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Guillain-Barré-syndrome and immunological diseases
206
P01.18 STUDIES O N TOLERAHCE I N D U C T I O N T O A U T O I M M U N E I N P L A M M A T I O N O F T H E C E N T R A L N E R V O U S SYSTEM. Maria A. Smykova a~l MamyukiMiyasaka*. Neumsciances Research Unit, Woden Valley Hospital,Canben~ ACT. 2606. (06)248-5465 FAX (06)257-60438~1 *TokyoMe,trep. Imt Med. Sci.
Tncra1~utic interventionin autoimmtme disease.swould ideallyemploy the andgouic ep~topewhich is the target of the aumimmnnewocess to induce deletion, anoraye~ mpgmssim~ q~gif~mltymaUive~ . Previousw~kf~z~nour lab has shown that mAbs to edhesiou molecule~,though no{ capable of inhibiting the inflammatiouof passiveEAE, did in fact wovide a degree of protectiou against active EAE in rats. We ~ ask if the ~ couldbe used in coujunctiou with specificantigen (without adjuvant) to induce tolex~ce (re~tance) to EAE indectio~. Here we deacttbe the buinction of tolenmceby a sovanday infusion of MBP in-saline in ~mbinatiou with three ip injections of antt-CDlla (LFA-I) mAbs. This bd~ef10realmantinduces resistanceto EAE induction which persisU;for at iemtema~zmh. AmI~CD~IC, A M - I ~ ~ , ~ _ ~ when given in the same gestmannm did it synergizcwitb anti-CD1la when tbe two were ad~sinistea~ tosetber. H.httologicallesionsin MBP-CFA dmllenged ~ t tam slm~,~dadair se almenceof le~doasor mild ~ , winch whenixeP~t was coufined to the manthg¢~of the lower spinal cord. Lymplmodecell pmlife~aiouto MBP following challenge of tolerant rats was unaltered indicating that MBP reactive cells had not beco dekted. The tolerizing~ e n t did not prime rats for antibody woductiou to MBP and total antibody level in tolerant rats following challenge was signiflc~lly lower than controls. There was aLso a shift in the isotypeof mtib~ly IgOdlged~ an 18G2a:IgGlratio of 2:1 to 1:1 whichw.asdue m an increase in 18G1 productions. This result suggests a possible alteranon m CD4+ THI,TH2 profile in tolerant rats. Such deviation could account for the resistance to EAE h~inctiou.
P02.17 CYTOKINES, PROSTAGLANDINS AND LIPOCORTIN-1 ARE PRESENTIN THE BRAINS OF SCRAPIE-INFECTED MICE. A. Williams, A.-M. van Darer, F. Berkenboscht and H. Fraser BBSRC/MRC Neuropathogeneais Unit, Edinburgh and TDepartment of Pharmacology, Free University, Amsterdam The neuropathology of scrapie and Creutzfeldt-Jakob disease is characterized by Chronic neurodeg~hef#ttionWith vacu01atlon of neurons and/or neuropiL pmyloidplaque f o3_m~j0n in s0me epees end marked glial activation. Micr0~giia Showed Upr~0ulation of l e u k ~ a~tlgens with known functions in reQ'uitment, phagocytosis, leukocyte activation and antigen presentation which suggests that the microgiial response represents a modified inflammatow response. In the present studies, the presence of cytokines, prostaglandins (PGs) and lipocortin-1 was investigated in terminally-affected mice, using immunocytochemical techniques. There was marked induction of intedeukin (IL) -11~, tumour necrosis factor o, IL-6, PGs E~ and F~,, and lipocortin immunorectivity in those areas of the brain showing vacuolation, aatrocytosis end mieroglial activation. A comparison of the morphology of cells expressing the above factors with GFAP {astrocytic) end F4/80 (microgliat) staining showed that the immunoreacttve gila were predominantly aatrocYtes. It has previously been proposed that cytokines influence or mediate abnormal APP processing and ff~A4 deposition. The findtnga reported here indicate that similar mechanisms may atso be relevant in PrP processing and the pathogenesis of neurodegeneration in scrapie.
P13.15 GU~LA~N-BARt~-S'~RO~,~ AND m ~ U N O ~ O G ~ C A ~ D~.~..S
WniterhollerM. DiCla~ P B ~
A:Bngelhard~B N ~
Dept. ofNeorology,UniversityofErlangan,Germany There are many ~ports on patientssufferingfrom variouSor overlapping immunological diseases like mixed connective tissue disease.Multi organ involvement in autoimmune phetmmemt is thought to be due to similar immune mechanisms. We report three patients with severe acute GuillainBan~Syndmme and history or cnianidcnce of other i m n ' ~ , . ~ l diseases. Case 1: A 76-yeas-oldwoman was admitted to the hospital with petedldae and p ~ wankna& pasesthasias and absent tcndoll l ~ k a ~ e~:ti~ Werlhoff s disease) and GBS were diagnosed, both diseases - I T P ~ , being successfully treated with high-dose i m m a n o ~ (P~q6, 0,4mg/kg/d). Case 2: A 63-year.~ld woman with a 15 year instoW of ~ ' ~ developed parestheslas and severe pale~s of upper and low~ limbs with absent tendon reflexes dlLringan exa:edoation of i ~ - > e e w e l disease. CSF and e l e c t ~ l o g i ¢ findings were typical for ~ . Case 3: A 40-year-old woman had severe GBS with telxapiegiareqmgiag mechanicalventilation for months, She was still moderalety~ 2 yex~ aRer the outbreak of the disease when heginmng n~ud failureand exanthema with pos/tive ANA aad anfi-dsDNA led to the ~ of systemic lupus e ~ h o d c s (SI~). Conclusion: The clinical observationof the coincidence of acnte GBS and other immunological disezses may give evidence for ~milar pathornechanismsin both. We discuss the relevanceof these findings.
P06.25 PEPTIDE INDEPENDENT A~EMIBLY OF HLA-DR2 MOLECULES I ~ O M SUBuNrrs EXPRESSED IN E. COLI ~ and Jack L. S m z m i ~ DepL of B ~ lad Moleoul~ B ~ , ~ University,C-ambrida¢ MA 02138, USA
t'~c~efi,..~ ~,m,,,~thil!~ ~ t a t e , ~uble m ~ . D g 2 mzkgaes w m ~
fl with ~ - D R 2 . Recombinant for c r y ~ o n ~ -
~Daa~d
I~0~)we~ seWagty~
~c~i~ ~ !
perificafton b~ ~ m~crltk~ for ~
~ y . T h o m S O n wm m~ by m p ~ c he~ice¢
Remlm.'DRa md p a m ~ v~anermined ,,t hi~ levels follOWinginductiou by n,ro and wm~pro,ram by ~u.c~u~ danmmosr~y. R ~ w a s me~itond in m ~ ' ~ a mAb ~ f i c for ~ h ~ e d b ~ . fo~diagw~ cxtUcai~~ ou ptl. NacI ~ a m l m m ~ md the ratioo( ~ SlUta~oue but was indepemk~ of a high aITanity ~p~n~8.~.~, m~m~,~p~pe~yp,~a.~m~i~ .. with a DRa drain specific antibody (L243) yieldedeqasl qummues ~ I.ILA-DR2molecu~ cm be e.xwessediu the alzence of ~ anasm, w ~ m - ~ - . ~ ~ wm ho ~ m i s m ~ ~J~peptt~ ~ m m e d b~ m.A-DP,2 and t0 ~ ~e ~memre of m.A:DP.2 compleand~ h ~ , ~ . . ; n~41n bedc protein peptiC.
P06.24
P06.26
Switch of autoreactive h u m a n T cell clones f r o m a T H 2 to a T G F f l l secreting phenotype with low affinity T-ceil receptor stimulating pepflde/MHC complex Anja WhtCl]lqgen,~ Scholz, Hikoaki l~dmura, Alessandro Sette*, David A. Bailer; Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical ~m~i, Boeton, MA 02115,
DEVELOPMENT OF CSF OLIGOCLONAL BANDING AFI-~R CNS TRAUMA
*c y m O S e ,
m'wCA.
,,
Stimulation o! murme t - c e u clones with altered peptide ligands (APL), -that trig~wx only a suboptimal TCR signal can induce cytokine secretion without thymidine incorporation as compared to the native cognate peptide. As changes of the cytok/nes secrctod by T cells alter their regulatory function, we investigated wh~ther APL modified at previously identified TCR contact residues can sin~l-arly alter the cytokines secreted by h u m a n au~orehctive T-c~II-cltme~: Stimulstiow of TH2--MBP reactive T-cell clones recognizing the immunodominant M B P peptide 85-99 modified at T C R contact residues induced ncw r n R N A synthesis of T G F B I while switching off m R N A synthesis of IL-~ and IL- IO. This was confirmed by the induction of TGF[~I secretion in the absence of either IL--4 and fL-10 secretion or thymidinc incorporation. Localized tissue secretion by T cells of TGr~I, a potent physiologic inhibitorof cell cycle induction can downrc~ulate i m m u n e responses. Thus the switch of cytokinc ~ynthcsis zxum H.,-&tO xuz-u x-by ~ . . . . . ~e]f-pe~ ....... y important in regulating and limiting the immune responses to self antigen,
~ l , Msail~I, j . m ~ 2 c ~ : ~ - ~ ~ , ~ Maim Gan~ny
scho~ Ha~ver and2Neero~y, uinver.~
imredaction: If C.M. Poser'sh ~ that heain~ may act aea ~ . _ . fao~ ~ the ~ of aX~W~tioaaMS, by ~ a tnach in ~e ~ ~ma ~m~, mva~, ~aeU ~ t sevm~ the ~ et ~ s i / t m d M ~ CSF'at~t ~ "_'~=~ ~ ~ ; in
aler m e ~ t ¢ i ~ r ~
s ~ r t r u m m f f n d a)mat ~ t t ~ e
~l~fme
~,eme,iee nnd i~no ~e o ~ t ~ S ~ ~,~an,edon dint~ ~ >O . T a n d a with nn ~eu ~ e ~ l ~-2~
~ ~
5
:
~ ~ ~ l m ~aavo m ~ ~
~. ~
~
~ ~
add~ouel ~¢*m (m~ a~, ~ ~ - - - - - - m ~ a i ~ mtan n n d ~ decidewhetherthe ~ a m pmSmms nnd oven MS will m e n ~ itself dinicalty
-
P01.18 STUDIES O N TOLERAHCE I N D U C T I O N T O A U T O I M M U N E I N P L A M M A T I O N O F T H E C E N T R A L N E R V O U S SYSTEM. Maria A. Smykova a~l MamyukiMiyasaka*. Neumsciances Research Unit, Woden Valley Hospital,Canben~ ACT. 2606. (06)248-5465 FAX (06)257-60438~1 *TokyoMe,trep. Imt Med. Sci.
Tncra1~utic interventionin autoimmtme disease.swould ideallyemploy the andgouic ep~topewhich is the target of the aumimmnnewocess to induce deletion, anoraye~ mpgmssim~ q~gif~mltymaUive~ . Previousw~kf~z~nour lab has shown that mAbs to edhesiou molecule~,though no{ capable of inhibiting the inflammatiouof passiveEAE, did in fact wovide a degree of protectiou against active EAE in rats. We ~ ask if the ~ couldbe used in coujunctiou with specificantigen (without adjuvant) to induce tolex~ce (re~tance) to EAE indectio~. Here we deacttbe the buinction of tolenmceby a sovanday infusion of MBP in-saline in ~mbinatiou with three ip injections of antt-CDlla (LFA-I) mAbs. This bd~ef10realmantinduces resistanceto EAE induction which persisU;for at iemtema~zmh. AmI~CD~IC, A M - I ~ ~ , ~ _ ~ when given in the same gestmannm did it synergizcwitb anti-CD1la when tbe two were ad~sinistea~ tosetber. H.httologicallesionsin MBP-CFA dmllenged ~ t tam slm~,~dadair se almenceof le~doasor mild ~ , winch whenixeP~t was coufined to the manthg¢~of the lower spinal cord. Lymplmodecell pmlife~aiouto MBP following challenge of tolerant rats was unaltered indicating that MBP reactive cells had not beco dekted. The tolerizing~ e n t did not prime rats for antibody woductiou to MBP and total antibody level in tolerant rats following challenge was signiflc~lly lower than controls. There was aLso a shift in the isotypeof mtib~ly IgOdlged~ an 18G2a:IgGlratio of 2:1 to 1:1 whichw.asdue m an increase in 18G1 productions. This result suggests a possible alteranon m CD4+ THI,TH2 profile in tolerant rats. Such deviation could account for the resistance to EAE h~inctiou.
P02.17 CYTOKINES, PROSTAGLANDINS AND LIPOCORTIN-1 ARE PRESENTIN THE BRAINS OF SCRAPIE-INFECTED MICE. A. Williams, A.-M. van Darer, F. Berkenboscht and H. Fraser BBSRC/MRC Neuropathogeneais Unit, Edinburgh and TDepartment of Pharmacology, Free University, Amsterdam The neuropathology of scrapie and Creutzfeldt-Jakob disease is characterized by Chronic neurodeg~hef#ttionWith vacu01atlon of neurons and/or neuropiL pmyloidplaque f o3_m~j0n in s0me epees end marked glial activation. Micr0~giia Showed Upr~0ulation of l e u k ~ a~tlgens with known functions in reQ'uitment, phagocytosis, leukocyte activation and antigen presentation which suggests that the microgiial response represents a modified inflammatow response. In the present studies, the presence of cytokines, prostaglandins (PGs) and lipocortin-1 was investigated in terminally-affected mice, using immunocytochemical techniques. There was marked induction of intedeukin (IL) -11~, tumour necrosis factor o, IL-6, PGs E~ and F~,, and lipocortin immunorectivity in those areas of the brain showing vacuolation, aatrocytosis end mieroglial activation. A comparison of the morphology of cells expressing the above factors with GFAP {astrocytic) end F4/80 (microgliat) staining showed that the immunoreacttve gila were predominantly aatrocYtes. It has previously been proposed that cytokines influence or mediate abnormal APP processing and ff~A4 deposition. The findtnga reported here indicate that similar mechanisms may atso be relevant in PrP processing and the pathogenesis of neurodegeneration in scrapie.
P13.15 GU~LA~N-BARt~-S'~RO~,~ AND m ~ U N O ~ O G ~ C A ~ D~.~..S
WniterhollerM. DiCla~ P B ~
A:Bngelhard~B N ~
Dept. ofNeorology,UniversityofErlangan,Germany There are many ~ports on patientssufferingfrom variouSor overlapping immunological diseases like mixed connective tissue disease.Multi organ involvement in autoimmune phetmmemt is thought to be due to similar immune mechanisms. We report three patients with severe acute GuillainBan~Syndmme and history or cnianidcnce of other i m n ' ~ , . ~ l diseases. Case 1: A 76-yeas-oldwoman was admitted to the hospital with petedldae and p ~ wankna& pasesthasias and absent tcndoll l ~ k a ~ e~:ti~ Werlhoff s disease) and GBS were diagnosed, both diseases - I T P ~ , being successfully treated with high-dose i m m a n o ~ (P~q6, 0,4mg/kg/d). Case 2: A 63-year.~ld woman with a 15 year instoW of ~ ' ~ developed parestheslas and severe pale~s of upper and low~ limbs with absent tendon reflexes dlLringan exa:edoation of i ~ - > e e w e l disease. CSF and e l e c t ~ l o g i ¢ findings were typical for ~ . Case 3: A 40-year-old woman had severe GBS with telxapiegiareqmgiag mechanicalventilation for months, She was still moderalety~ 2 yex~ aRer the outbreak of the disease when heginmng n~ud failureand exanthema with pos/tive ANA aad anfi-dsDNA led to the ~ of systemic lupus e ~ h o d c s (SI~). Conclusion: The clinical observationof the coincidence of acnte GBS and other immunological disezses may give evidence for ~milar pathornechanismsin both. We discuss the relevanceof these findings.
P06.25 PEPTIDE INDEPENDENT A~EMIBLY OF HLA-DR2 MOLECULES I ~ O M SUBuNrrs EXPRESSED IN E. COLI ~ and Jack L. S m z m i ~ DepL of B ~ lad Moleoul~ B ~ , ~ University,C-ambrida¢ MA 02138, USA
t'~c~efi,..~ ~,m,,,~thil!~ ~ t a t e , ~uble m ~ . D g 2 mzkgaes w m ~
fl with ~ - D R 2 . Recombinant for c r y ~ o n ~ -
~Daa~d
I~0~)we~ seWagty~
~c~i~ ~ !
perificafton b~ ~ m~crltk~ for ~
~ y . T h o m S O n wm m~ by m p ~ c he~ice¢
Remlm.'DRa md p a m ~ v~anermined ,,t hi~ levels follOWinginductiou by n,ro and wm~pro,ram by ~u.c~u~ danmmosr~y. R ~ w a s me~itond in m ~ ' ~ a mAb ~ f i c for ~ h ~ e d b ~ . fo~diagw~ cxtUcai~~ ou ptl. NacI ~ a m l m m ~ md the ratioo( ~ SlUta~oue but was indepemk~ of a high aITanity ~p~n~8.~.~, m~m~,~p~pe~yp,~a.~m~i~ .. with a DRa drain specific antibody (L243) yieldedeqasl qummues ~ I.ILA-DR2molecu~ cm be e.xwessediu the alzence of ~ anasm, w ~ m - ~ - . ~ ~ wm ho ~ m i s m ~ ~J~peptt~ ~ m m e d b~ m.A-DP,2 and t0 ~ ~e ~memre of m.A:DP.2 compleand~ h ~ , ~ . . ; n~41n bedc protein peptiC.
P06.24
P06.26
Switch of autoreactive h u m a n T cell clones f r o m a T H 2 to a T G F f l l secreting phenotype with low affinity T-ceil receptor stimulating pepflde/MHC complex Anja WhtCl]lqgen,~ Scholz, Hikoaki l~dmura, Alessandro Sette*, David A. Bailer; Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical ~m~i, Boeton, MA 02115,
DEVELOPMENT OF CSF OLIGOCLONAL BANDING AFI-~R CNS TRAUMA
*c y m O S e ,
m'wCA.
,,
Stimulation o! murme t - c e u clones with altered peptide ligands (APL), -that trig~wx only a suboptimal TCR signal can induce cytokine secretion without thymidine incorporation as compared to the native cognate peptide. As changes of the cytok/nes secrctod by T cells alter their regulatory function, we investigated wh~ther APL modified at previously identified TCR contact residues can sin~l-arly alter the cytokines secreted by h u m a n au~orehctive T-c~II-cltme~: Stimulstiow of TH2--MBP reactive T-cell clones recognizing the immunodominant M B P peptide 85-99 modified at T C R contact residues induced ncw r n R N A synthesis of T G F B I while switching off m R N A synthesis of IL-~ and IL- IO. This was confirmed by the induction of TGF[~I secretion in the absence of either IL--4 and fL-10 secretion or thymidinc incorporation. Localized tissue secretion by T cells of TGr~I, a potent physiologic inhibitorof cell cycle induction can downrc~ulate i m m u n e responses. Thus the switch of cytokinc ~ynthcsis zxum H.,-&tO xuz-u x-by ~ . . . . . ~e]f-pe~ ....... y important in regulating and limiting the immune responses to self antigen,
~ l , Msail~I, j . m ~ 2 c ~ : ~ - ~ ~ , ~ Maim Gan~ny
scho~ Ha~ver and2Neero~y, uinver.~
imredaction: If C.M. Poser'sh ~ that heain~ may act aea ~ . _ . fao~ ~ the ~ of aX~W~tioaaMS, by ~ a tnach in ~e ~ ~ma ~m~, mva~, ~aeU ~ t sevm~ the ~ et ~ s i / t m d M ~ CSF'at~t ~ "_'~=~ ~ ~ ; in
aler m e ~ t ¢ i ~ r ~
s ~ r t r u m m f f n d a)mat ~ t t ~ e
~l~fme
~,eme,iee nnd i~no ~e o ~ t ~ S ~ ~,~an,edon dint~ ~ >O . T a n d a with nn ~eu ~ e ~ l ~-2~
~ ~
5
:
~ ~ ~ l m ~aavo m ~ ~
~. ~
~
~ ~
add~ouel ~¢*m (m~ a~, ~ ~ - - - - - - m ~ a i ~ mtan n n d ~ decidewhetherthe ~ a m pmSmms nnd oven MS will m e n ~ itself dinicalty
-