not play a critical role in the development of experimental allergic conjunctivitis in mice. Immunol. Lett., 119: 91-96. CrossRef |
62: Sun, X., S. Somada, K. Shibata, H. Muta and H. Yamada et al., 2008. A critical role of CD30 ligand/CD30 in controlling inflammatory bowel diseases in mice. Gastroenterology, 134: 447-458. CrossRef |
63: Sun, X., H. Yamada, K. Shibata, H. Muta and K. Tani et al., 2010. CD30 ligand is a target for a novel biological therapy against colitis associated with Th17 responses. J. Immunol., 185: 7671-7680. CrossRef |
64: Szlosarek, P.W. and F.R. Balkwill, 2003. Tumour necrosis factor α: A potential target for the therapy of solid tumours. Lancet Oncol., 4: 565-573. CrossRef | Direct Link |
65: Tansey, M.G. and D.E. Szymkowski, 2009. The TNF superfamily in 2009: New pathways, new indications and new drugs. Drug Discovery Today, 14: 1082-1088. CrossRef |
66: Taylor, L., M. Bachler, I. Duncan, S. Keen and R. Fallon et al., 2002. In vitro and in vivo activities of OX40 (CD134)-IgG fusion protein isoforms with different levels of immune-effector functions. J. Leukocyte Biol., 72: 522-529. Direct Link |
67: Thompson, A.E., S.W. Rieder and J.E. Pope, 2011. Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheumatism, 63: 1479-1485. CrossRef |
68: Tizard, I.R., 2004. Cytokines and the Immune System. In: Veterinary Immunology: An Introduction, Tizard, I.R. (Ed.). 7th Edn. Saunders, Pennsylvania, USA., pp: 133-144
69: Tracey, D., L. Klareskog, E.H. Sasso, J.G. Salfeld and P.P. Tak, 2008. Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacol. Ther., 117: 244-279. CrossRef | Direct Link |
70: Tracey, K.J. and A. Cerami, 1994. Tumor necrosis factor: A pleiotropic cytokine and therapuetic target. Annu. Rev. Med., 45: 491-503. CrossRef |
71: Tremelling, M., C. Berzuini, D. Massey, F. Bredin and C. Price et al., 2008. Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population. Inflamm. Bowel Dis., 14: 733-737. CrossRef |
72: Tyring, S., K.B. Gordon, Y. Poulin, R.G. Langley, A.B. Gottlieb, M. Dunn and A. Jahreis, 2007. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol., 143: 719-726. CrossRef |
73: Watkins, L.R., S.F. Maier and L.E. Goehler, 1995. Immune activation: The role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain, 63: 289-302. CrossRef |
74: Wolfe, F. and K. Michaud, 2004. Heart failure in rheumatoid arthritis: Rates, predictors and the effect of anti-tumor necrosis factor therapy. Am. J. Med., 116: 305-311. CrossRef | PubMed |
75: Yang, J., Y. Chu, X. Yang, D. Gao and L. Zhu et al., 2009. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum., 60: 1472-1483. CrossRef |
76: Zhang, J., X. Wang, H. Fahmi, S. Wojcik and J. Fikes et al., 2009. Role of TL1A in the pathogenesis of rheumatoid arthritis. J. Immunol., 183: 5350-5357. CrossRef |
77: Zhang, Z., W. Zhong, D. Hinrichs, X. Wu and A. Weinberg et al., 2010. Activation of OX40 augments Th17 cytokine expression and antigen-specific uveitis. Am. J. Pathol., 177: 2912-2920. CrossRef |
78: Zimmerer, J.M., P.H. Horne, L.A. Fiessinger, M.G. Fisher, T.A. Pham, S.L. Saklayen and G.L. Bumgardner, 2012. Cytotoxic effector function of CD4-independent, CD8+ T cells is mediated by TNF-α/TNFR. Transplantation, 94: 1103-1110. CrossRef | Direct Link |
|
|
|
 |