Presidents Free Connnunications
`
`8 7
`
`WEDNESDAY. 9 APRIL 2003
`
`• L.-M. Stott 1
`
`• L. Ca irn s ' and
`
`258
`The induclion ol' lolerance lo J{hl) in HLA DR 15
`transgenic mice
`S. ). llrban iak l.2 . /\. M. ll a ll 1
`R. N. Barker '
`1 /JqmrlliiPIII of Mediri11e 1111rf Tlwrape111ics. U11iversii!J II( 1\ lwrrli'm. Ul\:
`2Smttisli Natio11al Hloorf Tmii.,/ilsinn SavitT. Alwrdt'l'il. Ul\
`Th e Rhl) prot ein is a cl inica lly im portant red cell ;dl oa nti gcn that
`induces the production o f anti-D in RhD-negalivc
`in d ividu a ls.
`Becau se of the immun ogeni cit y of Rhl). all blood don at ions arc
`typed a nd mat ched for thi s a nti gen. and l{ h D- neg<~l i v e wom en arc
`m;ma ged lor th e preven tio n o f haemoly ti c di sease of th e newborn
`wi th prophylact ic anti-IJ
`immunog lobulin.
`llndcrs tanding
`th e
`mechanism s by whic h helper T-ccl ls co ntrol
`th e antibody
`res pon se to Rh D wou ld enable the des ig n of a lt ernati ve slr<l tcgics
`such i!S active to leration . We have show n that CD-J.+ helper 'I'
`cells from ;dloimm u nized don o rs can pro liferate and produ ce both
`IFN-ga mm a <1nd
`IL--J.
`in respon se to sy nth eti c pc ptides derived
`from
`th e f{hiJ sequence.
`indi cat in g a ThO b;da nccd cy tokin e
`res pon se. Th e respon ses arc Il L!\ class II restricted. w ith II Li\ (cid:173)
`DR I 5 being over-represent ed in good responders. Certa in pe ptides
`<1rc imm unodominan t. and indu ce proli lera tive responses in most
`all o im mun ized donors. These peptides arc c<~ ndidatcs for
`th e
`indu ction o f toleran ce to th e RhD protein by th e mu cosal rout e.
`On
`t he oth er h and. som e pe ptides
`from
`th e HhD protein
`prele renti ;dl y indn cc IL- l 0 produc ti o n by putative Tr I regu l <~ t ory
`cell s ;, vitro. and th ese pcpt ides inhibit T-ccll prol ife r<llion
`in
`respon se to stimulation wi th purilicd RhU protein ill vitro. Th ese
`pcptid es may be u sed to ind uce toleran ce by th e pare nt eral rout e.
`We have used a IILi\-D IU 5 tran sgen ic m ou se m odel to sh ow th<~t
`'!'-cell s from mi ce imm u nized w ith t he Rhl) protein proli le ra te in
`respon se to purifi ed J{h l) prot ein a nd to Rh iJ pc ptides. and serum
`ant ihod ics spccilic for huma n cryt hrncytes arc
`;dso produ ced.
`Mucosa l admi nistrat ion o f innnun odo minant RhD pcpt idcs. o r
`parent eral admini stra tion o f IL- l 0
`in clncin g pcptides prior to
`im muniw tion w ith f{h l) protei n . inhi bit s both '1'-ccll proliferation
`;mel an ti body produc tio n . Th ese res ult s su ggest that sy ntheti c
`f{hf) pcptides C< lll indu ce tol era nce to th e RhD prot ein a nd ma y
`be of va lu e in th e prevention of immuni za tion in RhD-n egativc
`individual s.
`
`259
`A humanized monoclonal anHbody againsl vWF A I
`domain inhihils vWf: HiCol' adivil)' and J)lalclcl adhesion
`in human volunteers
`• C. Clark e! . 0 . lkcmura 1
`
`S. J. Machin 1
`. Y. Ikeda ' and Y. (;yotok ll '1
`J. 1\ . Ta lbot 2
`1 /Jeparl/111'111 of' llui'IIIIII OIII!J!J . UCL, Lo11rfo11 , UK: 2 Mt•rf,•va l Lid.
`Mmll'lwsler. Ul\: 1 Ai ill lllllllto l'lltll'lllll<'l'lltimls lilll'llf!I' Ltd. l< eillii/1 . Ul\:
`111iiiiOII/Oto Co .. l11c. 'J'ok!tll. /llfll/11 : ' f)q)(lrl/11 1'111 of' l lllemal Mcrfil'illl',
`Keio Ulli lll'rsii!J , 'J'ok,IJO. /tiJIIIII
`i\)W200 (1\ jinomoto) , a h11111 <111ized lgC-J. monoclonal <~n lihody
`directed a gain st th e i\ I domain of vo n Wi ll clmmd factor (v WF ).
`spcc ilicall y inhibit s vl<\iF : plii telct Cl' lb receptor i nt e r<~ction s . i\ t
`
`• S. Kageya m<1 1• I.) . 1vi<ll'kie 1
`
`•
`
`Oral Communication
`
`Presidents Free Communications
`
`257
`Eculizumab, a C5 complemenl blocldng anlibody, is lhe
`lirsl I heraJ))' lo re duce I ransfusion re<tuire menls in
`patienls with paroxysmal nocturnal haemoglobinuria
`(PNH)
`
`1
`• ) . Marsh ! , D. Ele but c 2 , c. F. Mojcik ' .
`• C. fl a il 1
`P. IIi li m en
`S. i\. Rollins' . M. Cu ll cn 1
`• S. ). Ric h a rds' a nd R. P. Ro th er '
`I /Jqmrll/11'111 or llii l'lll!ltnlorf!l. l.t•{'((s 'f'l'tll' llill{/ llospitals N ilS Tru st.
`Lt·cds. Ul\: J/Jt'f)(frtnll'l/1 of' llal'llllll oforf!l . St C:t'III"!Jt' 's 1/nspilaf Medical
`School. l.o111fon. UK:
`lt•.rion l'liiii'IIIIIC<'IIIil'llls Inc .. Clll'sliire,
`Coilnt•clil'lll, USA
`l'il roxysm; d n octurnal h<~ cmog l obin uri a (i' NI I) is c hara cterized by
`intrav<~ sc ul ar h<~ cm o l ysis and venou s
`thrombosis du e
`to
`th e
`unopposed effect of compl em e nt on PNII red cell s <~nd platel ets.
`respect ive ly. Ec uliwm a b is il hum a ni zed m o noclo n a l antibody th a t
`inh ibits terminal comple m ent activ<~lion . Eleven
`binds l' 5 <1n d
`tran sfu s io n-de pend ent PNII p<~ ti cnt s h<1 ve co mpl eted 01 3-m o nth
`pil o t st11dy receivin g n O() m g cc uli zumab by intravenou s infu sion
`over lO min week ly i(>r four doses an d th en <)()() m g every ot her
`week. Adverse event s were re lativel y minor and self-limi tin g.
`Th e bioch emi ca l param e ters of haem o lys is dramatically improved
`for a ll p<~li c nts wi thin a week. Me; m LIJ II dccrc<~ sed from
`30XY ± 5YY ll/ L
`597 ± 32 l! / L
`bei(>re
`a ft er
`trea tm ent
`Lo
`(/' = 0.002) and i\ST from 77 ± 2 0 to 2(1 ± 3 lJ/ L (/' = 0 .0 4).
`Epi sodes of h <~em og lob inu r iil redu ced by YO% (I' < 0.001 ). Qua lit y
`life (EORTC () Ll' 31l)
`im proved sig nili can tly post-cc u li zumab
`o f
`compared lo prc-ec u lizu mab . One pati ent bega n trea tm ent during
`a severe acute h<~em o ly ti c episode with 01 1mos t blac k urin e a nd
`w ithin 24 h th ere wa s a ro mpl etc rcsol11ti o n o f her ha cmog lobi (cid:173)
`nuria <~ nd sy mptom s.
`'l'r; m sfu sion s for "" pati ents were signi li (cid:173)
`ca ntly redu ced in th e 3 month s o f ecu li zumab comp<~rcd w ith th e
`previou s 12 month s from 2.2 to 0. 7 unit s/ m on th (I' = 0 .(Hl 3).
`Th e redu ction in tr01nsfu s ion s was most d ra m<1ti c in th e seve n
`pati ent s wit h ou t thrornbocy t openi <~ fro m 2 . 3 to 0. 2 unit s/ mon th
`(/' = 0 .00 I ). Th ere was an in crease in I' Nil type II I red ce lls from
`to 5~. 7% post-ec ulizu mab
`a m ean o f 15.6% pre-ec ulizumab
`(/' = tUHl 5) du e to th e ir pro tec tion fro m compl em ent -med iated
`lys is <~n d th e redu cti o n in tra nsfu s ion s . There was n o change in
`th e pro portio n of I' H n e utrophils . m onocy tes or platelets. All
`patient s h ave con tinu ed on cc u li zumab in an ex ten sio n study. In
`is we ll
`to lerated. decreases h acmolysis.
`summary, cc ulizuma h
`improves symptom s <1nd sig nilicantly redu ces tmn sfu sio n s in P
`II
`pa tient s.
`Jo:c uli zurn a h appears to be the lirsl cfkct ivc th erapy for
`ha c mol ys is in I'N II a nd rn cr it s furth er development. Thi s is th e
`firs t tri a l o f <In a nti -co mpl em ent a nti body th era py in I' NH. Th e
`res pon ses were re ma rkable both in red ucti on in h acnw lys is and
`tran sfu s ion s and ill th e imp roveme nt in qua li ty of life . Thu s it is
`th e first c lkcti vc th erapy I(Jr hacmo lys is in PNII and wou ld a lso be
`expec ted to reduce th e risk o f th rombosis (this study could n ot
`01ddrcss thi s). The tria l was perform ed a t two centres in th e liK
`o nl y.
`
`11\
`
`© 2 00 I Blackwell Pu blish ing. Brilis/1 /nllnllll 1!{ 1/m'IIIIII DIII(f!l. 12 1 (S uppl. I ). X7- Y5
`
`1
`
`AMG1042
`
`
`
`8 7
`
`WEDNESDAY. 9 APRIL 2003
`
`• L.-M. Stott 1
`
`• L. Ca irn s ' and
`
`258
`The induclion ol' lolerance lo J{hl) in HLA DR 15
`transgenic mice
`S. ). llrban iak l.2 . /\. M. ll a ll 1
`R. N. Barker '
`1 /JqmrlliiPIII of Mediri11e 1111rf Tlwrape111ics. U11iversii!J II( 1\ lwrrli'm. Ul\:
`2Smttisli Natio11al Hloorf Tmii.,/ilsinn SavitT. Alwrdt'l'il. Ul\
`Th e Rhl) prot ein is a cl inica lly im portant red cell ;dl oa nti gcn that
`induces the production o f anti-D in RhD-negalivc
`in d ividu a ls.
`Becau se of the immun ogeni cit y of Rhl). all blood don at ions arc
`typed a nd mat ched for thi s a nti gen. and l{ h D- neg<~l i v e wom en arc
`m;ma ged lor th e preven tio n o f haemoly ti c di sease of th e newborn
`wi th prophylact ic anti-IJ
`immunog lobulin.
`llndcrs tanding
`th e
`mechanism s by whic h helper T-ccl ls co ntrol
`th e antibody
`res pon se to Rh D wou ld enable the des ig n of a lt ernati ve slr<l tcgics
`such i!S active to leration . We have show n that CD-J.+ helper 'I'
`cells from ;dloimm u nized don o rs can pro liferate and produ ce both
`IFN-ga mm a <1nd
`IL--J.
`in respon se to sy nth eti c pc ptides derived
`from
`th e f{hiJ sequence.
`indi cat in g a ThO b;da nccd cy tokin e
`res pon se. Th e respon ses arc Il L!\ class II restricted. w ith II Li\ (cid:173)
`DR I 5 being over-represent ed in good responders. Certa in pe ptides
`<1rc imm unodominan t. and indu ce proli lera tive responses in most
`all o im mun ized donors. These peptides arc c<~ ndidatcs for
`th e
`indu ction o f toleran ce to th e RhD protein by th e mu cosal rout e.
`On
`t he oth er h and. som e pe ptides
`from
`th e HhD protein
`prele renti ;dl y indn cc IL- l 0 produc ti o n by putative Tr I regu l <~ t ory
`cell s ;, vitro. and th ese pcpt ides inhibit T-ccll prol ife r<llion
`in
`respon se to stimulation wi th purilicd RhU protein ill vitro. Th ese
`pcptid es may be u sed to ind uce toleran ce by th e pare nt eral rout e.
`We have used a IILi\-D IU 5 tran sgen ic m ou se m odel to sh ow th<~t
`'!'-cell s from mi ce imm u nized w ith t he Rhl) protein proli le ra te in
`respon se to purifi ed J{h l) prot ein a nd to Rh iJ pc ptides. and serum
`ant ihod ics spccilic for huma n cryt hrncytes arc
`;dso produ ced.
`Mucosa l admi nistrat ion o f innnun odo minant RhD pcpt idcs. o r
`parent eral admini stra tion o f IL- l 0
`in clncin g pcptides prior to
`im muniw tion w ith f{h l) protei n . inhi bit s both '1'-ccll proliferation
`;mel an ti body produc tio n . Th ese res ult s su ggest that sy ntheti c
`f{hf) pcptides C< lll indu ce tol era nce to th e RhD prot ein a nd ma y
`be of va lu e in th e prevention of immuni za tion in RhD-n egativc
`individual s.
`
`259
`A humanized monoclonal anHbody againsl vWF A I
`domain inhihils vWf: HiCol' adivil)' and J)lalclcl adhesion
`in human volunteers
`• C. Clark e! . 0 . lkcmura 1
`
`S. J. Machin 1
`. Y. Ikeda ' and Y. (;yotok ll '1
`J. 1\ . Ta lbot 2
`1 /Jeparl/111'111 of' llui'IIIIII OIII!J!J . UCL, Lo11rfo11 , UK: 2 Mt•rf,•va l Lid.
`Mmll'lwsler. Ul\: 1 Ai ill lllllllto l'lltll'lllll<'l'lltimls lilll'llf!I' Ltd. l< eillii/1 . Ul\:
`111iiiiOII/Oto Co .. l11c. 'J'ok!tll. /llfll/11 : ' f)q)(lrl/11 1'111 of' l lllemal Mcrfil'illl',
`Keio Ulli lll'rsii!J , 'J'ok,IJO. /tiJIIIII
`i\)W200 (1\ jinomoto) , a h11111 <111ized lgC-J. monoclonal <~n lihody
`directed a gain st th e i\ I domain of vo n Wi ll clmmd factor (v WF ).
`spcc ilicall y inhibit s vl<\iF : plii telct Cl' lb receptor i nt e r<~ction s . i\ t
`
`• S. Kageya m<1 1• I.) . 1vi<ll'kie 1
`
`•
`
`Oral Communication
`
`Presidents Free Communications
`
`257
`Eculizumab, a C5 complemenl blocldng anlibody, is lhe
`lirsl I heraJ))' lo re duce I ransfusion re<tuire menls in
`patienls with paroxysmal nocturnal haemoglobinuria
`(PNH)
`
`1
`• ) . Marsh ! , D. Ele but c 2 , c. F. Mojcik ' .
`• C. fl a il 1
`P. IIi li m en
`S. i\. Rollins' . M. Cu ll cn 1
`• S. ). Ric h a rds' a nd R. P. Ro th er '
`I /Jqmrll/11'111 or llii l'lll!ltnlorf!l. l.t•{'((s 'f'l'tll' llill{/ llospitals N ilS Tru st.
`Lt·cds. Ul\: J/Jt'f)(frtnll'l/1 of' llal'llllll oforf!l . St C:t'III"!Jt' 's 1/nspilaf Medical
`School. l.o111fon. UK:
`lt•.rion l'liiii'IIIIIC<'IIIil'llls Inc .. Clll'sliire,
`Coilnt•clil'lll, USA
`l'il roxysm; d n octurnal h<~ cmog l obin uri a (i' NI I) is c hara cterized by
`intrav<~ sc ul ar h<~ cm o l ysis and venou s
`thrombosis du e
`to
`th e
`unopposed effect of compl em e nt on PNII red cell s <~nd platel ets.
`respect ive ly. Ec uliwm a b is il hum a ni zed m o noclo n a l antibody th a t
`inh ibits terminal comple m ent activ<~lion . Eleven
`binds l' 5 <1n d
`tran sfu s io n-de pend ent PNII p<~ ti cnt s h<1 ve co mpl eted 01 3-m o nth
`pil o t st11dy receivin g n O() m g cc uli zumab by intravenou s infu sion
`over lO min week ly i(>r four doses an d th en <)()() m g every ot her
`week. Adverse event s were re lativel y minor and self-limi tin g.
`Th e bioch emi ca l param e ters of haem o lys is dramatically improved
`for a ll p<~li c nts wi thin a week. Me; m LIJ II dccrc<~ sed from
`30XY ± 5YY ll/ L
`597 ± 32 l! / L
`bei(>re
`a ft er
`trea tm ent
`Lo
`(/' = 0.002) and i\ST from 77 ± 2 0 to 2(1 ± 3 lJ/ L (/' = 0 .0 4).
`Epi sodes of h <~em og lob inu r iil redu ced by YO% (I' < 0.001 ). Qua lit y
`life (EORTC () Ll' 31l)
`im proved sig nili can tly post-cc u li zumab
`o f
`compared lo prc-ec u lizu mab . One pati ent bega n trea tm ent during
`a severe acute h<~em o ly ti c episode with 01 1mos t blac k urin e a nd
`w ithin 24 h th ere wa s a ro mpl etc rcsol11ti o n o f her ha cmog lobi (cid:173)
`nuria <~ nd sy mptom s.
`'l'r; m sfu sion s for "" pati ents were signi li (cid:173)
`ca ntly redu ced in th e 3 month s o f ecu li zumab comp<~rcd w ith th e
`previou s 12 month s from 2.2 to 0. 7 unit s/ m on th (I' = 0 .(Hl 3).
`Th e redu ction in tr01nsfu s ion s was most d ra m<1ti c in th e seve n
`pati ent s wit h ou t thrornbocy t openi <~ fro m 2 . 3 to 0. 2 unit s/ mon th
`(/' = 0 .00 I ). Th ere was an in crease in I' Nil type II I red ce lls from
`to 5~. 7% post-ec ulizu mab
`a m ean o f 15.6% pre-ec ulizumab
`(/' = tUHl 5) du e to th e ir pro tec tion fro m compl em ent -med iated
`lys is <~n d th e redu cti o n in tra nsfu s ion s . There was n o change in
`th e pro portio n of I' H n e utrophils . m onocy tes or platelets. All
`patient s h ave con tinu ed on cc u li zumab in an ex ten sio n study. In
`is we ll
`to lerated. decreases h acmolysis.
`summary, cc ulizuma h
`improves symptom s <1nd sig nilicantly redu ces tmn sfu sio n s in P
`II
`pa tient s.
`Jo:c uli zurn a h appears to be the lirsl cfkct ivc th erapy for
`ha c mol ys is in I'N II a nd rn cr it s furth er development. Thi s is th e
`firs t tri a l o f <In a nti -co mpl em ent a nti body th era py in I' NH. Th e
`res pon ses were re ma rkable both in red ucti on in h acnw lys is and
`tran sfu s ion s and ill th e imp roveme nt in qua li ty of life . Thu s it is
`th e first c lkcti vc th erapy I(Jr hacmo lys is in PNII and wou ld a lso be
`expec ted to reduce th e risk o f th rombosis (this study could n ot
`01ddrcss thi s). The tria l was perform ed a t two centres in th e liK
`o nl y.
`
`11\
`
`© 2 00 I Blackwell Pu blish ing. Brilis/1 /nllnllll 1!{ 1/m'IIIIII DIII(f!l. 12 1 (S uppl. I ). X7- Y5
`
`1
`
`AMG1042
`
`
`
`2003
`
`Abstracts of the papers presented at the
`Annual Scientific Meeting of the
`British Society for Haematology
`
`Glasgow, UK
`7-9 April 2003
`
`fiJ
`
`Blackwell
`Publishing
`
`0963-1860(200305)121 : 05+1 ; 1-E
`
`This m at erial w as cDpied
`at th e· NLM and may t>e
`Subj ect US Copyright Laws
`
`2
`
`
`
`British Journal of Haematology
`
`The offi cia l jou rnal of the Bri tish Society lo r Hac matology (!' resident M. Greaves: Sel'l'l'/llr!J j. T. l{e illy: 'f'rms11rl'l' C. 1{. ). Sin ger:
`Hepn•se11 L11tive 011 EdiLoriul Board C. H. ). Singer). 2 Carlt on !l ouse TcJT<JCc. Lo ndon SW I Y '5/\ F.
`
`Editors
`
`ia n ll ann London
`
`Finbarr Coll er l.ondon
`
`john Rei lly Shejfil'id
`
`Assoc ia te Ed it o rs
`
`1\ . 1<. Burn ell Curdi/1'
`II. E. 13roxmeyer lndiunupo/is
`B. 13cn nct l /I/Jrrdeen
`M. Y. Co rdon London
`M. Greaves !1 /Jerdem
`1\ . Foa Ho111e
`I. R. Peak e Slwj/il'id
`M. j . Pippard 011nde1'
`D. Prova n London
`I. !\. G. Roberts London
`N. Russe ll Nollin(Jiuun
`S. L. Th ein London
`L. Wi lli a mson Crun/Jrid!fl'
`
`Ed itoria l Board
`
`J. Boult wood O.r/iml
`Y. Beuzard Puris
`B. j. 13ai n Londo11
`T. Bagli n Crun/1ridrw
`I. R. Pea ke (Ch<Jirm a n ) Shej/ield
`C. Ca ma sc hcll a Tori11 o
`C. j . Eaves Voni'OII VI'r
`P. Fenau x Li//1•
`1\. Coodeve Slwlfir•ld
`!\ . 1{. Cree n Crllllilrir/.w
`j. IJ. Cri fli n Hos /011
`II . Heslop ll o11slon
`T. L. ll olyoake C:!uS(fO\V
`M. LeBea u Cl1im!fo
`D. Lin ch Lonr/011
`B. I. Lord Mrnll'lwsln
`C. Mcc ucc i l'eru!tiu
`D. 1{. Mi ller TII .\'Nio l'urk. N )'
`P. /\. II. Moss Hinniii(Jhmll
`!\. Nurd en 13onlerlll .\'
`C. Prenti ce l.ondon
`IJ . i{und fl'/'u sull'ln
`0. P. Smith 0 11/1/in
`T. lJc hiy<J ma K!Jolo
`). j. /VI . va n IJonge n Hollcnlmn
`/\11. Worwood Curdij)
`
`Pa st l ~dito rs
`
`1{. /VI. ll ;m listy ( l lJ69- 7 1)
`D./\. C. C<:dt on ( 1 %6- 6/i)
`Rose mary Bi ggs ( 1%2- 65)
`). V. Dacic ( l lJS)- 6 1)
`1{. B. Th ompso n ( 19 72- 7-l)
`/\. jaco bs ( 19 7 5- 77)
`S. /VI. Lew is ( 197/i- ii O)
`I. Ch<ma rin ( 19ii l- ii3)
`E. C. Co rdon -S m ith ( 19ii-l-- ii6)
`/VI. Worwood ( 19/i/- lJI)
`I. 1{. Peake ( l lJ9 2- %)
`/VI. Crc<Jves ( 199 7- 200 I )
`D. C. Osc ier ( 199 7- 200 I )
`
`Shdli cld Olli ce
`
`lnn ell an Offi ce
`
`Sl'il'll li{ic h'ditor Sus<Jn W<:dt on
`
`t;dit oriul Assislunl l.orn <J Wyc her ley
`
`Published tw ice per c<J len d;u· mont h (once in
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`© 2 011 3 13 la ckwell Publi shin g Ltd
`
`fiJ
`
`Blackwell
`Publi shing
`
`3
`
`
`
`Brit"sh j ournal of hae atology.(IM )
`v. 121, suppl. 1 (May 2003)
`General Collec ion
`W1 BR535
`2003-04-28 09: 02:39
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
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`'fb
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`2003
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`4
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