Human leukocyte antigens.docx

7/26/2019 Human leukocyte antigens.docx

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Human Leukocyte Antigens (HLA) Associated Drug

Hypersensitivity : Consequences of Drug Binding to HLA

Astract

Recent publications have shown that certain human leukocyte antigen (HLA) alleles arestrongly associated with hypersensitivity to particular drugs. As HLA molecules are a critical

element in T-cell stimulation it is no surprise that particular HLA alleles have a direct

!unctional role in the pathogenesis o! drug hypersensitivity. "n this conte#t a direct

interaction o! the relevant drug with HLA molecules as described by the p-i concept appears

to be more relevant than presentation o! hapten-modi!ied peptides. "n some HLA-associated

drug hypersensitivity reactions the presence o! a risk allele is a necessary but incomplete

!actor !or disease development. "n carbama$epine and HLA-%&'*+ certain T-cell receptor

(T,R) repertoires are reuired !or immune activation. This additional reuirement may be

one o! the missing links/ in e#plaining why most individuals carrying this allele can tolerate

the drug. "n contrast abacavir generates polyclonal T-cell response by interacting speci!ically

with HLA-%&0*' molecules. T cell stimulation may be due to presentation o! abacavir or o!

altered peptides. 1hile the presence o! HLA-%&2*' allele substantially increases the risk o!

allopurinol hypersensitivity it is not an absolute reuirement suggesting that other !actors

also play an important role. "n summary drug hypersensitivity is the end result o! a drug

interaction with certain HLA molecules and T,Rs the sum o! which determines whether the

ensuing immune response is going to be harm!ul or not.

Adverse drug reactions (A3Rs) are a ma4or cause o! morbidity and mortality worldwide. 5p

to a third o! A3Rs are attributable to unpredictable drug hypersensitivity and a signi!icant

proportion o! these are immune mediated. 3rug-speci!ic T cells are !reuently involved in the

pathogenesis and a growing number o! drug hypersensitivity reactions are !ound inassociation with human leukocyte antigen (HLA) alleles. 6trongest associations have been

described !or abacavir hypersensitivity syndrome and !luclo#acillin-induced hepatoto#icity

with HLA-%&0*' carbama$epine-induced 6tevens78ohnson syndrome9to#ic epidermal

necrolysis (6869T:;) with HLA-%&'*+ in Han ,hinese and allopurinol-induced H, " molecules so !ar. ,omprehensive lists o! these

associations have been published elsewhere and will not be reproduced here. This review will

!ocus on using these HLA associations as models to e#plain how drugs can stimulate T cells.

!mmunopat"o#ogy of $ ce##%&ediated Drug

Hypersensitivity

Hapten9pro-hapten and p-i (pharmacological interactions o! drugs with immune receptors)

concepts are crucial in understanding how a drug activates the immune system and initiates

delayed-type hypersensitivity by activating T cells. These concepts have been e#tensively

reviewed elsewhere and will be discussed brie!ly here.

%ecause a typical drug is not antigenic on its own because o! its small si$e it must !irst bind

to a high molecular weight protein to be immunogenic. A stable covalent binding o! a

chemically reactive drug to a larger protein or peptide is then able to !orm a neoantigenwhich can be recogni$ed directly via immunoglobulin or by T cells a!ter undergoing antigen


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processing o! the hapten7carrier comple#. The chemical properties o! hapten-like drugs are

crucial !or the generation o! antigenic epitopes and activation o! the innate immune system.

6ome haptens like beta-lactam antibiotics have a tendency to bind to particular amino acids

and this has been well characteri$ed !or penicillin that has a propensity to bind to lysine

residues. Theoretically this generates many di!!erent new antigenic determinants owing to a

vast array o! available lysine residues in target proteins in vivo. ,onseuently the elicitedimmune responses are e#pected to be variable and penicillins are indeed known to cause

both predominant antibody responses and delayed-type T-cell responses. However recent

reports have shown that piperacillin can bind up to '? o! @ lysine residues in human serum

albumin indicating that there are some pre!erential


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Dne should be aware that these distinctions between covalent and noncovalent binding are

not straight!orward in reality as both may occur together in vivo. The drugs known to interact

in p-i manner are also known to produce potentially reactive metabolites ('*). As there is a

paucity o! de!initive proo! on mass spectrometry or crystallography that HLA-restricted

drugs are covalently bound to a carrier and as the direct binding o! a drug to the T,R or>H, molecule o!ten relies on indirect evidence the controversy surrounding the immune

mechanisms involved will likely persist !or some time. The drug-speci!ic immune response

i! restricted to T cells may be clinically similar in both cases as ultimately drug-speci!ic T

cells are e#panded and are able to orchestrate the immune response and in!lammation.

'pidemio#ogy of HLA Association and Drug Hypersensitivity

The development o! drug hypersensitivity depends on both genetic and environmental !actors

(Table +). Among genetic !actors HLA alleles play an important role (Table '). This is

particularly well illustrated by abacavir and its association with HLA-%&0*' allele.

"ndividuals with this allele have appro#imately a *E chance o! developing abacavirhypersensitivity syndrome while no one without this allele is predicted to develop an

immunologically con!irmed hypersensitivity reaction (+*). ,onseuently the guidelines

recommend that the presence o! HLA-%&0*' allele should be e#cluded be!ore initiating

antiretroviral therapy with abacavir representing one o! the !irst success!ul e#amples o!

personali$ed medicine (+'). Likewise 5nited 6tates ood and 3rug Administration have

issued warnings !or carbama$epine stating that HLA-%&'*+ allele should be checked prior

to its initiation in patients with ancestry !rom the areas in which this allele is present. Dn the

other hand even though the association between !luclo#acillin and HLA-%&0*' allele is

very strong because o! its low positive predictive value (FFG) routine testing is not

recommended.

These HLA associations with severe mani!estations o! drug hypersensitivity are intriguing

!indings because o! their e#clusive restrictions. HLA-%&0*' molecule is closely related to

HLA-%&2*' molecule as they only di!!er by a !ew amino acid residues and both belong to

HLA-%'0 serotype. They also share a number o! potential peptides that can bind to >H,

grooves. However abacavir hypersensitivity and allopurinol hypersensitivity are e#clusively

associated with HLA-%&0*' allele and HLA-%&2*' allele respectively. "n contrast

HLA-%&'*+ molecule and HLA-A&?'*' molecule are structurally remote but are both

associated with carbama$epine hypersensitivity. The reasons !or these parado#ical !indings

are yet to be elucidated.

A number o! studies have been conducted across various ethnic groups and some o! these

have concluded that drug hypersensitivity and HLA association are dependent on ethnicity

(++ +?). Linkage diseuilibrium has been considered as a potential e#planation !or these

discrepancies but di!!erences in allele !reuencies (A) must also be taken into account. or

e#ample in the Han ,hinese population carbama$epine-induced 6869T:; is strongly

associated with HLA-%&'*+ (DR '?0) (B). However this association was not !ound in

:uropean or 8apanese studies where the prevalence o! this allele is I'E and *.'E

respectively (Table ?). :ven though the risk o! developing carbama$epineinduced 6869T:; is

substantially higher !or those who carry this allele these studies likely !ailed to pick up this

association as the A is very low in these cohorts. Dn the other hand carbama$epine

hypersensitivity is !ound to be associated with HLA-A&?'*' (DR +.@?7??.@) in thesegroups where the A o! this gene is higher (Table ?) (+C +B). "nterestingly HLA-A&?'*'


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allele was also identi!ied by Hung et al. to be associated with carbama$epine-induced

maculopapular e#anthem (>F:) in Han ,hinese. This is e#pected because Han ,hinese also

have the A o! '.2E !or HLA-A&?'*'.

The use!ulness o! predictive testing is also in!luenced by A. The association o! HLA-

%&0*' allele with abacavir hypersensitivity syndrome was mainly con!irmed in ,aucasianpopulations where the A is high. However the studies per!ormed in Taiwanese and Jorean

population where HLA-%&0*' is rare (I'E) showed that there were HLA-%&0*'-

negative patients with clinically suspected abacavir hypersensitivity (+0 +2). "n these

populations it is not clear whether HLA-%&0*' testing is clinically use!ul or not.

urthermore it must be noted that '**E sensitivity o! HLA-%&0*' testing !or abacavir

hypersensitivity was !ound a!ter eliminating the patch test7negative group but when

clinically diagnosed hypersensitivity reaction was used as the criterion the sensitivity became

much lower at C.E (+*). This discrepancy between patch test7positive and patch test7

negative patients was interpreted as a sign !or true or !alse/ immunemediated abacavir

hypersensitivity. However many variables may play a role in patch test reactions and a

negative patch test does not necessarily e#clude an immune-mediated mechanism

!mmuno#ogy of Aacavir Hypersensitivity in HLAB*+:,- % .nique !nteraction of

Drug /it" HLA

Abacavir hypersensitivity syndrome is mani!ested clinically by a combination o! !ever rash

malaise nausea vomiting and diarrhea and it can sometimes be !atal upon rechallenge. The

!irst discovery o! its association with HLA-%&0*' allele appro#imately '* years ago was an

e#citing development !or drug hypersensitivity research (? ?*). %ecause o! its narrow HLA

restriction and high FFG o! C0.@E it provides a uniue model to study the pathogenesis o!

drug hypersensitivity.

An initial study by>artin et al. (?') suggested an involvement o! the innate immune system

in abacavir hypersensitivity reactions whereby abacavir activates antigen-presenting cells

(AF,) via H6F0*-mediated Toll-like receptor pathway. However there have been no !urther

reports that con!irm this !inding. The generation o! abacavir-speci!ic T-cell lines !rom

abacavir-naKve HLA-%&0*'-positive donors demonstrated that abacavir-speci!ic T cells

reuire HLA-%&0*' molecule !or activation. The restriction to HLA-%&0*' was

e#clusive as ,32 T cell7driven drug-speci!ic response was abolished i! HLA%& 0*' was

replaced by closely related HLA-%&0*? or even by a single crucial amino acid mutation.

This implies that a single amino acid in HLA-%&0*' may be the determining !actor in the

development o! abacavir hypersensitivity.

%ecause abacavir reactivity was considered to be TAF and tapasin dependent it was

suggested that processing is reuired !or abacavir presentation (+@). "n this model abacavir or

its metabolite would be hapteni$ed to a protein that then undergoes processing be!ore it is

loaded onto the HLA%&0*' peptide-binding groove. Met this hypothesis does not e#plain

the e#treme selectivity !or HLA-%&0*' because this pool o! potentially generated

abacavir-modi!ied peptides would likely be loaded onto various other >H, " molecules. An

alternative e#planation that reconciled the e#clusive association o! HLA-%&0*' molecule

with abacavir reactivity and the reuirement !or TAF and tapasin was recently illustrated by

Adam et al. (??). Their study demonstrated that T-cell reactivity to abacavir was determined

by the T,R avidity !or the drug. %ecause o! the diminished e#pression o! >H, " on TAF andtapasin-de!icient cells Tcell reactivity to abacavir was there!ore very likely reduced as well.


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urthermore abacavir was shown to be neither metaboli$ed nor processed inside AF,. This

supports a noncovalent yet rather strong interaction o! abacavir molecules with HLA-

%&0*' which is consistent with p-i concept.

This noncovalent binding was lately veri!ied by modeling and crystallography data

demonstrating the incorporation o! abacavir into the anchor pocket o! HLA-%&0*' duringits !ormation (?C ?). This drug binding alters the landscape o! the peptide-binding cle!t

a!!ecting the potential peptide repertoire that is loaded onto this >H, " molecule (ig. +A%).

Feptide elution e#periments revealed that in addition to the usual %&0*' binding peptides

abacavir-treated HLA%&0*'-positive AF, presented also altered peptides compared to the

untreated control AF,. "n the absence o! abacavir HLA-%&0*' molecules particularly

displayed peptides with a tryptophan or phenylalanine at position @ !itting into the pocket

o! the HLA-%&0*' molecule. "n the presence o! the drug however some identi!ied

HLA%&0*'-embedded peptides bore smaller amino acid residues at position @

predominantly valine leucine or isoleucine. Thus the noncovalent >H, interaction o!

abacavir alters sel!-peptide loading onto HLA-%&0*' molecules. ,onseuently new

endogenous peptides are selected to be displayed on the cell sur!ace o! AF, and theseneoantigens then initiate polyclonal T-cell response to sel!-epitopes. This abacavir-induced

alteration in the presented peptide repertoire provides a novel e#planation !or drug-dependent

autoimmunity. Analogous to altered peptide repertoire by abacavir drug-a!!ected peptide

loading has been already described !or >H, class "" system by using compounds known as

>H, loading enhancer/ (>L:) (?0). These >L: can improve the trans!er o! peptides onto

>H, "" molecule resulting in an increased immune response in a manner similar to abacavir

that increases the loading o! peptides with valine leucine or isoleucine at ,-terminus.

However it remains to be determined to what e#tent this phenomenon contributed to the

disease mani!estation in abacavir hypersensitivity and whether it can be generali$ed to other

HLAassociated drug hypersensitivity reactions.

Although the altered peptide hypothesis outlined above provides a novel possible e#planation

!or abacavir-induced hypersensitivity reactions the suggested model does not consider the

!ull spectrum o! this speci!ic allergic response. The study !rom Adam et al. (??) revealed that

appro#imately C*E o! all analy$ed abacavir-speci!ic T-cell clones (T,,) reacted

immediately or very !ast (I+7 min) to the addition o! abacavir in solution (Adam 8 Merly 3

and Fichler 18 unpublished data). This is too !ast to allow peptide loading and presentation

strongly suggesting that at least part o! abacavir- speci!ic T,, react with abacavir itsel! and

not an altered peptide. "nterestingly the very same immediately reacting clones were also

stimulated by AF, that were abacavir-treated !or more than '+ h a!ter which abacavir in

solution was removed. How these clones can recogni$e immediately presented abacavir onthe AF, sur!ace and a!ter a long incubation remains to be determined. The possibilities o!

how abacavir could be directly recogni$ed are illustrated in ig. +,. The drug could !or

e#ample bind to incompletely/ !illed HLA-%&0*' molecule or even empty molecule.

Alternatively abacavir may be recogni$ed by T,R in the presence o! sel!-peptides. However

these possibilities need to be proven.

!mmuno#ogy of Carama0epine Hypersensitivity in HLAB-*:,1 % Comp#e2

!nteractions of a Drug /it" $C3and HLA A##e#e


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As mentioned above HLA-%&'*+ allele has been strongly associated with carbama$epine-

induced 6869T:; in Han ,hinese. 1hy HLA-%&'*+ is a risk !actor !or only 6869T:; and

not 3R:66 or >F: is unknown. "t is tempting to hypothesi$e that because 6869T:;

3R:66 and >F: are distinct clinical mani!estations HLA-%&'*+ molecule is only able to

recruit T cells with speci!ic phenotypes. However this e#planation is inadeuate as HLA-%&?'*' allele is associated with carbama$epine-induced 6869T:; 3R:66 and >F:. "n

!act this association with di!!erent clinical mani!estations points to the possibility that these

clinical entities must somehow share common !eatures in drug T,R and HLA interactions.

Analogous to abacavir and HLA-%&0*' carbama$epine interacts speci!ically with HLA-

%&'*+ molecules. However it was !ound that other structurally related HLA-%0 !amily

members can also present carbama$epine (?2). This interaction is processing and metabolism

independent in a manner that is most consistent with the p-i concept (?@). The study by Jo et

al. shed !urther light on this sub4ect by showing that in addition to the HLA allele the

availability o! T,R is crucial !or the development o! carbama$epine-induced 6869T:;. They

!ound that two most immunodominant ,3R? clonotypes o! T,R G%-''-"6N6M and G%-''-NLANG3; were shared among !ive and two o! the eight patients with

carbama$epineinduced 6869T:; respectively. urther analysis revealed that these clonotypes

could be !ound in F%>, or blister cells o! patients with carbama$epine-induced 6869T:;

but not in carbama$epine-tolerant control sub4ects including those with HLA-%&'*+ allele.

"nterestingly these clonotypes were present at a low !reuency (07'CE) in healthy sub4ects

with HLA%&'*+ alleles. 1hen F%>, !rom these healthy individuals were cultured with

carbama$epine in vitro carbama$epine-speci!ic T-cell response could be demonstrated

whereas this could not be obtained in HLA-%&'*+-positive donors who do not have these

clonotypes. Thus this study provides strong evidence that in addition to the associated HLA

allele particular T,R also play a role in the development o! the immune response against

carbama$epine.

This !inding may e#plain at least in part why most individuals with HLA-%&'*+ allele do

not develop carbama$epine hypersensitivity. This is in sharp contrast to abacavir

hypersensitivity and HLA-%&0*' allele where drug-speci!ic T cells were reported to

contain multiple T,R clonotypes without shared T,R variable beta gene usages between

individuals implying that particular seuences o! T,R do not appear to play a ma4or role. "n

summary the available repertoire o! T,R in combination with HLA-%&'*+ is a risk !actor

!or carbama$epine-induced 6869T:; but this reuirement !or T,R does not seem to be the

case !or abacavir hypersensitivity and HLA-%&0*'. %ecause this additional prereuisite is

not reuired !or the generation o! abacavir-speci!ic T cells it should be no surprise that theFFG !or HLA- %&0*' allele is higher than that !or HLA-%&'*+.

A##opurino# Hypersensitivity and HLAB*4:,- % 5ne Association for Diverse

&anifestations

HLA-%&2*' allele is strongly associated with allopurinolinduced 6869T:;. 1hile the

initial study by Hung et al. did not analy$e allopurinol-induced 6869T:; and 3R:66

separately more than hal! o! the patients in that study had 3R:66 and all o! them were !ound

to have the HLA%&2*' allele making it highly likely that allopurinolinduced 3R:66 is

also associated with HLA-%&2*'. This strong association with allopurinol-induced 3R:66

was also con!irmed in a Jorean study (C'). As is the case !or HLAA&?'*' andcarbama$epine-induced 6869T:; 3R:66 and >F: how one HLA allele restriction can


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mani!est itsel! in diverse clinical mani!estations is yet to be clari!ied. Howeverin contrast to

HLA-A&?'*' a recent Australian study !ound that none o! '+ patients with allopurinol-

induced >F: had HLA-%&2*' possibly hinting that this association may be limited to

more severe phenotypes.

1hat additional risk !actors could contribute to allopurinol hypersensitivityO Renal !ailurehas long been associated with this syndrome and this association appears to be maintained

even when HLA-%&2*' alleles were considered. "n addition a Jorean study o! patients

with chronic renal insu!!iciency taking allopurinol revealed that '2E (@9*) o! HLA-%2-

positive patients developed allopurinol-induced 6,AR (CC). This is much higher than the

previously estimated FFG o! +.0E with HLA-%&2*' (2). urthermore a recent study has

!ound that a daily dose o! +** mg or more was associated with an increased risk !or

6869T:;. Futting these together it can be speculated that either renal impairment or higher

dosage results in higher serum levels o! allopurinol and9or its metabolite o#ypurinol which

in turn increases the risk o! generating drug-speci!ic T cells.

"n addition to the availability o! drug levels and HLA associations viral in!ections have longbeen known to play a role in drug hypersensitivity. This is particularly relevant !or 3R:66 in

which the reactivation o! herpes virus seems to play a key role in its pathogenesis (CB C0).

According to the study by 3aubner et al. (C2) patients with multiple drug hypersensitivity

o!ten had 3R:66 and the drug-speci!ic T cells !rom these patients were !ound to have

preactivated T-cell phenotypes. There!ore it was suggested that this in vivo T-cell activation

is attributable to chronic stimulation by latent herpes viruses which result in upregulation o!

costimulatory molecules subseuently providing additional signals !or the generation o!

drug-speci!ic T cells upon e#posure. Alternative to this hypothesis the 8apanese group has

suggested that 3R:66 is mainly driven by antiviral T cells that can cross-react with drugs

(CB). inally Ficard et al. (C0) postulated that the culprit drug may somehow induce the

reactivation o! herpes viruses which then triggers an antiviral immune response. "n the

conte#t o! allopurinol-induced 3R:66 how viral reactivation HLA-%&2*' molecules and

allopurinol interact in the conte#t o! T cell7driven antiviral9antidrug immune responses is yet

to be elucidated.

As outlined above the available T,R repertoire is another important !actor !or drug

hypersensitivity. The T,R repertoire is highly variable and this is determined by T,R gene

rearrangements and thymic selection which in turn is also determined by >H, molecules

and sel!-peptide repertoires as well as by the history o! antigen load such as in!ections.

There!ore it is possible that a repertoire o! T,R reuired !or drugspeci!ic T-cell response is

deleted in the process o! negative selection as other HLA alleles may present sel!-peptides o!su!!icient a!!inity resulting in cell death. "! such protective/ HLA alleles were absent then

the risk o! developing drug hypersensitivity would be higher. Dn the other hand the converse

may also be true and the potentially dangerous T,R repertoire may be selected in those with

risk alleles. "n support o! this hypothesis the association between proportion o! shared T,R

seuences and shared HLA class " alleles has been recently demonstrated (C@). urthermore

Josmrl4 et al. (*) showed that HLA alleles play an important role in T,R selection and

illustrated that those with HLA-%&0*' allele are likely to have more T cells that can cross-

react with mutants o! target epitopes. inally as a history o! in!ections in an individual can

a!!ect the pool o! circulating T,R repertoires this may also result in an e#pansion o! T cells

that react with a drug.


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There are other known risk !actors but whether they are also relevant !or HLA-associated

drug hypersensitivity is unknown (Table +). ,ombining these known risk !actors together the

!ollowing scenarios can be considered. The presence o! HLA-%&2*' allele alone is

inadeuate as although allopurinol itsel! may interact speci!ically with the >H, molecule

this in itsel! is insu!!icient to generate drugspeci!ic T cells (ig. ?A). This can e#plain why

the FFG is only +.0E (2). However when there is drug accumulation because o! an alterationin dosage or renal !ailure more allopurinol or o#ypurinol may be presented by HLA-%&2*'

molecules culminating in su!!icient signals !or T-cell activation (ig. ?%). This can be

postulated !rom the abacavir-speci!ic T,, data discussed above which shows that T,R

avidity determines Tcell reactivityP T cells with lower avidity will be recruited with

increasing concentration o! the drug (??). "n the absence o! HLA-%&2*' molecules the

chance o! developing allopurinol hypersensitivity is very low (ig. ?,). However i! a

concurrent herpes viral in!ection results in strong enough costimulation e#pansion o! cross-

reactive T cells or !avorable allopurinol interaction with viral peptide loaded on >H, "

molecules then this may be enough to generate drug-speci!ic T cells (ig. ?3). There!ore the

presence o! HLA-%&2*' allele is pre!erential but not essential !or the development o!

allopurinol hypersensitivity and the barrier !or the development o! drug hypersensitivity maybe overcome i! other risk !actors are present.

5t"er .nreso#ved !ssues and t"e 6uture Direction in HLA and Drug Hypersensitivity

3aly et al. (C) have recently identi!ied the association between HLA-%&0*' and

!luclo#acillin-induced hepatoto#icity. However as this study dealt e#clusively with

hepatoto#icity it is not known whether other mani!estations such as rash or nephritis are also

associated with %&0*' or not. ;onetheless as rash is not a prominent !eature o!

!luclo#acillin-induced hepatoto#icity why other target organs are spared remains a mystery

('). urthermore how HLA-%&0*' allele can be associated with hypersensitivity to two

structurally unrelated drugs with completely di!!erent clinical mani!estations is also

unknown. "n contrast to abacavir hypersensitivity the FFG o! !luclo#acillin-induced

hepatoto#icity is e#tremely low at *.'+E which implies that di!!erent mechanisms may be

involved in these disease mani!estations.

1ith increasing technology and sophisticated tools available to analy$e genes more HLA

associations with drug hypersensitivity are likely to emerge. "n addition advances in

computer modeling and screening tools will likely improve the prediction o! drug

hypersensitivity. "t is interesting to note that Mang et al. (+) were able to predict the

interaction o! HLA-%&0*' molecule with abacavir using a bioin!ormatics approach ratherthan in vivo or in vitro models. 6uch methods when coupled with e#perimental data will

prove to be invaluable tools !or drug hypersensitivity research and !or the pharmaceutical

industry.

Conc#usion

The recent discovery o! strong HLA associations with drug hypersensitivity has opened an

e#citing chapter in drug hypersensitivity research as it provides a uniue model to study drug

hypersensitivity. 1hile in vitro data so !ar have been limited comple# interactions o! drugs

with HLA molecules peptides and T,R are beginning to be understood. The role o!processing and direct interaction o! abacavir with HLA-%&0*' molecule have been both


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illuminating and pu$$ling particularly in view o! the recently described altered sel!-peptide

repertoire and T-cell reactivity kinetics (??7?B). The study o! HLA%&'*+ and its

pathogenic role in carbama$epine-induced 6869T:; has highlighted that the presence o!

particular ,3R? in T,R is also crucial in the immunopathogenesis. "n addition the

comple#ity o! allopurinol-induced 6,AR with its diverse clinical mani!estations in the

conte#t o! other relevant risk !actors such as viral in!ection will need !urther investigations.Dver the coming years it is likely that !urther evidence !or more comple# interactions

between drug and immune system will emerge demanding more holistic e#planations that

will reuire inputs !rom multiple disciplines. urther advances in this perple#ing !ield will

make these presently unpredictable reactions more predictable and preventable.

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Human leukocyte antigens.docx