- Email: [email protected]
Major histocompatibility complex antigens in human liver transplants
Major histocompatibility
complex antigens in human liver transplants
Liver transplantntion is performed successfully acm55 major HLA differences between donor and recipient. This may be ittfluenced by the organ specific expression of major bistocampatibility complex (MHC) molec”k3 which determine *lx local immune reactivity and rejection response. The tissue expressian of MHC molecules on parenchymal and infiltrating ECUShas been shtdied in transplanted human liver using monoclonal antibodies and immunohistologjcal m&&s. A strong induction of class I (HLA-A,B,C; &-microgIohulin) and class II (HLA-DR,DO,DP) MHC antigem was demonstrated 3n hepatocytes, bile duct epitbetiunt and endothelial cells during rejection episodes and viral and bacterial infections. The massive induction of donor antigens on hepatocyfes, bile ducts and endothelia forms part of, and may also augment. therejectlon response. quiescmt without infectiota or nJection after transpl&ttation, however. a rather restricted expression of class f and class 1I donor MHC antigens ls present. In addition, the donor Kupffer alk and interstitial den&tic cells are gmdualiy replaced by recipient accky &Is expressing self-MHC molectde~. Tlxe changes in antigen density and distribution d donor MIX alloantigens as the replacement of acceswry cells capable of presenting antigens to Tlymphocytes may influence the course of immune reactivity and the rejxtion response in the liver. Tbk may partly explain
During
states
the favotttable clinical cause long after transplantation. Reliinary clinical investigations of the effect of HLA matching have shown a dualistic effect of the matcbbtg of class 1 or class II HLA antigens. Tbe role of HLA matching in liver traw plants in large clinical studies, with specific immunological
testing however, remains to be investigated. This may lead to
prospective HLA matching with wider organ availability atd improved preservation time in the future. Further studies should investigate in detail the T-ceil receptor-MHC interaction in liver tissue during rejection as well as other types of iamwte feactiott. ‘IIt.? analysis of the alloantigen expression ix tissue and its modulation by different immunosuppressants and cytokitta may be of diagnostic and therapeutic aid.
The genetic polymorphism of molecular groups causing individual s;fimnces fcmns the basis of the problem of histocompatibiity in organ transplantation. The polymorphic epitopes of the moleculer of the major histocmnpatibility complex (MHC) are the major transplantation antigens (1,Z). Their expression ln the membrane of different types of donor cell causes recipient sensitization aud de-
velopment of an alloantigen-directed immune msponse. In addition, it has became clear that MHC molecules form the ligand of tb.. T-cell aptor for the presentation and mcqtition of antigens (3). The regulation of the expression of s&MHC molecules in ti~ue may therefore determine the type and course of an immune response (4). Whereas a static expression of these molecules has ken assumed in the past, it is ww clear that their expression is dynamic and underlies regulatory influences (1.2).
G. STEtNHOFF
10 Two classes of major transplantation
molecule bearing
polymorphic epitopes ere enccded by genes of the MHC on chromosome 6. The class I molecule (HLA-A, B end C) is a glycoprotein composed of .%n alpha-chain with three immunoglobelin-like domains. The polymorphic sequence is restricted to the alpha-l and -2 domains that are also binding sites for the T-cell receptor molecuk. The non-covalent associated beta-chain, completing the receptor complex of the class 1 MHC molecuIc,&tticrogIobulin, is not encoded by the MHC but on chromosome 15, is not polymorphic and contains one domain. Three different polymorphic class I molecules are expressed that were defined serologically by their difference in antigetticity (HLA-A, HLA-B, HLA-C). The class II molecules are glycoproteins and composed of an alpha- and e betachain that are both polymorphic @LA-DR, HLA-DP, HLA-DQ) and both contain two domain regions. Additional HLA-D region gene5 have been defined (HLADO. HLA-D”. HLA-DX. HLA-DZ) that ma” have diffen&et undebnedprod&ts (5). regions of both class I and class II
-
Thepolymorphic
molecules me the binding site of the T-cell receptor mokcule (5.6). The polymorphism of this binding site between individuals allows the distinction between self and nonself (6,7). At the cleft of the polymorphic alpha-l and aloha-2 domains of the MHC molecule the peptide fragiems of foreign antigens are bound and presented (g,9i. In transplanted organs, a Tsell sensidzation to non-self antigen is induced due to the difference in the polymorphic sequence of the HLA molecuk. By similarity in sequence, clones aoss-reactive with viral or bacterial antigens may be activated.
The T-cell reactivity
mined by the expression
of the HLA
the expression
transplant models have demonstrated a massive induction of donor class I and class II MHC molecules an graft cells during acute rejection (13-15). Immunosuppressive drugs such as cyclosporine A have been shown to abrogate the production of lymphokines and the induction of class II molecules (2). The regulation of the expression of donor end recipient MHC molecules in transplanted organs may therefore determine the alloreactititiy and be of importance for the outmme and function of the graft. ‘I%eavailability of monoclonal antibodies to a variety of monomorphic and polymorphic epitopes of the different MHC molecules and the development of sensitive inmmnohistological methods has prompted the intensive study oi the regulation of the tissue expre&on of MHC molecules. Not onIy the two classes of MHC molectde were studied in their cellular expression, but also the differential regulation of the expression of the different MHC molecules so far &fined. Tissue biopsies have been taken from liver in different pathological states end sequentiaIty after liver transplaotaticm. This allowed the study of changes in MHC antigen expression during rejation other complications and under immunosuppressive
end drug
treatment.
first is deter-
molecules
on the
membrane of graft cells and second by the presentation of autologous accessory cells (dendritic cells, macrophages). Futthemtore, the binding of T-lymphocytes may be determitiad by the additional expression of adhesion molecules (IO). Studies concerning
tions and infections (1,2,13-15); these may also be capeble of presenting antigens (16). Lymphokines have been identified es the mediators of the induction of MHC expression (17-19). During immune reactions in organ transplants the induction of MHC antigens on donor cell types additionally increases the target antigens for the alloreactive T-lymphocytes. Studies in experimental organ
of the two classes of
MHC molecu!es: class 1 (HLA-A,B,C) and class 11 (HLA-DR,DQ,DP) on different cell types using monoclonal antibodies have shown a heterogeneous distribution in normal human tissue (lIJ2). Whereas class I MHC antigens were expresstd on the majority of cell types, the class II MHC antigen expression wes mainly restricted to B-lymphocytes and accessory cells (11,12). The limited distribution of class II MHC an&n positive accessory cells (dendritic cells, macrophages) ia tissue may therefore cause a local restriction of T-lymphoryte reactivity and sensitization. However, a number of studies have shown that class II MHC antigens can be induced on a number of additional cell types during immune reac-
Expressionof classI MHC molecules Early studies have shown that MHC molecules are not uniformly expressed on the different parenchymal mmpottents of organs (20-23). Hepatoqtes of the Liver were found to express no or low amounts of MHC molecules (21,22). In normal human liver class I (HLA-A,B,C), MHC antigens are not, or only in low density, expressed by human hepatocytes (24.25). Increased expression of alpha-chain and @z-microglobulin class I MHC antigena was found on hepatocyte membranes in a number of pathological states and during rejection efter liver trensplantation (24,26-28). No major difference in the density and pattern of expr&on wes noted between the alphachain of HLA-A,B,C md that of µglabulin (26). Studies employing sequential follow-up biopsies during various complications after liver tnosplantation could show that the induction of class I MHC antigens on hep atocyt: membranes occurred not only during rejection
licpameyte Bileductcpithelium
.(l, -
(C) ++
Endothelial cell K”pffe,C4 Ponaldendriticcell
++
-
++
++
1:
::
+!++ ++
but also during various inllammatory
-
-
+ +
+,+
-
-
and infectious pro-
cesses (26). The induction of class 1 MHC antigens was revenible after cessation of the inflammation and afier successful rejection mmmmt (26). In graft biopsies without any complication, the pmtem of express&m resembled that of normal liver, but a part of the hepatofytes remained class I MHC amigen positive. In an experimental model of bile duct ligation in the tat. Inner et al. could show, that not only immmtologjcal stimuli, but cholestasis alone was able to inctease the class I expression on hepatocytes (29). In addition, in a rat liver transplant model it could be demonstrated by S&Wet al. that class I MHC antigens were induced on hspamcyte membranes not only in acute rejection but also in non-rejeetina isogmfts (30). Interestingly, in human transpIams in the majority of biopsies taken before and during the transplant operation, an induction of class I MHC antigens branes damage
was found
OR hepatacyte
(l&%)26).This may very well be caused or inflammatory
seta to monomorphic epitopes. Moreover, an equal induction of HLA-A and HLA-B antigens during rejection could be demonstrated in nequetttial biopsies of a limited number of patients (33). It is not known, however, if HLA-C molecules are induced and exprewd in a manner similar to that of HL&A and HLA-B. The production and expression of the different class I MHC moleales may very well undertie genetically determined individual differences. Futthermore, it is unckar whether the regu-
memby toxic
lation of the production
reactions in the donor and dur-
of &-miao~btdin
is regulated
cyte membranes has been further r!ifferemiated using HLA-A and HLA-B specific antibodies directed against polymorphic epitopes (31). In patiena with an appropriate diirence in HLA type, it could be shown that the
by the same stimuli as the class I alpha-chain in hepatccytes or may be produced in response to other factors. Although class I MHC antigens are expressed on bile duct epithelia, endotbelia, Kupffer cells and intentilial cell types in the normal human liver. an increased expression of HLA-A and HLA-B antigens can be demonstrated on bile duct epithelia during rejection and infections such as
induced antigens were donor derived (31,32). The expres-
cholangitis (33).
sion and induction phenomena for both donor HLA-A and HLA-B were the same as previously found with anti-
Thus, although induction phenomena can be demonstrated qualitatively an the normally negmlve hepato-
fng hepatectomy. The de nova class I MHC antigen induction on hepato-
Normal *ate *cuterejccdan CMV hspthis Chol~“gitk Clwkstasis
+,-
_
_
_
+
-
_
-
+
.
-
-
++ ++ ++ +
+ + -
_
-
++
++ + ++ -
+,+,+ -
+,-
++ +i
1:
+
+,-
r
+,-
::
+,-
-
-
:+ ++
1:
-
cytes, these may also occur quantitatively Ott other cell types such es bile duct epithelia and endothclia. This, however, cannot be quantified by the conventional immunohistological methods. Expression of claw11MHCmolecules MHC classII molecules are induced
during rcjeftion,
infection and inflammatory complications on parachymal liver cells in a maoner similar to that of class I MHC molecules, but their expression is more restricted. In normal liver. HLA-DR antigensare only expressedby Kupffer cells. oortal interstitial cells and e few endothelia (12,23,2j,i6). HLA-DO and HLA-DP arc only present on a subpopulation of Kupffer cells and portal interstitial cells (26). Bile duct epithelia and hepatocytes are negative for class II molecules es detected by immunohistologicai methods (12). De nOV0 expression Of HLA.DR On bile dun epithelia in rejected liver grafts was first rcported by Takacs and Demetris (34,35). The detailed analysis of the HLA-DR induction on biliary epitbelium in human liver grafts revealed that an induction takes place both with rejection end infectious complications lcholaneitir. CMV heoatitis) (261 and that durine. tranr plantation a few bile ducts already display HLA-l% entigens (32). With strong induction of HLA-DR, also HLADP antiecns were wexoressed (26). Interestingly, in pa. tients developing rejection with a &nishing bile duct syn-
~
.
I.
,..
drome, strong expression of HLA-DR and HLA-DP was found on the bile duct remnants (26). The de nova expression of HLA-DR antigens on hep. atocyte membranes was observed in liver grafts during acute rejection
and CMV hepatitis
(26). This was found
focally around infiltrates in ecctc rejection
and at sites of
inflammation in CMV hepatitis. HLA-DP and HLA-DQ were not found to be aexpressed on the positive cells. In experimental studies in ret and rhesus monkey the weak induction of class II MHC antigens on a limited number of hepatocyte membranes could also be demonstrated (30.36). In these models the induction was related to the rejection
process and was reversible
atocyte membranes similar to that in liver grafts during rejection (39-41). In vitro rinterferon was able to induce HLA-DR on cultured hepatocytes (40). Moreover, in liver grafts with CMV hepatitis without rejection an induction of bath class 1 and HLA-DR antigens was observed on hepatocyte membranes (26). A clear discrhnination of the immune processes causing the induction of class I and class II MHC molecules thus is not possible. Moreover, in many situations after transplantation different stimuli may exist, that cannet be distinguished by dinical data, histological and immunohistological mwph&gY. MHC antigens are not only induced liver cells, but also oo vsscularendothelial
on parcnchyma cells of the p-
tal vessels and the sinusoids (26). These cells are the major contact site to circulathtg lymphocytes and may play an important role in the elicitation and regulation of local immune responses. HLA-A. B and DR are expressedon endothelial cells in quiescent state after transplantation. HLA-DP and on a few endothclial cells HLA-DQ can bc additionally found during rejection and severe inflammation (26). In liver transplants the endothelial cella rcmained of donor type and expressed donor class I and classII MHC antigens as detected by antibodies directed to polymorphic epitopcs of donor or recipient HLA (31). In contrast, sinusoidal Kupffer cells of the donor disap pared gradually during the normal pmtopcrative coome and rapidly within a few weeks in the ease of severe rejection or infection (31,32). Thus,
in the patients
with mismatched
HLA
type,
a
mixed cell population of endothelial cells expressing do. nor MHC molefules and recipient Kupffer cells exists. So far, it is not known how this expression
of self and tton.seK
MHC molecules io the liver sinusoids may interfere with allogenic and non-allogenic immune reactions. This might very well be of importance for the development end dini. cal course of viral hepatitis and hepatitis B reinfection ht liver transplants.
within S-10 days af-
ter effective rejection treatment (36). Other authors studying isolated hepatocytes in transplant aspiration biopsies found variable numbers of HLADR positive hcpatocytes during rejection that decreased after effective treatment (37,36). 11 is not clear, however, whether the induction of HLA-DR on hepatwyles is a rejection related process initiated by the local release of lymphokines, or is due to local viral reactivation with viral hepatitis (39.40). In many patients a combination of stimuli can be postulated. Studies of non-transplanted livers with hepatitis B infection and primary biliary cirrhosis were able to show focal induction of HLA-DR antigenson hep-
A diagnostic use of the assessment of MHC antigen expression in liver tissue after transplantation has been pastolated by some authors. The detection of induction phenomena as the HLA-DR expression on bile ducts and hepatocytes indicates severe complications (26.42). The pattern of induction and localization may indicate the kind of the immune process (rejection vs. cholangitis/viral hepatitis) or by the lack of immune stimulation other processes, such as ischemia end toxic damage (26.42). However. the analysis of patterns of MHC antigens is a non-
specific parameter found during different types of immune reaction and tissue inflammation. Although the induction of HLA-DR antigens oo hepatmes in early acute rejection may correlate with the clinical and histological diagnosis (37.38) at later term, it may also indicate viral hepatitis (26). It can be used, however, to evaluate the effectiveness of immunosuppression as rejection
and autuimmwx
hepatitis.
At present, the limited analysis of immunological eventa, patient data and the small and heterogeneous patient population studied, however. caooot justify definite conclusions about 8 differential or dualistic effect of matching in claw I or class II MHC loci in human liver
pE?Ent.
transplants. Moreover, similar effects of HLA-DR matching should occur in patients with autoimmune or vial disease receiving heart, pancreas and renal allografts. The benefit of HLA matching and the analysis of po~toperative immune events in liver pr.afS first have to be characterized in large scale prospective. clinical studies and specific laboratory investigations.
ROkOfMAlNdChhg
Future direetiom
With recent progress in organ procurement and prolongation of preservation time, the discussion of the beneficial &feet of pmspatke HLA matching in the major MHC loci between donor and recipient has become actuelized. Tbe long-term o”tcome of renal and bone marrow transplants has been widely improved by HLA matching (43.44). Recently, with the availability of a large owber of patients who received a bean or B liver transplant. retrospective analysis concerning the &feet of HLA mis
The tissue interaction of the T-cell receptor (TCR) and different MHC molecules in viva during the process of antigen presentation and alloretiivity has to be iovestigated in more detail. The av&bility of appropriate reagents and more advanced immtmohistologieal and immunogold-electromnicrowopic methods may enable study of the receptor density, T-cell receptor/MHC interaction and the propagation by adhesion molecules such as CDZ, LFAI, ICAM-I, ICAMand LFA3 (10). The question arises, of whether a different interaction of T-
treatment and the donor alloantigen exposure of the 8&t as a guide for the immunosuppression. An increase of donor class II antigens on parenchymsl and endothelial cells especially, may represent P risk situation for the trans. plant even when histological signs of rejection are not ap
matches on rejection and graft outcome has been psible. In a study of 2ooo heart transplants, a beneficial effect of matching of HLAB and HLA-DR MHC antigas on .graft oubwme results mumble
has been demonstrated
(45.46). These
the effect seen in renal transplants
(44).
lymphocyte subpopulations with accessory cells of the donor type or alloantigen-presenting recipient acceswry cells (Kupffer cellslintentitial dendritic cells) may occur. The tissue distribution of the different accessmy cell sub-
In a series of 5&l liver trans@n~s, however. a different
populations
outcome of MHC elm I (HLA.AB)
!&I of T-lymphocyte reactivity. Moreover, their expression of different MHC produck and adhesion molecules may determine T-lymphocyte reactivity. The expression of th- allo-aotigenic sites of the diier. ent MHC molecules on the liver cell types may differ depending on the HLA type and cell membrane-related factors. Tbis could influence the T-lymphocyte reactivity and
and MHC class II
(HLA-DR) matched flafts was reported (47). The outcome of @ts marched for class II (HLA-DR) loci was infexiot to tbosc without match. This surprising effect has been intensively discussed and a similar negative effect of HLA-DR matching as a potential cause of the vanishing bile duct syndrome has been demonstrated in other papas (48). Two other authors, however, dextiid a correlation of HLA-DR mismatch vdtb vanishing bile duct syndrome (49) and a cholangitic/cholestatic rejection type (51). Both enhancement of 811antiviral and autoimmune or the T-cell response to minor histocnmpatibility antigens in gmfts with full HLA-DR wmpadbility are possible mechanisms oi graft injury. This may lead torecurrent disease, hut may ako augment the rejection act+ ity by the induction of donor HLA and secondary nensitization to alloantigens. Ako, a sensitization to notwnnpatible clars I molecules can be mediated by compatible HLA-DR. These mechanisms can be discussed in a variety of patients with liver d&ass such as PBC, PSC, viral
could then determine
the localization
and
the alloantigenicity of the different MHC molecules. The tissue immune reactions may be characterized more clearly and effects of intervention by immmmsuppressants, monoctonal antibodies and eytokioes can be described. A more detailed knowledge of the induction of donor antigens and their molecular interaction with recipient T-tymphocytes may, then, lead to a more specific immunosuppreuive treatment. The binding eharacterisiia of alloantigen specific T-lymplmcytes and mapping of the reactive T-cell receptors by anti-idiotypic antibodies are further fields of idterest. A major field of development will be in situ DNA/RNA hybridization techniques to study the translation of the
G. STEINHOFF
14 difft mt MHC molecules during cellular induction. In vitro studiesmust distinguishbetween the effects of the different
cytokines
an the MHC
gene transaiption
may be produced by liver cells (50) may be studied using molecular genetic methods.
and
Also, senmdary and direct effects of immunosuppressiveand other drugs may be characterized with a more advancedmethodology. The production of&-microglohulin as a soluble protein and of possibleadditional translation.
non-classicalclansI and classII MHC gene products that
1 Haok AW, OS! I?. Expression of cks 1 trsnsykrdadon antigens. Tmnspkntati.0” 1986; 42: m-17. 2 HaSara” PP. Wadgymar A, Aotcnricd P. The reS”klion of CIprerrio” of major hisbxompatibifity complex pmducts. Tm”splantation 19S6:41: 413-U). 3 scbwaru RH. ‘f’.-lymphwte recoS”irio” of antigen in asso&.do” with the gene pmduct of the major histommpatibifity corn. OkX. *““uRe”,m”l”“ol1985:3: 217-61. 4 hmacmaf6. ROk of hmc gene produstr in immu”e l@a6”“. science w.31; 212: L?zv-38. 5 Trowhkl, Campbell RD. Physical mapofthe hvman “LArc@on. Imm”“o, Today ,988: 9: 34-5. 6 Simgo” E. Function of the MHC. Immunology 1988; soppl. 1: 27-30.
10 ousti. ML, Stso”to” DE, Springer TA. Supergenefamiliarnest inthe imouna system.lmnmnol Today 1988:9: 213-15. 11 Dar AS, Fuggle S”, Fabre JW, Ting A, Morris PI. The detailed distribution of “LA-A&C antiSens in normal human orSaw.. Tra”spk”latio” ,984; 38: 287-92. 12 Daar AS, Fuggle SV. Fabx JW, Ti”g A, Morris R. The detaikd distribution of MHC cksr If antigens in normal human orgam. Tra”spk”taion 19% 38: 293-96. 13 Lampen IA. SuitternAJ, Chikom PM. Expcessio”of Ia snligol in epidermal kaatinacytes in graft-versus-hostdisease. Nature 19S,:i93 149~SO. 14 DC W.?alRMW. Bogman MJJ, Maas- CN. et al. Yarkbk erpree sion of Ia antigenson the vascularcndothelium of moue ski” alIoSrafls. Nawe ,981; 303: 4X-29. IS Milton AD, Fabre JW. Massive inducrio” of donor type class1 and classIf major histocompatibilitycompkx antigensin njectingcardiactilogmftsi” the rat. JExpMed 19&%161: 9S-112. 16 Londei M, Lamb 1% Bowzzo GH, et al. Epilhelial cellsexpressing aberm”, MtfC class11 detenoinants ca” present antigen Lo doned human Tcolk. Nature ,9S4:312: 639-41. 17 l&dab, P. GIc%er I, Lwy P, T0rey M. Insrferon tieamle”t Of “Ike: enhancedcx.pnsriDnof bbtommpvlibility aotigcnr on ly”l. phoidcelk. PoxNat, Acad S&USA 1976; 73: 1284-87. 18 Sleeg PS, Sack MB, Ma”” DL, Strong DM, Oppsnheim 13. I”. wrfcro” regulation of DR antigen expressionsnd a%a”riSe”. pmscnring capabililks of the pmmyekwy6c ccU Line HL6n. Sand J lmmuno, ,985: 21: 425-M. 19 GmcnewoScn G. Buurma” WA. “a” der Linden “. Lympha. kine dependenceof in viva expressionof MHC II antigensby endotbctium. Nature 1985:316: MI-63 20 Da& HS. Taylor JE. Daniel MR. Differences be&we” piS tis-
Acknowkdgement This work was supported by the Deutsche Forschubgsgemr’nschaft, ForscbergruppeOrgantransplantation.
22 Pan EL. Dircnity of expressionof H-2 antigms 0” mow liver ce”s demonrtrated by bm”o”ofeni,i” kbe”i”S. Tm”splmtad”” l97s:n: 45-S. 23 Natali PG, Cr Martko C, Quarants ‘I. et al. Expressio” of lalike omipsns in “onoll “on-hnnphoid riaucr. Tm”s+4~.tstioo 1981;31: 75-S. 24 Barbalk ‘2, Wmdr 1, Morton ,A, “eminS KA, M&,ichacl A, MsGbcc IOD. Immunobktwhwdal a”alysia of HLA (A.&C) amiyns in liver dixirc o&S P monacknal antibody. Gut 1981; a: 985-91.
27 Nagafoehi Y. Thomas HC, Hobbs REF. Sckuer PP. bpresim of beta.2 micmSlobulin on hcpatayrer after liver tmnqdanu. tion. LMCC, 1985: i: 551-554.
29 hmer GK, Nagfwbi Y, Pulkr Lu. Hobbs KEF. li,ocpssd cxpnmioo of major histoampaibility sntigem in Bc liver as * rem wit Of cbokstarb. Tm”spkolntio” 19SSG 45: 749-x. 30 SetMA, Milton AD, *“cer SC, “ovsrio D. Fabre ,W. Donor cIw I and dw II major birtocompatfbifhy -flex aotigca cxpressionfollowing liver aSoyafd”g in rejecting awJ ~cjcctfng rat Brai. m”lb:natio”r. Transpkomlio” 1988; 46: 32-40. 31 Stcinhdf ii, Wonigeit K, Harppreebt 1, lohaso” IP, Pkbtmayr R. Expressionol dmmr and recipkrd cll~s I and ckm II major hktommpatibilfly mmpkx antipns in human liver grafts. l’raw Pk”lPmc ,987: 19: 3761-64. 32 Ooow AS”, Houtboff HI, Hokern, S. Beck” JM. Gips ‘XX, Poppcma S. Em&o” of major histocompatibiSrymmpkr a”tiSe”l and q.kccme”r of dooor cellsby tipk”t o”es B ho,“aZl lkor Smfl%*a”spkotation 198); 43: 291-96. 33 StrkhoffG. Won&b K, PichfmayrR. Pol.ynmrphkHLA-Aand HLA-B antigensare induced in rejcctiog liver grafts. Tra”s@ot Pox 1988:20: w3-7MJ.
36 Steinhoff d. lo”ker M, GobunatisO, et al. Course of untreated acute rejeaio” and effea ofrepeared anti-CD3 monocknnl anti.
MHC ANTIGENS IN LIVER TRANSPLANTATION
pk&tim,1990in press.
I or A, Faure JL. Neidccker I. Muin M. ChamDetier P. T&v&an P. Mmiwrin~ of lhr nllografts using fine-&edlc aspiration biwy: value of heparwj?e MHC-DR cxprc~sian in tbc dkgnosisofacate rejection. Transplant Proc 1987:19: 3810-11. 38 Vogel W, WohlfaMerT. l-hen P, Iudmakr 0. Knapp W. Margreirer R. Langirvdinal study cd major bistocampatibiliw cumpka antigen expression on hepatocytc in fineneedle a&&n biop$ks from humsn liver grafti. Tramplant Roe 1988; 20: 6w.49. 39 Van den Gord II. De Vor R. Dermel VI. in d!u di&bution of majorhk.tacomparibdRy mmpkr praduc~s and viral antigens in cbmnk hepatitis S infection: evidences lhat HBcAg containing ixpalcqtcr may expreu HLA-DR antigens. Hcpntology 19%; 6: 981-69. 40 Frana A. BamabaV,NntaliP,BalsanoC,MuscaA, BalsanoF. ExpreJsiw of class I and claa q major bis~ommpatibility cornP$.&igens 00 human bepa?cytes. Hepatdogy 19% 8:
3? Zanier
41 SpcaJer!I. paW OR, Hoffmann RM, et al. Differeatialsxpression of MHC dass II subregion products on bile dun epbheIial cells sod bcpato~ytcs in patients with primary biliary cirrhosis. Hepatol~ 1988;8: 459-62. 42 Steir&ff 0, Wanigeit K. Laudwi W. R&e 6, Picblmayr R. Diamwsti r&vance of altered MHC-antipen exacssion in hum&livcrtmqlalaols. HJ Peipcr, cd. Lang&b&, Arch%: CbinugjrcbcsFotum. Berlin: Springer, 1987.267-72.
1s 43 CSReilly P_J.C-t devclopncntr in marrow tmnsplplantattin. Transplant Prac 1987;19:92-102. 44 Opeh G. Effect of HLA matchiae in lO.OMlcvckxcadne treated c&w kidney umph,tn. Tran+ant Pm l/87; is: 64-46. 45 Yacoub i*i. Wstemtcin P, Lhayk P. ct al. Tbc ir~fluenccoi iiiAmatching in cardiac allogmft recipients receiving cyclmporine and ualhiorins. Trar&ant Roe 1987~19:2487-69.
47 Markus BH. Duqucrnoy RJ,Gordon RD, et al. Histocompacibilby and liver tm@amt outcame. DM HLA ned a dualistic cffeet? Transplantation 19%8:46:372-77. 48 Dooaklwa Pr, Akxander GJM, 0. Grady JG, cf al. Evidew lor an immune rerpomc to HLA das I antigens in Ihe vanishing bile duct syndrome after liver rtampku~ation. Lance1 19S7; i: 945. 49 Bans KP. Moore SB. Perkiner ID, Wiiaer RH. Grambscb PM, from RF. Influence of positive lympbacyit Batch and HLA mismatching w vanishing bik duct syodmme in human liver Sqrafts. T,acqk,,ti 1%; 45: 37d-79. sf: Spacer SC, F&e JW. IdeatiEati in rat liwr and serum of water-s&xbk cl=1 MHC molccekr pos%blyb~&ogous to the murinc G10 gene prod”“. JEIp Med 1987;L&s:159%16wI. 51 Gubematis 0, Kemnik J. Twcb G, p*hlma~ R. HLA ~mpatibility and different features of liver allograft reiecliw. TramsplantInt 1988;I: 155-60.
complex antigens in human liver transplants
Liver transplantntion is performed successfully acm55 major HLA differences between donor and recipient. This may be ittfluenced by the organ specific expression of major bistocampatibility complex (MHC) molec”k3 which determine *lx local immune reactivity and rejection response. The tissue expressian of MHC molecules on parenchymal and infiltrating ECUShas been shtdied in transplanted human liver using monoclonal antibodies and immunohistologjcal m&&s. A strong induction of class I (HLA-A,B,C; &-microgIohulin) and class II (HLA-DR,DO,DP) MHC antigem was demonstrated 3n hepatocytes, bile duct epitbetiunt and endothelial cells during rejection episodes and viral and bacterial infections. The massive induction of donor antigens on hepatocyfes, bile ducts and endothelia forms part of, and may also augment. therejectlon response. quiescmt without infectiota or nJection after transpl&ttation, however. a rather restricted expression of class f and class 1I donor MHC antigens ls present. In addition, the donor Kupffer alk and interstitial den&tic cells are gmdualiy replaced by recipient accky &Is expressing self-MHC molectde~. Tlxe changes in antigen density and distribution d donor MIX alloantigens as the replacement of acceswry cells capable of presenting antigens to Tlymphocytes may influence the course of immune reactivity and the rejxtion response in the liver. Tbk may partly explain
During
states
the favotttable clinical cause long after transplantation. Reliinary clinical investigations of the effect of HLA matching have shown a dualistic effect of the matcbbtg of class 1 or class II HLA antigens. Tbe role of HLA matching in liver traw plants in large clinical studies, with specific immunological
testing however, remains to be investigated. This may lead to
prospective HLA matching with wider organ availability atd improved preservation time in the future. Further studies should investigate in detail the T-ceil receptor-MHC interaction in liver tissue during rejection as well as other types of iamwte feactiott. ‘IIt.? analysis of the alloantigen expression ix tissue and its modulation by different immunosuppressants and cytokitta may be of diagnostic and therapeutic aid.
The genetic polymorphism of molecular groups causing individual s;fimnces fcmns the basis of the problem of histocompatibiity in organ transplantation. The polymorphic epitopes of the moleculer of the major histocmnpatibility complex (MHC) are the major transplantation antigens (1,Z). Their expression ln the membrane of different types of donor cell causes recipient sensitization aud de-
velopment of an alloantigen-directed immune msponse. In addition, it has became clear that MHC molecules form the ligand of tb.. T-cell aptor for the presentation and mcqtition of antigens (3). The regulation of the expression of s&MHC molecules in ti~ue may therefore determine the type and course of an immune response (4). Whereas a static expression of these molecules has ken assumed in the past, it is ww clear that their expression is dynamic and underlies regulatory influences (1.2).
G. STEtNHOFF
10 Two classes of major transplantation
molecule bearing
polymorphic epitopes ere enccded by genes of the MHC on chromosome 6. The class I molecule (HLA-A, B end C) is a glycoprotein composed of .%n alpha-chain with three immunoglobelin-like domains. The polymorphic sequence is restricted to the alpha-l and -2 domains that are also binding sites for the T-cell receptor molecuk. The non-covalent associated beta-chain, completing the receptor complex of the class 1 MHC molecuIc,&tticrogIobulin, is not encoded by the MHC but on chromosome 15, is not polymorphic and contains one domain. Three different polymorphic class I molecules are expressed that were defined serologically by their difference in antigetticity (HLA-A, HLA-B, HLA-C). The class II molecules are glycoproteins and composed of an alpha- and e betachain that are both polymorphic @LA-DR, HLA-DP, HLA-DQ) and both contain two domain regions. Additional HLA-D region gene5 have been defined (HLADO. HLA-D”. HLA-DX. HLA-DZ) that ma” have diffen&et undebnedprod&ts (5). regions of both class I and class II
-
Thepolymorphic
molecules me the binding site of the T-cell receptor mokcule (5.6). The polymorphism of this binding site between individuals allows the distinction between self and nonself (6,7). At the cleft of the polymorphic alpha-l and aloha-2 domains of the MHC molecule the peptide fragiems of foreign antigens are bound and presented (g,9i. In transplanted organs, a Tsell sensidzation to non-self antigen is induced due to the difference in the polymorphic sequence of the HLA molecuk. By similarity in sequence, clones aoss-reactive with viral or bacterial antigens may be activated.
The T-cell reactivity
mined by the expression
of the HLA
the expression
transplant models have demonstrated a massive induction of donor class I and class II MHC molecules an graft cells during acute rejection (13-15). Immunosuppressive drugs such as cyclosporine A have been shown to abrogate the production of lymphokines and the induction of class II molecules (2). The regulation of the expression of donor end recipient MHC molecules in transplanted organs may therefore determine the alloreactititiy and be of importance for the outmme and function of the graft. ‘I%eavailability of monoclonal antibodies to a variety of monomorphic and polymorphic epitopes of the different MHC molecules and the development of sensitive inmmnohistological methods has prompted the intensive study oi the regulation of the tissue expre&on of MHC molecules. Not onIy the two classes of MHC molectde were studied in their cellular expression, but also the differential regulation of the expression of the different MHC molecules so far &fined. Tissue biopsies have been taken from liver in different pathological states end sequentiaIty after liver transplaotaticm. This allowed the study of changes in MHC antigen expression during rejation other complications and under immunosuppressive
end drug
treatment.
first is deter-
molecules
on the
membrane of graft cells and second by the presentation of autologous accessory cells (dendritic cells, macrophages). Futthemtore, the binding of T-lymphocytes may be determitiad by the additional expression of adhesion molecules (IO). Studies concerning
tions and infections (1,2,13-15); these may also be capeble of presenting antigens (16). Lymphokines have been identified es the mediators of the induction of MHC expression (17-19). During immune reactions in organ transplants the induction of MHC antigens on donor cell types additionally increases the target antigens for the alloreactive T-lymphocytes. Studies in experimental organ
of the two classes of
MHC molecu!es: class 1 (HLA-A,B,C) and class 11 (HLA-DR,DQ,DP) on different cell types using monoclonal antibodies have shown a heterogeneous distribution in normal human tissue (lIJ2). Whereas class I MHC antigens were expresstd on the majority of cell types, the class II MHC antigen expression wes mainly restricted to B-lymphocytes and accessory cells (11,12). The limited distribution of class II MHC an&n positive accessory cells (dendritic cells, macrophages) ia tissue may therefore cause a local restriction of T-lymphoryte reactivity and sensitization. However, a number of studies have shown that class II MHC antigens can be induced on a number of additional cell types during immune reac-
Expressionof classI MHC molecules Early studies have shown that MHC molecules are not uniformly expressed on the different parenchymal mmpottents of organs (20-23). Hepatoqtes of the Liver were found to express no or low amounts of MHC molecules (21,22). In normal human liver class I (HLA-A,B,C), MHC antigens are not, or only in low density, expressed by human hepatocytes (24.25). Increased expression of alpha-chain and @z-microglobulin class I MHC antigena was found on hepatocyte membranes in a number of pathological states and during rejection efter liver trensplantation (24,26-28). No major difference in the density and pattern of expr&on wes noted between the alphachain of HLA-A,B,C md that of µglabulin (26). Studies employing sequential follow-up biopsies during various complications after liver tnosplantation could show that the induction of class I MHC antigens on hep atocyt: membranes occurred not only during rejection
licpameyte Bileductcpithelium
.(l, -
(C) ++
Endothelial cell K”pffe,C4 Ponaldendriticcell
++
-
++
++
1:
::
+!++ ++
but also during various inllammatory
-
-
+ +
+,+
-
-
and infectious pro-
cesses (26). The induction of class 1 MHC antigens was revenible after cessation of the inflammation and afier successful rejection mmmmt (26). In graft biopsies without any complication, the pmtem of express&m resembled that of normal liver, but a part of the hepatofytes remained class I MHC amigen positive. In an experimental model of bile duct ligation in the tat. Inner et al. could show, that not only immmtologjcal stimuli, but cholestasis alone was able to inctease the class I expression on hepatocytes (29). In addition, in a rat liver transplant model it could be demonstrated by S&Wet al. that class I MHC antigens were induced on hspamcyte membranes not only in acute rejection but also in non-rejeetina isogmfts (30). Interestingly, in human transpIams in the majority of biopsies taken before and during the transplant operation, an induction of class I MHC antigens branes damage
was found
OR hepatacyte
(l&%)26).This may very well be caused or inflammatory
seta to monomorphic epitopes. Moreover, an equal induction of HLA-A and HLA-B antigens during rejection could be demonstrated in nequetttial biopsies of a limited number of patients (33). It is not known, however, if HLA-C molecules are induced and exprewd in a manner similar to that of HL&A and HLA-B. The production and expression of the different class I MHC moleales may very well undertie genetically determined individual differences. Futthermore, it is unckar whether the regu-
memby toxic
lation of the production
reactions in the donor and dur-
of &-miao~btdin
is regulated
cyte membranes has been further r!ifferemiated using HLA-A and HLA-B specific antibodies directed against polymorphic epitopes (31). In patiena with an appropriate diirence in HLA type, it could be shown that the
by the same stimuli as the class I alpha-chain in hepatccytes or may be produced in response to other factors. Although class I MHC antigens are expressed on bile duct epithelia, endotbelia, Kupffer cells and intentilial cell types in the normal human liver. an increased expression of HLA-A and HLA-B antigens can be demonstrated on bile duct epithelia during rejection and infections such as
induced antigens were donor derived (31,32). The expres-
cholangitis (33).
sion and induction phenomena for both donor HLA-A and HLA-B were the same as previously found with anti-
Thus, although induction phenomena can be demonstrated qualitatively an the normally negmlve hepato-
fng hepatectomy. The de nova class I MHC antigen induction on hepato-
Normal *ate *cuterejccdan CMV hspthis Chol~“gitk Clwkstasis
+,-
_
_
_
+
-
_
-
+
.
-
-
++ ++ ++ +
+ + -
_
-
++
++ + ++ -
+,+,+ -
+,-
++ +i
1:
+
+,-
r
+,-
::
+,-
-
-
:+ ++
1:
-
cytes, these may also occur quantitatively Ott other cell types such es bile duct epithelia and endothclia. This, however, cannot be quantified by the conventional immunohistological methods. Expression of claw11MHCmolecules MHC classII molecules are induced
during rcjeftion,
infection and inflammatory complications on parachymal liver cells in a maoner similar to that of class I MHC molecules, but their expression is more restricted. In normal liver. HLA-DR antigensare only expressedby Kupffer cells. oortal interstitial cells and e few endothelia (12,23,2j,i6). HLA-DO and HLA-DP arc only present on a subpopulation of Kupffer cells and portal interstitial cells (26). Bile duct epithelia and hepatocytes are negative for class II molecules es detected by immunohistologicai methods (12). De nOV0 expression Of HLA.DR On bile dun epithelia in rejected liver grafts was first rcported by Takacs and Demetris (34,35). The detailed analysis of the HLA-DR induction on biliary epitbelium in human liver grafts revealed that an induction takes place both with rejection end infectious complications lcholaneitir. CMV heoatitis) (261 and that durine. tranr plantation a few bile ducts already display HLA-l% entigens (32). With strong induction of HLA-DR, also HLADP antiecns were wexoressed (26). Interestingly, in pa. tients developing rejection with a &nishing bile duct syn-
~
.
I.
,..
drome, strong expression of HLA-DR and HLA-DP was found on the bile duct remnants (26). The de nova expression of HLA-DR antigens on hep. atocyte membranes was observed in liver grafts during acute rejection
and CMV hepatitis
(26). This was found
focally around infiltrates in ecctc rejection
and at sites of
inflammation in CMV hepatitis. HLA-DP and HLA-DQ were not found to be aexpressed on the positive cells. In experimental studies in ret and rhesus monkey the weak induction of class II MHC antigens on a limited number of hepatocyte membranes could also be demonstrated (30.36). In these models the induction was related to the rejection
process and was reversible
atocyte membranes similar to that in liver grafts during rejection (39-41). In vitro rinterferon was able to induce HLA-DR on cultured hepatocytes (40). Moreover, in liver grafts with CMV hepatitis without rejection an induction of bath class 1 and HLA-DR antigens was observed on hepatocyte membranes (26). A clear discrhnination of the immune processes causing the induction of class I and class II MHC molecules thus is not possible. Moreover, in many situations after transplantation different stimuli may exist, that cannet be distinguished by dinical data, histological and immunohistological mwph&gY. MHC antigens are not only induced liver cells, but also oo vsscularendothelial
on parcnchyma cells of the p-
tal vessels and the sinusoids (26). These cells are the major contact site to circulathtg lymphocytes and may play an important role in the elicitation and regulation of local immune responses. HLA-A. B and DR are expressedon endothelial cells in quiescent state after transplantation. HLA-DP and on a few endothclial cells HLA-DQ can bc additionally found during rejection and severe inflammation (26). In liver transplants the endothelial cella rcmained of donor type and expressed donor class I and classII MHC antigens as detected by antibodies directed to polymorphic epitopcs of donor or recipient HLA (31). In contrast, sinusoidal Kupffer cells of the donor disap pared gradually during the normal pmtopcrative coome and rapidly within a few weeks in the ease of severe rejection or infection (31,32). Thus,
in the patients
with mismatched
HLA
type,
a
mixed cell population of endothelial cells expressing do. nor MHC molefules and recipient Kupffer cells exists. So far, it is not known how this expression
of self and tton.seK
MHC molecules io the liver sinusoids may interfere with allogenic and non-allogenic immune reactions. This might very well be of importance for the development end dini. cal course of viral hepatitis and hepatitis B reinfection ht liver transplants.
within S-10 days af-
ter effective rejection treatment (36). Other authors studying isolated hepatocytes in transplant aspiration biopsies found variable numbers of HLADR positive hcpatocytes during rejection that decreased after effective treatment (37,36). 11 is not clear, however, whether the induction of HLA-DR on hepatwyles is a rejection related process initiated by the local release of lymphokines, or is due to local viral reactivation with viral hepatitis (39.40). In many patients a combination of stimuli can be postulated. Studies of non-transplanted livers with hepatitis B infection and primary biliary cirrhosis were able to show focal induction of HLA-DR antigenson hep-
A diagnostic use of the assessment of MHC antigen expression in liver tissue after transplantation has been pastolated by some authors. The detection of induction phenomena as the HLA-DR expression on bile ducts and hepatocytes indicates severe complications (26.42). The pattern of induction and localization may indicate the kind of the immune process (rejection vs. cholangitis/viral hepatitis) or by the lack of immune stimulation other processes, such as ischemia end toxic damage (26.42). However. the analysis of patterns of MHC antigens is a non-
specific parameter found during different types of immune reaction and tissue inflammation. Although the induction of HLA-DR antigens oo hepatmes in early acute rejection may correlate with the clinical and histological diagnosis (37.38) at later term, it may also indicate viral hepatitis (26). It can be used, however, to evaluate the effectiveness of immunosuppression as rejection
and autuimmwx
hepatitis.
At present, the limited analysis of immunological eventa, patient data and the small and heterogeneous patient population studied, however. caooot justify definite conclusions about 8 differential or dualistic effect of matching in claw I or class II MHC loci in human liver
pE?Ent.
transplants. Moreover, similar effects of HLA-DR matching should occur in patients with autoimmune or vial disease receiving heart, pancreas and renal allografts. The benefit of HLA matching and the analysis of po~toperative immune events in liver pr.afS first have to be characterized in large scale prospective. clinical studies and specific laboratory investigations.
ROkOfMAlNdChhg
Future direetiom
With recent progress in organ procurement and prolongation of preservation time, the discussion of the beneficial &feet of pmspatke HLA matching in the major MHC loci between donor and recipient has become actuelized. Tbe long-term o”tcome of renal and bone marrow transplants has been widely improved by HLA matching (43.44). Recently, with the availability of a large owber of patients who received a bean or B liver transplant. retrospective analysis concerning the &feet of HLA mis
The tissue interaction of the T-cell receptor (TCR) and different MHC molecules in viva during the process of antigen presentation and alloretiivity has to be iovestigated in more detail. The av&bility of appropriate reagents and more advanced immtmohistologieal and immunogold-electromnicrowopic methods may enable study of the receptor density, T-cell receptor/MHC interaction and the propagation by adhesion molecules such as CDZ, LFAI, ICAM-I, ICAMand LFA3 (10). The question arises, of whether a different interaction of T-
treatment and the donor alloantigen exposure of the 8&t as a guide for the immunosuppression. An increase of donor class II antigens on parenchymsl and endothelial cells especially, may represent P risk situation for the trans. plant even when histological signs of rejection are not ap
matches on rejection and graft outcome has been psible. In a study of 2ooo heart transplants, a beneficial effect of matching of HLAB and HLA-DR MHC antigas on .graft oubwme results mumble
has been demonstrated
(45.46). These
the effect seen in renal transplants
(44).
lymphocyte subpopulations with accessory cells of the donor type or alloantigen-presenting recipient acceswry cells (Kupffer cellslintentitial dendritic cells) may occur. The tissue distribution of the different accessmy cell sub-
In a series of 5&l liver trans@n~s, however. a different
populations
outcome of MHC elm I (HLA.AB)
!&I of T-lymphocyte reactivity. Moreover, their expression of different MHC produck and adhesion molecules may determine T-lymphocyte reactivity. The expression of th- allo-aotigenic sites of the diier. ent MHC molecules on the liver cell types may differ depending on the HLA type and cell membrane-related factors. Tbis could influence the T-lymphocyte reactivity and
and MHC class II
(HLA-DR) matched flafts was reported (47). The outcome of @ts marched for class II (HLA-DR) loci was infexiot to tbosc without match. This surprising effect has been intensively discussed and a similar negative effect of HLA-DR matching as a potential cause of the vanishing bile duct syndrome has been demonstrated in other papas (48). Two other authors, however, dextiid a correlation of HLA-DR mismatch vdtb vanishing bile duct syndrome (49) and a cholangitic/cholestatic rejection type (51). Both enhancement of 811antiviral and autoimmune or the T-cell response to minor histocnmpatibility antigens in gmfts with full HLA-DR wmpadbility are possible mechanisms oi graft injury. This may lead torecurrent disease, hut may ako augment the rejection act+ ity by the induction of donor HLA and secondary nensitization to alloantigens. Ako, a sensitization to notwnnpatible clars I molecules can be mediated by compatible HLA-DR. These mechanisms can be discussed in a variety of patients with liver d&ass such as PBC, PSC, viral
could then determine
the localization
and
the alloantigenicity of the different MHC molecules. The tissue immune reactions may be characterized more clearly and effects of intervention by immmmsuppressants, monoctonal antibodies and eytokioes can be described. A more detailed knowledge of the induction of donor antigens and their molecular interaction with recipient T-tymphocytes may, then, lead to a more specific immunosuppreuive treatment. The binding eharacterisiia of alloantigen specific T-lymplmcytes and mapping of the reactive T-cell receptors by anti-idiotypic antibodies are further fields of idterest. A major field of development will be in situ DNA/RNA hybridization techniques to study the translation of the
G. STEINHOFF
14 difft mt MHC molecules during cellular induction. In vitro studiesmust distinguishbetween the effects of the different
cytokines
an the MHC
gene transaiption
may be produced by liver cells (50) may be studied using molecular genetic methods.
and
Also, senmdary and direct effects of immunosuppressiveand other drugs may be characterized with a more advancedmethodology. The production of&-microglohulin as a soluble protein and of possibleadditional translation.
non-classicalclansI and classII MHC gene products that
1 Haok AW, OS! I?. Expression of cks 1 trsnsykrdadon antigens. Tmnspkntati.0” 1986; 42: m-17. 2 HaSara” PP. Wadgymar A, Aotcnricd P. The reS”klion of CIprerrio” of major hisbxompatibifity complex pmducts. Tm”splantation 19S6:41: 413-U). 3 scbwaru RH. ‘f’.-lymphwte recoS”irio” of antigen in asso&.do” with the gene pmduct of the major histommpatibifity corn. OkX. *““uRe”,m”l”“ol1985:3: 217-61. 4 hmacmaf6. ROk of hmc gene produstr in immu”e l@a6”“. science w.31; 212: L?zv-38. 5 Trowhkl, Campbell RD. Physical mapofthe hvman “LArc@on. Imm”“o, Today ,988: 9: 34-5. 6 Simgo” E. Function of the MHC. Immunology 1988; soppl. 1: 27-30.
10 ousti. ML, Stso”to” DE, Springer TA. Supergenefamiliarnest inthe imouna system.lmnmnol Today 1988:9: 213-15. 11 Dar AS, Fuggle S”, Fabre JW, Ting A, Morris PI. The detailed distribution of “LA-A&C antiSens in normal human orSaw.. Tra”spk”latio” ,984; 38: 287-92. 12 Daar AS, Fuggle SV. Fabx JW, Ti”g A, Morris R. The detaikd distribution of MHC cksr If antigens in normal human orgam. Tra”spk”taion 19% 38: 293-96. 13 Lampen IA. SuitternAJ, Chikom PM. Expcessio”of Ia snligol in epidermal kaatinacytes in graft-versus-hostdisease. Nature 19S,:i93 149~SO. 14 DC W.?alRMW. Bogman MJJ, Maas- CN. et al. Yarkbk erpree sion of Ia antigenson the vascularcndothelium of moue ski” alIoSrafls. Nawe ,981; 303: 4X-29. IS Milton AD, Fabre JW. Massive inducrio” of donor type class1 and classIf major histocompatibilitycompkx antigensin njectingcardiactilogmftsi” the rat. JExpMed 19&%161: 9S-112. 16 Londei M, Lamb 1% Bowzzo GH, et al. Epilhelial cellsexpressing aberm”, MtfC class11 detenoinants ca” present antigen Lo doned human Tcolk. Nature ,9S4:312: 639-41. 17 l&dab, P. GIc%er I, Lwy P, T0rey M. Insrferon tieamle”t Of “Ike: enhancedcx.pnsriDnof bbtommpvlibility aotigcnr on ly”l. phoidcelk. PoxNat, Acad S&USA 1976; 73: 1284-87. 18 Sleeg PS, Sack MB, Ma”” DL, Strong DM, Oppsnheim 13. I”. wrfcro” regulation of DR antigen expressionsnd a%a”riSe”. pmscnring capabililks of the pmmyekwy6c ccU Line HL6n. Sand J lmmuno, ,985: 21: 425-M. 19 GmcnewoScn G. Buurma” WA. “a” der Linden “. Lympha. kine dependenceof in viva expressionof MHC II antigensby endotbctium. Nature 1985:316: MI-63 20 Da& HS. Taylor JE. Daniel MR. Differences be&we” piS tis-
Acknowkdgement This work was supported by the Deutsche Forschubgsgemr’nschaft, ForscbergruppeOrgantransplantation.
22 Pan EL. Dircnity of expressionof H-2 antigms 0” mow liver ce”s demonrtrated by bm”o”ofeni,i” kbe”i”S. Tm”splmtad”” l97s:n: 45-S. 23 Natali PG, Cr Martko C, Quarants ‘I. et al. Expressio” of lalike omipsns in “onoll “on-hnnphoid riaucr. Tm”s+4~.tstioo 1981;31: 75-S. 24 Barbalk ‘2, Wmdr 1, Morton ,A, “eminS KA, M&,ichacl A, MsGbcc IOD. Immunobktwhwdal a”alysia of HLA (A.&C) amiyns in liver dixirc o&S P monacknal antibody. Gut 1981; a: 985-91.
27 Nagafoehi Y. Thomas HC, Hobbs REF. Sckuer PP. bpresim of beta.2 micmSlobulin on hcpatayrer after liver tmnqdanu. tion. LMCC, 1985: i: 551-554.
29 hmer GK, Nagfwbi Y, Pulkr Lu. Hobbs KEF. li,ocpssd cxpnmioo of major histoampaibility sntigem in Bc liver as * rem wit Of cbokstarb. Tm”spkolntio” 19SSG 45: 749-x. 30 SetMA, Milton AD, *“cer SC, “ovsrio D. Fabre ,W. Donor cIw I and dw II major birtocompatfbifhy -flex aotigca cxpressionfollowing liver aSoyafd”g in rejecting awJ ~cjcctfng rat Brai. m”lb:natio”r. Transpkomlio” 1988; 46: 32-40. 31 Stcinhdf ii, Wonigeit K, Harppreebt 1, lohaso” IP, Pkbtmayr R. Expressionol dmmr and recipkrd cll~s I and ckm II major hktommpatibilfly mmpkx antipns in human liver grafts. l’raw Pk”lPmc ,987: 19: 3761-64. 32 Ooow AS”, Houtboff HI, Hokern, S. Beck” JM. Gips ‘XX, Poppcma S. Em&o” of major histocompatibiSrymmpkr a”tiSe”l and q.kccme”r of dooor cellsby tipk”t o”es B ho,“aZl lkor Smfl%*a”spkotation 198); 43: 291-96. 33 StrkhoffG. Won&b K, PichfmayrR. Pol.ynmrphkHLA-Aand HLA-B antigensare induced in rejcctiog liver grafts. Tra”s@ot Pox 1988:20: w3-7MJ.
36 Steinhoff d. lo”ker M, GobunatisO, et al. Course of untreated acute rejeaio” and effea ofrepeared anti-CD3 monocknnl anti.
MHC ANTIGENS IN LIVER TRANSPLANTATION
pk&tim,1990in press.
I or A, Faure JL. Neidccker I. Muin M. ChamDetier P. T&v&an P. Mmiwrin~ of lhr nllografts using fine-&edlc aspiration biwy: value of heparwj?e MHC-DR cxprc~sian in tbc dkgnosisofacate rejection. Transplant Proc 1987:19: 3810-11. 38 Vogel W, WohlfaMerT. l-hen P, Iudmakr 0. Knapp W. Margreirer R. Langirvdinal study cd major bistocampatibiliw cumpka antigen expression on hepatocytc in fineneedle a&&n biop$ks from humsn liver grafti. Tramplant Roe 1988; 20: 6w.49. 39 Van den Gord II. De Vor R. Dermel VI. in d!u di&bution of majorhk.tacomparibdRy mmpkr praduc~s and viral antigens in cbmnk hepatitis S infection: evidences lhat HBcAg containing ixpalcqtcr may expreu HLA-DR antigens. Hcpntology 19%; 6: 981-69. 40 Frana A. BamabaV,NntaliP,BalsanoC,MuscaA, BalsanoF. ExpreJsiw of class I and claa q major bis~ommpatibility cornP$.&igens 00 human bepa?cytes. Hepatdogy 19% 8:
3? Zanier
41 SpcaJer!I. paW OR, Hoffmann RM, et al. Differeatialsxpression of MHC dass II subregion products on bile dun epbheIial cells sod bcpato~ytcs in patients with primary biliary cirrhosis. Hepatol~ 1988;8: 459-62. 42 Steir&ff 0, Wanigeit K. Laudwi W. R&e 6, Picblmayr R. Diamwsti r&vance of altered MHC-antipen exacssion in hum&livcrtmqlalaols. HJ Peipcr, cd. Lang&b&, Arch%: CbinugjrcbcsFotum. Berlin: Springer, 1987.267-72.
1s 43 CSReilly P_J.C-t devclopncntr in marrow tmnsplplantattin. Transplant Prac 1987;19:92-102. 44 Opeh G. Effect of HLA matchiae in lO.OMlcvckxcadne treated c&w kidney umph,tn. Tran+ant Pm l/87; is: 64-46. 45 Yacoub i*i. Wstemtcin P, Lhayk P. ct al. Tbc ir~fluenccoi iiiAmatching in cardiac allogmft recipients receiving cyclmporine and ualhiorins. Trar&ant Roe 1987~19:2487-69.
47 Markus BH. Duqucrnoy RJ,Gordon RD, et al. Histocompacibilby and liver tm@amt outcame. DM HLA ned a dualistic cffeet? Transplantation 19%8:46:372-77. 48 Dooaklwa Pr, Akxander GJM, 0. Grady JG, cf al. Evidew lor an immune rerpomc to HLA das I antigens in Ihe vanishing bile duct syndrome after liver rtampku~ation. Lance1 19S7; i: 945. 49 Bans KP. Moore SB. Perkiner ID, Wiiaer RH. Grambscb PM, from RF. Influence of positive lympbacyit Batch and HLA mismatching w vanishing bik duct syodmme in human liver Sqrafts. T,acqk,,ti 1%; 45: 37d-79. sf: Spacer SC, F&e JW. IdeatiEati in rat liwr and serum of water-s&xbk cl=1 MHC molccekr pos%blyb~&ogous to the murinc G10 gene prod”“. JEIp Med 1987;L&s:159%16wI. 51 Gubematis 0, Kemnik J. Twcb G, p*hlma~ R. HLA ~mpatibility and different features of liver allograft reiecliw. TramsplantInt 1988;I: 155-60.