MHC genes in HLA-associated disease

MHC

genes in HLA-associated a

disease

C.T. Nepom Virginia

Mason

Research Center

and the Department

School of Medicine, Current

Opinion

of Immunology,

Seattle, Washington,

in Immunology

Introduction Although markers within the human leukocyte antigen (HLA) gene complex on chromosome 6 have been known to be associated with certain diseases for more than 15 years, the molecular basis for these associations has, until recently, remained unclear. Recent studies, however, primarily using the techniques of molecular biology, have documented patterns of nucleotide sequence vanations that are shared among HLA genes in certain diseases. This new focus on specific nucleotide contributions to HLA-associated diseases represents a major advance in the conceptual and technical experimental approaches to the genetics of autoimmunity. It is now appropriate to move beyond identifying susceptible haplotypes and to begin to construct explicit models of disease involving single candidate susceptibility genes. In this article, I will summarize progress in this area, and consider those HI&associated diseases where, not only has the major histocompatibility complex (MIX) haplotype been identitied, but a specific gene on a susceptible haplotype has been implicated; in addition, I will discuss those few cases where a specific sequence or epitope within a single gene or gene product has been identilied as the probable molecular basis for the genetic association.

Candidate susceptibility genes The identification of specific disease susceptibility genes within the human MHC has been confounded by the fact that most MIX haplotypes consist of a series of tightly linked loci. Thus, a marker identified on the haplotype associated with disease [i.e., DR3 in type I diabetes and celiac disease; DR4 in type I diabetes and rheumatoid arthritis (RA)] does not necessarily represent any specific gene on that haplotype. Instead, it is necessary to identify individually each of the specific genes encoded by different linked loci on a single disease-associated haplotype, and then to evaluate the connection of each of these genes with the disease individually. In this form of analy

University

of Washington

USA

1990, 2:588-592

sis, individual loci within a haplotype which account for the association of that haplotype with disease are identified; for instance, DQP with type I diabetes on haplotypes that type as HLA-DR4, and DRj31 with RA also on haplotypes that type as HLADR4 [ 11. Recent studies have successfully used this molecular perspective to clarify the interpretation of the genetic contribution to HLAassociated diseases in several specific cases illustrated in Fig. 1 and briefly reviewed below. Type

I diabetes Controversies swirl around both the mechanisms and the molecular basis for the associations between HIA and insulin-dependent diabetes mellitus (IDDM). One fact that is agreed upon is that the HIA-DQ3.2 gene, a spe cihc allele at the DQP locus, is the single most commonly associated gene in diabetic Caucasians. As such, it accounts for the association of the linked serologic HIADR4 specificity previously described in numerous studies of diabetes. Several controversial questions are still unarswered, however. Are there other specific HLA genes that modify the relative contribution of the DQ3.2 gene to disease? Is DQ3.2 a dominant or recessive gene? What is the role, if any, of spectic residues such as codon 57 within the DQ3.2 molecule in diabetes? There certainly are other HLA genes, as well as HIA DQ3.2, which contribute to the genetic risk of IDDM. Fqr example, the synergistic risk in heterozygotes with HLA DR3 and DR4 haplotypes is well documented; however, the structural basis for this synergy remains completely unknown. Numerous investigators have speculated that perhaps a DQct molecule from the DR3 haplotype and a DC@ molecule from the DR4 haplotype form a unique trans-associated class II dimer that is important in pathogenesis. Such dimers have been shown to exist in diabetics (Nepom et al, Diabetes 1987, 36:11&1171, and in transfection studies they form stable class II dimers with distinct T-cell recognition properties [2] (Kwok et al, J Immunol1988,141:3123_3127). Nevertheless, since most diabetics are not heterozygous for DR3/4, such interactions are unlikely to be an essential part of the disease-associated pathway. A variation on this concept

Abbreviations HLA-human leukocyte antigen; IDDMinsulin-dependent diabetes mellitus; MHC-major histocompatibility complex; NO&non-obese diabetic; RA-rheumatoid arthritis.

@ Current Science Ltd ISSN 0952-7915

MHC

Haplotype designation (HLA-DR, D specificity)

T

Class II alleles (DQ-DR DQAl*

DQBI”

disease NeDom

interval) DRBl*

DRI, Dwl

0101

0501

DR2, Dw2

0102

0602

1501

DR2, Dw12

0103

0601

1502

DR2, Dw21

0102

0502

DR3, Dw3

penes in HLA-associated

1601 0301

DR4, Dw4 DR4, Dw4 DR4, Dw14 DR4, Dw13 DR4, DwlO DR4, Dw15

0405

DR6, Dw9

1401 1301

DR6, Dw18 0102

DR6, Dw19

0301

DR5, Dw5 DR7, Dw17

0604

1302 1101 0701

w

DR7, Dwll

0201

DRB, Dw8.1

0401

0402

DR8, Dw8.3

0103

0601

0803

DR9, Dw23

0301

0303

0901

DRwlO

0301

0501

1001

0701 0801

Fig. 1. Major histocompatibility genes in human leukocyte antigen (HLA)-associated disease. Individual alleles are shown for the DQAI CDQu), DQBI CDQfl), and DRBI (DRP) Ioci, listed by linkage pattern for haplotypes which correspond to the HLA-DRI-DRwlO specificities. Genes are designated by the 1990 revised HLA nomenclature adapted by the World Health Organization Nomenclature Committee. Candidate disease susceptibility genes are indicated for four autoimmune diseases where specific alleles have been shown to account for the association between HLA and that disease.

has been proposed recently [3], suggesting that DQcl from the DR4 haplotype and DQl from a DR7, DQw2 haplotype are associated with IDDM on a single haplotype in non-Caucasians. This suggested that interaction is unlikely to be an important genetic element in IDDM, however, because these postulated cl/p interactions are apparently not associated with IDDM in Puns linkage (i.e., in heterozygotes), but only in c& linkage. A much more likely interpretation is that something else on the non-DR4 haplotype is contributing to disease. In addition, more subtle types of &modifying genetic elements may also contribute in a minor way to IDDM susceptibility: of the three different DR4 haplotypes which carry the DQ3.2 gene, there is a consistent ‘rank order’ for the order of prevalence of the haplotypes in IDDM (Dw4, DQ3.2 > DwlO, DQ3.2 > Dw14, DQ3.2). Whether this represents some ‘epistatic’ effect of HLADR [4] or simply the presence of other contributing genetic elements is unknown. HIADQ3.2, the most likely candidate gene for IDDM sus ceptibility, appears to act as a dominant permissive genetic element; IDDM is apparently initiated in genetically susceptible individuals by an, as yet, unknown environmental precipitant. An extensive analysis by Thomson et al. [5] provides direct genetic support for the notion that the DR4associated contribution (i.e, DQ3.2) is inherited as a predominantly dominant risk element. In terestingly, however, nonDR4 contributions, particularly from the HIA-DR3 haplotype, showed a different pattern

that was most consistent with a recessive mode of inheritance. This may imply that there is a completely different genetic element on the DR3 haplotype contributing to disease susceptibility. The notion that DQ3.2 is a dominant susceptibility trait for IDDM is inconsistent with the hypothetical ‘codon 57’ model, which proposes that an aspartic acid at codon 57 of the DQP chain ‘protects’ lrom IDDM (Todd et al, Nature 1987, 329:59%603). The ‘codon 57’ hypo thesis is derived from the observation that haplotypes that carry a IXjl3 allele positive for an aspartic acid at codon 57 are negatively correlated with IDDM. Several recent studies have confirmed this general Iinding in Caucasians, but not in Oriental diabetics [6--g]. However, even among Caucasians, many patients with IDDM carty at least one Asp 57.positive ‘protective’ allele [8]. In a direct test of whether such haplotypes do protect against IDDM, siblings within families who shared an Asp57positive DQP allele were examined to see whether they also had IDDM (Nepom and Robinson. In Molecular Biology and Autoimmune Disease edited by Macgregor and Demaine. Springer-Verlag, 1989, pp 251-262). In this study, an equal number of affected and unaffected siblings shared such haplotypes, which is inconsistent with the notion of dominant ‘protection’ being conferred by an Asp 57.positive DQ gene. The best way of reconciling the codon 57 hypothesis with the combined data set is to treat the presence of

589

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Autoimmunity

an aspartic acid at the D@ codon 57 as merely a linked marker, albeit within the coding region, for certain haplotypes. Since these haplotypes include DR4, DQ3.2 and DR3, DQw2, this codon 57 polymorphism is a convenient marker on most of the known susceptible haplotypes in Caucasians; however, it is equally apparent that the residue at codon 57 does not, itself, account for genetic susceptibility to IDDM. The specific immunologic roles of residues at codon 57, and at the other polymorphic residues characteristic of DQ3.2, are likely to be somewhat complex. Using site& rected mutagenesis, Kwok et al. [2,9] demonstrated that the major serologic specificities associated with DQ3.2 correspond to amino acid residues at codon 45, and that allorecognition by T-cell clones is heavily intluenced by multiple polymorphic sites on the p chain. In these studies, the residue at codon 57 contributes in a significant way to interactions between polymorphic DQcl chains and recognition of specific sites on the j3 chain by dif ferent T-cell clones. Thus, a likely mechanism of action would be that residues at codon 57, along with other polymorphic sites in the class II molecule, form a composite class II recognition element permissive for disease.

Celiac disease

has long been known to be associated with HIADR3. The authors of two recent studies [ 10,111 also noted that many non-DR3 celiacs were heterozygous for haplotypes that separately carried the same DQcl and DC@ chains normally found on DEW-positive haplotypes. In other words, over 90% of celiac patients studied carried a characteristic DQcl/j3 dimer. As with IDDM, these data are most consistent with the notion of a dominant DQ permissive susceptibility element responsible for the association between HLA and disease. Celiac disease

In addition to the DQ association with celiac disease, a preferential association with DP has been reported [ 11,121, which may indicate that there is a second MHCencoded susceptibility gene. It has been noted that the most highly associated DP alleles, and the DQ susceptibility determinant, share a positively charged residue around codon 71 of the j3 chain. As is the case in IDDM, however, this residue is not unique to alleles associated with celiac disease and, at best, plays some co-ordinating role with other residues on the susceptibility allele.

Pemphigus

vulgaris

Pemphigus vulgaris is another autoimmune disease in which two different HIA haplotypes are associated with disease. However, unlike IDDM and celiac disease, the two susceptibility genes in pemphigus vulgaris appear to be unlinked both genetically or functionally; that is, they appear to be representative of two ethnic populations, and may represent independent genetic pathways to this disease, without evidence of synergy. Sharf et al. [13] found that the association between pemphigus vulgaris and HLADRw6 is due to the association with a particular DQj3 allele termed DQfl1.3, found in 86% of DR6

patients compared with 3% of controls. In contrast, the Gsociation between pemphigus vulgaris and DR4 cannot be accounted for by specific alleles of the DC@ locus and is probably due to a specific allele, termed DwlO, at the DRBl locus. No specilic DP alleles were increased in the patient populations. By analogy with the situation in IDDM, which implicates DQ3.2 as a susceptibility gene, it is most likely that these genes (DwlO and DQp1.3) are candidate susceptibility genes for pemphigus vulgaris, and not just markers for other linked elements on the susceptible haplotypes. The important message from this example appears to be that completely different class II genes on different haplotypes may independently confer susceptibility to the same disease. Just because DC@ is responsible in one haplotype does not mean it will be DQfl in other haplotypes. Rheumatoid

arthritis

candidate genes have been identified which account for the association between HIA and RA, namely the Dw4 and Dw14 genes of the DRj.!ll locus (Nepom et al, J Clin Immunoll987, l:l-7). Dw4 and Dw14 are ‘subtypes’ of HI&DR4, and account for the well known association between HLA-DR4 and RA. Of clinical interest is the recent description [ 141 of a large group of RA patients in which the HLA-DR4 specificity was associated with destructive RA in both seropositive and seronegative RA patients, indicating that disease severity is correlated with HLA rather than with laboratory parameters such as rheumatoid factor. Specific

Not all patients with RA carty a Dw4 or Dw14 gene. Using oligonucleotide probes to DNA sequences characteristic of a segment of the Dw14 allele, however, a surprising observation was made [ 151: the majority of nonDR4 patients carried an identical Dwl4-like nucleotide sequence in a portion of the DRP gene. A single oligonucleotide probe based on this sequence therefore identified not only DR4 susceptibility genes but also DRp genes in most of the DR4-negative patients with RA The nucleotide sequence recognized by this probe encodes part of the DRj3 polypeptide’s lirst domain, centred 03 codon 71, a residue directly implicated in T-cell recogntion of this allele (Seyfried et al, Hum Immunoll988, 21:289299). These findings indicate that a shared nucleotide sequence contributes shared epitopes among different HIA genes, which may well explain the apparent genetic heterogeneity among patients with RA Thus, in RA, this discrete fragment of nucleotide sequence within the DRpl gene, rather than any single allele, appears to be the primary susceptibility determinant in disease. Thus, me contribution of HLA to RA appears to be an example of shared epitopes acting as the primary genetic determinants associated with disease susceptibility (Greg&en et al, ArtbritisRbeum 1987,30:120%1213). The relationship between this DRP epitope and disease severity was also evaluated; the Dw4/14 and 14.like epitope markers identified 85% of patients with erosive symmetrical poly arthritis (i.e., severe RA), but were not increased among a group of less severe non-erosive seronegative RA patients.

MHC

_ AS these reports illustrate, RA is currentlv the best exam

of the implication 0f.a specific nucl&ide sequence and portion of an HLA class II molecule in a specific pathogenetic syndrome, namely the erosive polyarthritis characteristic of RA. These studies provide the opportunity to focus future work on specific aspects of postulated disease-associated pathways, since the contribution of HLA to RA could be mediated via determinant selection and antigen presentation, selection or skewing of the T-cell repertoire, or some sort of molecular mimicry mechanism. Indeed, Roudier et al. [ 161 described the pctential cross-reactivity between peptides characteristic of Epstein-Barr virus glycoprotein gpll0 and the homologous sequence within the DRj31 Dw4 molecule itself centred on codon 71 (i.e. within the disease-associated epitape). This interesting coincidence certainly warrants further study. pie

Annotated

genes in HIA-associated

references

disease Nepom

and recommended

reading ??

a*

Of interest Of outstanding

interest

NEPOM GT: Structural variation among major histocompatibiity complex class-II genes which predispose to autoimmunlty. Immunol Res 1989, 8:1638. An overall review of HIA class II genomic variation among some haplo-

1.

??

types associated with autoimmune disease, reflecting the state of knowledge during 1988, and emphasizing the diversity among linked class II genes as an experimental tool to identify disease-associated genes. 2. ??

KWOK WW, MXKE~SON E, MA%wI~~ S, MI~R ECB, HANSENJ, NEPOM GT: Polymorphic DQa and DQP interactions dictate

HLA class II determinants 1990, 171:85-95.

of alIo-recognition. J Ezxp Med

Site-directed mutagenesis and retroviralmediated gene transfer were used to analyse the capacity of particular sites on class Il dimers to

stimulate alloreactive human T-cell clones. Amino acid substitutions at 13, 26, 45, or 57 of the DQB chain dramatically altered T-cell reactivity which, in addition, was strongly inlIuenced by a chain poly morphisms present in the stimulatory class II dimer.

codons

Specific

immunotherapy

3.

The identification of individual candidate susceptibility genes and, in the case of RA, specific sequences within these genes, represents a major conceptual and practical advance in the field. Not only can more direct experimental approaches be used to test concepts of mechanisms and pathogenesis but, for the first time, specific immunotherapy based on modulation of the effect of the susceptibility gene itself can be designed. A number of recent reports in experimental autoimmune models illustrate this point [ 17-201. Successful therapies using class II-specific monoclonal antibodies have been reported for experimental autoimmune encephalomyelitis in a primate model of multiple sclerosis [ 171 and in a T-cell transfer model of IDDM in non-obese diabetic (NOD) mice [ 181. These studies represent an extension of similar studies which offer some helpful prospects for this form of im munotherapy. A novel but more speculative form of immunotherapy was reported by two groups [ 19,201 working on peptide analogs related to myelin basic protein, the antigen used to induce experimental autoimmune encephalomyelitis. Peptides were designed which bound to the MIX restriction element used in experimental autoimmune encephalitis-susceptible strains of mice, but which failed to stimulate encephalitogenic T cells in vivo. Immunization with this peptide at the same time as myelin basic protein fragments inhibited disease induction in both studies. Prospects for extending these observations to H&associated autoimmune diseases will require, at a minimum, the development of similar non-immunogenic peptides which effectively bind to the candidate disease susceptibility gene, and the even more challenging design of methods to interfere with an ongoing chronic autoimmune process. Nevertheless, the concurrent identification of distinct candidate susceptibility genes important in human disease and the development of peptide-based immunotherapy technology in animal models make the prospects for direct clinical applications much brighter.

0

TODD JA, M~JOMC C, FLETCHER J, JENKINS D, BRADWELLAR, BARNETI AH: Identification of susceptibility loci for insulin-

dependent diabetes meIlitus by trans-racial gene mapping. Nature 1989, 338~587-589. A HIA-DR7 haplotype not found in Caucasians was increased in black diabetics, suggesting the possibility that genes on that haplotype, such as DQa, may contribute to disease susceptibility. 4. ??

SHE.EHYMJ, SCHAR?SJ, ROWE JR, NEME DE GIMENEZMH, MESKE LM, ERL~CHm NEPOM BS: A diabetes-susceptible HLA hap

lotype is best de6ned by a combination of HLA-DR and -DQ alleles. J Chin Invest 1989, 83:83&835. Among 3 different DR4 haplotypes which carry the DQ3.2 gene, those with Dw4 and DwlO were more prevalent in IDDM than those with Dw14. 5. 00

THOMSONG, ROBINSONWP, KUHNER MK, JOE S, MACDONALD MJ, GOT~SCHALL JL, BARBOSAJ, RICH SS, BERTRAMSJ, BALJR MP, PAWANEN J, TAIT BD, SCHOBER E, MAYR WR, LUDV~GS~ON J, UNDBLOMB, FARID NR, THOMPSONC, DESCHAMPSI: Genetic

heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 1988, 43:79+816. A large number of Caucasian IDDM data sets were combined for this joint study of IDDM pathogenesis. HLA-DR3 was found to predispose in a ‘recessive-like’, and DR4 in a ‘dominant-like’ or ‘intemxdiate’ fashion; removal of DR3 and DR4 from the data set reveakxl a protective effect of DR2, and minor predisposing effects of DRl and DRw8. The highest genetic risk element was 19.2% for siblings sharing 2 haplotypes with a DR3/DR4 proband. HORN GT, BUGAWAN q IQNG CM, ERUCH HA: Allelic sequence variation of the HIA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. Proc Nat1 Acud Sci USA 1988, 85:6012-6016. Gene amplification and sequence analysis of DQa and DQB alleles in 6. 0

IDDM identiIitxl consistent patterns of amino acids associated with disease susceptibility alleles. Several sequence homologies were identified between the Epstein-Barr virus genome and linear portions of the DClp chains, identifying potential sites of molecular mimicry. 7. 0

MOREL PA, DOWAN JS, TODD JA, McDm

HO, TRUCCO M:

Aspartic acid at position 57 of the HLA-DQ B chain protects against type I diabetes: a family study. Proc Nat1 Acud Sci US4 1988, 85:8111-8115. Gene amplilication and oligonucleotide probe analyses were used to correlate an aspartic acid at codon 57 with IDDM among 27 multiplex Caucasian families. Asp 57 D@ chains were increased among non-diabetic haplotypes, while non-Asp 57 DQB chains were increased in haplotypes of diabetes.

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8. ??

R(?NNINGEN KS, I~E T, HAUTENSEN TS, ~SPLJRKL~ND A, THOR~BY E: The amino acid at position 57 of the HL4-DQP chain and

susceptibility to develop insulin-dependent diabetes mellitus. Hum Immunol 1989, 26215225. Oligonucleotide analysis of amp&d genomic DNA was used to correlate the Asp 57 DOB polymorphism with IDDM. While non-Asp 57 haplotypes were more prevalent in IDDM, Asp 57 did not appear to confer dominant protection. 9.

KWOK WW, LoTsHAw C, MILNERECB, KNTTTERJACK N, NEPOM

GT: Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellims susceptibility gene. Proc Nat1 Acud Sci USA 1989, 86:1027-1030. Site-directed mutagenesis of the DQ3.2 gene implicates an amino acid polymorphism at codon 45 in the major serological specilicities associated with the DQB molecule in IDDM. .

10. ??

SOLUDLM, MARKUSSEN G, EK J, GJERDE H, VARTDAL F, THORSBY E: Evidence for a primary association of celiac disease to

a particular HLA-DQ a/p heterodhner. J E.q Med 1989, 169:345-350. DR5, DQw7/DR7,DQw2 heterozygous individuals potentially express the same DQa/p heterodimer as that formed by DQa and DQP genes located in crj on the DR3,DQw2 haplotype. Almost all patients with celiac disease carried 1 of these characteristic DQa/p dimers. 11.

ERLICH HA: Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HL4-DR3 (DRwl7) haplotype. Proc Nat1 Acad Sci USA 1989, 86:6274-6278. In addition to the DQs/p heterodimer characteristic of haplotypes found in celiac disease, an association of 2 DPP alleles was found. The HL4 contribution to celiac disease could, therefore, be multigenic. KAGNOFF MF, HARJVOOD JI, BUGAWANm

??

12.

BUGAWANTL, ANGEWI G, LURKZKJ, ALJRKCHIOS, FERRUA GB, ERLICHHA: A combination of a particular HLA-DPP allele and an HLA-DQ heterodimer confers susceptibility to coeliac disease. Nature 1989, 339~470-473. 2 specific DPB alleles were increased in a population of Italian celiac disease patients. Individuals carrying both the celiac-associated DQa/j3 heterodimer and a specilic DP allele had increased risk, consistent with independently segregating susceptibility genes. ??

%HARF SJ, FREIDMANN A, STEINMAN L, BRAUTEI~C, ERLICHHA: Specific HLA-DQP and HLA-DRPl alleles confer susceptibility to pemphigus vulgaris. Prcc Nat1 Acad Sci USA 1989, 86:6215-6219. Among DP&v6pemphigus vulgarls patients, 4 different Dw haplotypes were found, all of which share the same DQfl allele, suggesting that this allele accounts for susceptibility on this haplotype. 13. ??

14. 0

CAIN A, EL~w~~D J, KIQUDA PT: Destructive arthritis, rheumatoid factor, and HLA-DR4. Arthritis h&urn 1989, 32:1221-1225. The assay for rheumatoid factor is a serologic assay for autoantibodies associated with RA; in this case-control study, HLA-DR4was associated with destructive R.4 in both seropositlve and seronegatlve patients, and DR4-positive patients, in general, had more severe disease as judged by radiological criteria than did DR4-negative patients.

15. 0-g

NEPOMGT, BVERSP, SEYFFUED C, HFU+Y LA, WIISKEKR, STAGE D, NEPOMBS: HLA genes associated with rheumatoid arthrl-

tis. Arthritis Rbeum 1989, 32:1521. Oligonucleotide probes were used to identify both DR4 and non-DR4associated MHC genes in RA. The Dw4 and Dw14 genes accounted for the DR4 association, and genes which shared a key sequence and epicope with the Dw14 gene accounted for the majority of the non-DR4 RA patients. 16. 0

ROUDIER J, PETERSEN J, RHODESGH, LUKAJ, CARSONDA: Sus-

17.

JONKER M, VAN LAMBALGEN R, MITCHELLDJ, DURHAM SK, S?EINMAN L Successful treatment of FAE in rhesus monkeys

ceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HIA-Dw4 DRB-1 chain and the Epstein-Barr virus glycoprotein gplI0. Proc Natl Acad Sci USA 1989, 86:51045108. Epsteirr-Barr virus glycoprotein gpll0 contains an amino acid sequence highly homologous to a key epitope within DRP genes associated with R& suggesting the possibility of molecular mimicry mechanisms in pathogenesis.

??

with MHC-class 11 (HLA-DQ) specilic monoclonal antibodies. J Autoimmun 1988, 1:33sui14. 5 out of 6 rhesus monkeys treated with antibodies to class II molecules survived for significantly longer than untreated controls when therapy was initiated at the first sign of clinical experimental autoimmune encephalomyelitis symptoms. 18. ??

BOITARDC, BACHJF: Therapy of autoimmune diseases with monoclonal antibodies to class II major histocompatiblllty complex antigens: the role of T lymphocytes. J Autoimmun

1988, 1:66%671. Anti-class II monoclonal antibody therapy induced T cells which were capable of transferring protection into irradiated NOD recipients. The mechanism of therapeutic effect of anti-class II treatment appeared fo be indirect, requiring an immunocompetent T-cell environment. URBAN JL, HORVATHSJ, HOODL: Autoimmune T cells: immune recognition of normal and variant peptide epitopes and peptide-based therapy. Cell 1989, 59~257-271. Peptlde analogs from the amino terminus of myelin basic protein were used which did not stimulate myelln basic protein-specific T-helper cells but which competitively bound to the la restriction element in experimental autoimmune encephalomyelitis-susceptible mice. Such peptldes competitively inhibited T-cell reactivity in Wro and prevented the induction of experimental autoirnmune encephalomyelitis in yivo when given at the time of myelin basic protein immunization. 19. em

20. *a

WRAITHIX, SMIUZKDE, MITCHELL DJ, STEINMAN L, McD!?vrrr HO: Antigen recognition in autoimmune encaphalomyelitis and the potential for peptide-mediated immunotherapy. Cell 1989, 59~247-255. A non-encephalitogenic peptide analog derived from myelin basic pro* teln was detived which inhibited in vitro binding of myelin basic protein peptides to the la restriction element. This peptide analog could inhibit experimental autoimmune encephalomyelitis in vivowhen given in combination with encephalltogenic myelin basic protein peptides at the time of disease induction.