gastrointestinal ( gi ) autoimmune diseases are characterized by the uninhibited immune response in the gi tract .
these diseases are characterized by an increased number of mononuclear cells in the intestinal epithelium , which can lead to destruction of intestinal crypts .
some common gi autoimmune diseases are crohn 's disease and ulcerative colitis , commonly known as inflammatory bowel disease ( ibd ) .
recently published data show that the incidence of ibd is the highest in canada , and direct costs alone in the healthcare system amount to $ 1.8 billion . as such
researchers have yet to answer what prompts the imbalance between tolerance and immune response leading to ibd . lately , ox40-ox40l interactions have come to light as potential treatment targets .
ox40l is part of the tumor necrosis family , expressed on antigen presenting cells ( apcs ) ( dendritic cells , macrophages , and b - cells ) , vascular endothelial cells , mast cells , natural killer cells , and on some t - cells .
the interaction of ox40 and ox40l plays a crucial role in clonal expansion of antigen - specific t - cells .
ox40l is also important in determining the amount of memory t - cells remaining after the immune response.[57 ] ox40l - ox40 interaction has been implicated in various inflammatory autoimmune diseases through many different animal models .
however , it is important to recognize that ox40l - ox40 interactions are important for normal immune response as well .
activation of ox40l produces anti - apoptotic proteins that aid in the survival and proliferation of t - memory cells .
co - stimulatory signals delivered through ox40 have been implicated in selectively promoting the differentiation of t - helper ( th)-2 cells , and help prolong antigen - specific proliferative response .
ox40-deficient mice are shown to have impaired t - cell proliferation , even though the initial nave t - cell response remains unimpaired .
these mice have also exhibited lower levels of anti - apoptotic protein : bcl-2 and bcl - xl .
this implies that ox40 's role is mainly in sustaining the immune response , and that ox40 indeed has a non - pathological role as well .
however , in normal mice , ox40-positive cells are observed only in lymphoid tissues , including peyer 's patches of the gut . in pathological condition ,
as demonstrated by mice with hapten - induced colitis or interleukin ( il)-2 knockout mice with spontaneous colitis , ox40-positive cells are found in the lamina propria .
when ox40 takes on a pathogenic role , it reactivates pre - existing self - reactive t - cells through constitutive activity.[51316 ] ox40 also starts to repress regulatory t - cells ( t regs ) , which is responsible for toning down the immune response , contributing to the balance between tolerance and immunity .
experiments conducted have shown that when anergic self - reactive t - cells are introduced in a host along with ox40 agonist , the self - reactive t - cells are activated from their anergic state , resulting in autoimmunity .
this statement is further supported by the administration of anti - ox40l monoclonal antibody , which reduced the clinical and histopathological disease . in vivo treatment with anti - ox40l antibodies
decreased t - cell inflltration in the colon and suppressed the production of primary inflammatory cytokines : interferon ( ifn)- , il-2 , and tumor necrosis factor ( tnf)- in the lamina propria . combining this treatment with anti - tnf- antibodies further improved the therapeutic effect by further reducing ifn- , il-2 , and tnf- production .
in addition to animal models , many association studies have been done with ibd patients that have shown higher expression of ox40 .
ox40 signals are known to be transmitted through tnf receptor  associated factors ( trafs ) .
traf2 and traf5 activate the nuclear factor kappa - b ( nf-b ) signalling pathway through ib kinase pathway  though this has yet to be proven .
recent studies have shown that traf2 is critical to ox40 signalling pathway , as traf2-deficient mice did not have the same degree of effector and memory t - cell generation as the wild - type .
the role of traf3 and traf5 is still unclear and needs to be investigated further .
ox40 also induces the expression of anti - apoptotic bcl-2 family members : bcl-2 , bcl - xl , and bfl-1 , which directly correlates with activity of nf-b1 as well .
this gives strong proof that nf-b pathway as known to researcher now is involved in ox40 signalling pathway .
overall , the bcl-2 family ensures that the cd4 t - cells do not undergo apoptosis after the immediate immune response , proven by studies showing that bcl-2-deficient mice failed to maintain high levels of cd4 t - cells 4 - 8 days after activation . ox40
signalling also maintains the active form of protein kinase b. protein kinase b leads to the expression of survivin , which is a member of the inhibitor of apoptosis ( iap ) family and regulates the division of t - cells .
pi3k connects this pathway to several cyclin - dependant kinases , such as cyclin a , which are involved in cell cycle progression . through a pathway , which may be linked to pi3k
, ox40 also increases the influx of ca in cd4 t - cells , leading to dephosphorylation and nuclear entry of transcription factors known as nuclear factor of activated t - cells ( nfats ) , which regulate the production of cell cytokines .
ox40 activation also downregulates cytotoxic t - lymphocyte antigen 4 ( ctla-4 ) , foxp3 , and interleukin ( il)-4 .
the decreased levels of these molecules , which are inhibitory in nature , lead to a strong response from t - cells helping them survive and proliferate .
it is believed that ox40 interaction also leads to elongation of mrna half - life , thus allowing more cytokines to be expressed .
considering the role that ox40 plays in the inflammatory immune response , it has the potential to treat some debilitating diseases . however , when using ox40 or ox40l as a possible treatment target , it is important to realize that at this point , researchers do not know what makes ox40 signalling 
one answer , though not complete , is provided by tslp , which is produced by mucosal epithelial cells or skin cells in response to allergens .
however , unlike regular dcs , these tslp - activated dcs express ox40l , which leads to the differentiation of nave t - cells into inflammatory th2 cells , and these do not produce il-10 , but produce tnf- instead .
papers indicate that both tslp and ox40 can induce inflammatory diseases in recombination activating gene-2 ( rag-2)deficient mice , indicating that the two molecules may share a common signalling pathway .
since tslp - activated dcs will produce inflammatory response , tslp can be viewed as a target for treatment that will implicitly remove inflammatory ox40 signalling . considering the above ,
even though ox40 and ox40l may seem to be a tempting target for curing all kinds of inflammatory disease , it is important to remember that ox40 has a normal role in the human body as well .
ox40-deficient mice did not show any severe side effects ; however , there were defects in t - cell proliferation and cellular immunity .
these side effects can not be risked when considering possible clinical applications of the ox40l - ox40 axis .
another question that arises is how ox40 or tslp can be knocked down in humans .
furthermore , there are many things that are still unclear in the ox40l - ox40 signalling pathway .
for example , the extent of involvement of nf-b and pi3k , which are molecules important for many other cell functions as well .
another thing that is unclear is whether it is ox40 's inhibition or ox40l 's inhibition that will lead to desired results .
a study found that using ox40l antibodies did not inhibit ibd , whereas using ox40 antibodies did .
overall , changing ox40l - ox40 interactions may be tempting ; however , the target of this change needs to be investigated .
ox40l - ox40 interaction has been implicated in various inflammatory autoimmune diseases through many different animal models .
however , it is important to recognize that ox40l - ox40 interactions are important for normal immune response as well .
activation of ox40l produces anti - apoptotic proteins that aid in the survival and proliferation of t - memory cells .
co - stimulatory signals delivered through ox40 have been implicated in selectively promoting the differentiation of t - helper ( th)-2 cells , and help prolong antigen - specific proliferative response .
ox40-deficient mice are shown to have impaired t - cell proliferation , even though the initial nave t - cell response remains unimpaired .
these mice have also exhibited lower levels of anti - apoptotic protein : bcl-2 and bcl - xl .
this implies that ox40 's role is mainly in sustaining the immune response , and that ox40 indeed has a non - pathological role as well .
however , in normal mice , ox40-positive cells are observed only in lymphoid tissues , including peyer 's patches of the gut . in pathological condition ,
as demonstrated by mice with hapten - induced colitis or interleukin ( il)-2 knockout mice with spontaneous colitis , ox40-positive cells are found in the lamina propria .
when ox40 takes on a pathogenic role , it reactivates pre - existing self - reactive t - cells through constitutive activity.[51316 ] ox40 also starts to repress regulatory t - cells ( t regs ) , which is responsible for toning down the immune response , contributing to the balance between tolerance and immunity .
experiments conducted have shown that when anergic self - reactive t - cells are introduced in a host along with ox40 agonist , the self - reactive t - cells are activated from their anergic state , resulting in autoimmunity .
this statement is further supported by the administration of anti - ox40l monoclonal antibody , which reduced the clinical and histopathological disease . in vivo treatment with anti - ox40l antibodies
decreased t - cell inflltration in the colon and suppressed the production of primary inflammatory cytokines : interferon ( ifn)- , il-2 , and tumor necrosis factor ( tnf)- in the lamina propria . combining this treatment with anti - tnf- antibodies further improved the therapeutic effect by further reducing ifn- , il-2 , and tnf- production .
in addition to animal models , many association studies have been done with ibd patients that have shown higher expression of ox40 .
ox40 signals are known to be transmitted through tnf receptor  associated factors ( trafs ) .
traf2 and traf5 activate the nuclear factor kappa - b ( nf-b ) signalling pathway through ib kinase pathway  though this has yet to be proven .
recent studies have shown that traf2 is critical to ox40 signalling pathway , as traf2-deficient mice did not have the same degree of effector and memory t - cell generation as the wild - type .
the role of traf3 and traf5 is still unclear and needs to be investigated further .
ox40 also induces the expression of anti - apoptotic bcl-2 family members : bcl-2 , bcl - xl , and bfl-1 , which directly correlates with activity of nf-b1 as well .
this gives strong proof that nf-b pathway as known to researcher now is involved in ox40 signalling pathway .
overall , the bcl-2 family ensures that the cd4 t - cells do not undergo apoptosis after the immediate immune response , proven by studies showing that bcl-2-deficient mice failed to maintain high levels of cd4 t - cells 4 - 8 days after activation .
ox40 signalling also maintains the active form of protein kinase b. protein kinase b leads to the expression of survivin , which is a member of the inhibitor of apoptosis ( iap ) family and regulates the division of t - cells .
pi3k connects this pathway to several cyclin - dependant kinases , such as cyclin a , which are involved in cell cycle progression . through a pathway , which may be linked to pi3k
, ox40 also increases the influx of ca in cd4 t - cells , leading to dephosphorylation and nuclear entry of transcription factors known as nuclear factor of activated t - cells ( nfats ) , which regulate the production of cell cytokines .
ox40 activation also downregulates cytotoxic t - lymphocyte antigen 4 ( ctla-4 ) , foxp3 , and interleukin ( il)-4 .
the decreased levels of these molecules , which are inhibitory in nature , lead to a strong response from t - cells helping them survive and proliferate .
it is believed that ox40 interaction also leads to elongation of mrna half - life , thus allowing more cytokines to be expressed .
considering the role that ox40 plays in the inflammatory immune response , it has the potential to treat some debilitating diseases .
however , when using ox40 or ox40l as a possible treatment target , it is important to realize that at this point , researchers do not know what makes ox40 signalling 
one answer , though not complete , is provided by tslp , which is produced by mucosal epithelial cells or skin cells in response to allergens .
however , unlike regular dcs , these tslp - activated dcs express ox40l , which leads to the differentiation of nave t - cells into inflammatory th2 cells , and these do not produce il-10 , but produce tnf- instead .
papers indicate that both tslp and ox40 can induce inflammatory diseases in recombination activating gene-2 ( rag-2)deficient mice , indicating that the two molecules may share a common signalling pathway .
since tslp - activated dcs will produce inflammatory response , tslp can be viewed as a target for treatment that will implicitly remove inflammatory ox40 signalling .
considering the above , even though ox40 and ox40l may seem to be a tempting target for curing all kinds of inflammatory disease , it is important to remember that ox40 has a normal role in the human body as well .
ox40-deficient mice did not show any severe side effects ; however , there were defects in t - cell proliferation and cellular immunity .
these side effects can not be risked when considering possible clinical applications of the ox40l - ox40 axis .
another question that arises is how ox40 or tslp can be knocked down in humans .
furthermore , there are many things that are still unclear in the ox40l - ox40 signalling pathway . for example , the extent of involvement of nf-b and pi3k , which are molecules important for many other cell functions as well . tampering with their signalling cascade can lead to other unforeseen side effects .
another thing that is unclear is whether it is ox40 's inhibition or ox40l 's inhibition that will lead to desired results
. a study found that using ox40l antibodies did not inhibit ibd , whereas using ox40 antibodies did .
overall , changing ox40l - ox40 interactions may be tempting ; however , the target of this change needs to be investigated .
ox40 signalling is pro - inflammatory , priming th2 to produce tnf-. however , even though the side effects in the ox40 deficient mice are little , there is no guarantee that side effects will not be present in humans .
hence , changing ox40l - ox40 signalling may result in a myriad of side effects through the complicated cellular pathways , demanding that caution be taken before doing any clinical trials .
 gastrointestinal ( gi ) autoimmune diseases have a high incidence in developed countries , such as canada and the us . 
 some common gi autoimmune diseases include ulcerative colitis and crohn 's disease . 
 these conditions are not only unpleasant for the patient , but also present a heavy burden on the healthcare system . 
 ox40l , a member of the tumor necrosis family , has been identified as a key player in the pathological inflammatory response , which characterizes gi autoimmune diseases . 
 ox40l is expressed in many cell types , including antigen presenting cells ( apcs ) , t - cells , vascular endothelial cells , mast cells , and natural killer cells . 
 the importance of ox40l - ox40 interactions in inflammatory autoimmune diseases is becoming more evident through different animal models , ranging from nematode models to mouse models . 
 this literature review attempts to summarize the current literature regarding the role of ox40l - ox40 interactions in gi autoimmune inflammatory diseases and comment on its potential for treatment . 
 various databases , including ovid medline and pubmed were used to retrieve articles regarding the role of ox40l - ox40 interactions in the pathogenesis of autoimmune diseases . 
 these articles were then reviewed and summarized in a comprehensive manner . 
 ox40l - ox40 interactions have a strong potential for becoming a treatment target ; however , there are still many gaps in the present knowledge , which need to be addressed before more definitive treatments can emerge . 
 it is also suggested that upstream events leading to ox40l activation , such as thymic stromal lymphopoietin ( tslp)-activated dendritic cells , be explored as treatment targets as well . 
 ox40l - ox40 interaction is a possible venue for treatment of gi diseases ; however , the underlying mechanisms of actions and the downstream effects of ox40l knock down need to be investigated . 
Introduction
Roles of OX40-OX40L interactions in GI autoimmune diseases
Signal transduction pathway
Treatment potential of OX40-OX40L axis
Potential roadblocks in using OX40L-OX40 axis
Conclusion