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Lymphocyte Responses to DR1/4 Restricted Ann Rheum Dis: First Published As 10.1136/Ard.53.3.171 on 1 March 1994

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Lymphocyte Responses to DR1/4 Restricted Ann Rheum Dis: First Published As 10.1136/Ard.53.3.171 on 1 March 1994 Annals of the Rheumatic Diseases 1994; 53: 171-177 171 Lymphocyte responses to DR1/4 restricted Ann Rheum Dis: first published as 10.1136/ard.53.3.171 on 1 March 1994. Downloaded from peptides in rheumatoid arthritis Margot A Skinner, Lisa Watson, Arie Geursen, Paul L J Tan Abstract examination of the synovium has shown a Objective-To determine whether analog prominent infiltrate of lymphocytes, the and unrelated DR1/4 binding peptides majority of which are activated T cells.2 In alter DR1/4 restricted responses of addition, several experimental treatment peripheral blood lymphocytes (PBL) from strategies which act primarily through their patients with rheumatoid arthritis (RA). effect on T cells are reported to be effective in Methods-PBL from 25 patients with RA the treatment of RA.' 3 and 12 healthy controls were cultured with The association of RA with major histo- DR1/4 restricted peptides of the influenza compatibility genes is well established4 and the haemagglutinin, amino acids 307-319 HILA DR4 (DRB1*04) and DR1 (DRBl*01) (HA) and matrix proteins, amino acids genes involved is well documented.5 Disease 17-29 (IM). Responses were determined susceptibility has been localised to the third by 3H-thymidine uptake proliferation hypervariable region of the i chain of DR assays and limiting dilution analysis. and in white groups is most commonly Competitor peptides were analogs HA- associated with Dw4 (DRB1*0401), R312 and HA-K313 differing from HA by one containing the amino acid sequence amino acid at the 312 or 313 position LLEQKRAA at positions 67-74 and VG at respectively or unrelated peptides which residues 85-86.5 This disease-associated bind to DR1I/4. epitope is present in Dw4 (DRB1*0401), the Results-The responses of eight patients most frequent DR subtype in white groups.5 with RA to the two stimulatory influenza Dw14 2 (DRB1*0408), Dw15 (DRB1*0405) peptides did not differ significantly from and DR1 1 (DRB1*0101) have a single substi- controls and this was confirmed by the tution at position 71, where a lysine replaces frequency estimate of T cells in PBL the arginine and Dw14 1 (DRB1*0404) has which responded to HA (mean frequency: this sequence in the 67-74 region. These 1 in 9 0 x 104, n = 5, in DR1/4+ RA patients, alleles also confer disease susceptibility 1 in 76X 104, n= 5, in DR1/4+ healthy particularly in ethnic groups where Dw4 is a http://ard.bmj.com/ controls). DR1/4 binding analogs of the less common allele.6 7 HA peptide inhibited HA specific peptide The role of the LLEQKRAA sequence in responses of PBL from patients with RA determining disease susceptibility to RA is not and controls. Inhibition was also detected understood at present. This sequence lies with unrelated peptides which bind to within the peptide antigen binding groove of DR1I4 but to which the individual did not the MHC molecules. Little is known about the respond. influence these residues have on T cells which on October 4, 2021 by guest. Protected copyright. Conclusion-Similar responses to two recognise peptides and which may be involved DR1I4 restricted peptides were observed in immune regulation in RA. Peptides which in patients with RA and controls. Both bind to such DR1/4 molecules may have a role antigen analog- and unrelated peptide- in causing or perpetuating the disease. Thus Department of major Molecular Medicine,* histocompatibility complexes peptides that are DR1/4 restricted can be used University of (MHC) can result in the inhibition of to analyse T cell responses dependent on the Auckland, antigen specific responses in multiclonal disease associated genes, and may be useful for School ofMedicine, human lymphocyte Auckland, populations. How- comparison when studying putative disease New Zealand ever, an analog peptide may be stimula- associated antigens. Several investigators have Margot A Skinner tory in some individuals. These results used high affinity MHC-binding peptides to Lisa Watson provide some initial data for the devel- Arie Geursen inhibit T cell activation by blocking the opment of a rational approach to antigen-binding site of MHC molecules.8 9 It Department of Rheumatology, MHC-specific immunomodulation in follows that unrelated DR1/4-binding peptides Auckland Hospital, rheumatoid arthritis. can potentially block the antigen presenting Auckland, site of the disease associated MHC Class II New Zealand (Ann Rheum Dis 1994; 53: 171-177) Paul L Tan* molecules and thus the cascade of molecular J events leading to the activation of arthritogenic Correspondence to: Dr M A Skinner, T cells may be prevented. Department of Molecular The contribution of cell mediated immunity to Peptides which Medicine, bind to DR1/4 have been School of Medicine, joint inflammation and destruction in described and include, residues 307-319 ofthe University of Auckland, rheumatoid arthritis (RA) is poorly understood influenza haemagglutinin,'0 residues 17-29 Private Bag 92019, of Auckland, New Zealand. but there is evidence of a role for T cell- the influenza matrix protein'0 residues 1-15 of Accepted for publication mediated immune responses in the patho- the 19-kd protein of Mycobacterium tuberculosis 17 November 1993 genesis of this disease.' Immunohistological (MT)" 12 and residues 38-50 of the 18-kd 172 Skinner, Watson, Geursen, Tan Mycobacterium leprae protein (ML3) 13 in Pty, Clayton, Australia. The M leprae 18-kd addition to the naturally processed peptides peptide ML3, amino acids 31-50 derived from MHC-related molecules. 14 (DAWREGEEFVVEFDLPGIK) and the M Competition studies using analogs of such tuberculosis 19-kd peptide, D3, amino acids Ann Rheum Dis: first published as 10.1136/ard.53.3.171 on 1 March 1994. Downloaded from peptides, to inhibit human peptide-specific T 31-50 (SGETTTAAGTTASPGAASGPK), cells, have been successful but have utilised were synthesised by the Protein Chemistry peptide-specific T cell lines and clones. Before Unit, Massey University, New Zealand. All such techniques can be used to develop an peptides were purified by reverse-phase high immunotherapeutic approach to RA the performance liquid chromatography and were lymphocyte responses of patients with RA to greater than 92% pure. these peptides must be determined. In previous work, we analysed the responses of lympho- cytes from patients with RA to the DR1/4 LYMPHOCYTE PROLIFERATION ASSAY restricted epitope of MT.'2 In this report we Heparinised peripheral blood was subjected to describe the responses ofperipheral blood lym- Ficoll-Hypaque (Pharmacia, Piscataway, NJ) phocytes (PBL) from healthy individuals and gradient separation. Lymphoid cells were patients with RA to three other DR1/4 re- harvested, washed three times in RPMI (Life stricted peptides and show that proliferative Technologies, Grand Island, NY) medium and responses can be altered by both non-stim- viable cells counted using trypan blue. The ulatory peptide analogs which bind to DR1/4 cells were cultured at 2 X 105 per well in 96 and by unrelated peptides to which an individ- well round bottom plates (Nunc, Denmark) in ual does not respond. a total volume of 200 [lI RPMI supplemented with 5% heat inactivated autologous serum (culture medium) and stimulated in triplicate Patients and methods with phytohemagglutinin (PHA) at 1 jg/ml, PATIENTS peptide (HA, IM, ML3), or medium alone. A total of 25 DR1/4+ patients with RA and 12 Peptides were added to give a final DR1/4+ healthy age-matched controls were concentration of 10 ,ug/ml, unless otherwise entered into the study. All patients had stated, a dose in the optimal range for seropositive erosive RA and fulfilled the stimulating T cell proliferation. American College of Rheumatology revised For competition studies, 2 x 105 PBL were criteria for RA. '5 There were 18 women and preincubated with the blocking peptide at 10 seven men aged 30-81 years. Their duration of pRg/ml, unless otherwise stated, in a total disease ranged from one to 52 years. Most volume of 190 Ru before the addition of the patients had at least four inflamed joints; eight stimulating peptide. Preliminary experiments patients had from 0 to 3 inflamed joints. indicated that blocking could be detected Two patients were taking no medication, although to a lesser extent when both two patients took paracetamol, 17 patients stimulatory and blocking peptides were added took non-steroidal anti-inflammatory drugs simultaneously but a four hour pre-incubation http://ard.bmj.com/ (NSAIDs), eight patients had prednisone with the blocking peptide gave more consistent (2-10 mg/day), and 21 patients received anti- results and was therefore used throughout. A rheumatic agents (8 took methotrexate, 5 control peptide from the 19-kd protein of M D-penicillamine, 3 intramuscular sodium tuberculosis (D3) to which DR1/4+ individuals thiomalate, 3 sulfasalazine and 2 azathioprine). do not respond'2 was included as a negative PBL from all patients and controls were control in competition experiments and did not DR1/4 typed either with the assistance of affect the response to stimulating peptides. on October 4, 2021 by guest. Protected copyright. M Roberts (Auckland Regional Blood Centre) Cultures were incubated at 37°C in 5% CO2 or by a PCR technique.7 The HLA status was in air for 5-6 days and pulsed with 0-25 pLCi confirmed by DR4 subtyping using a single 3H-thymidine (Dupont/NEN, Boston, MA) stranded conformational polymorphism for the last 18 hours. Cells were thus harvested technique'6 recently developed in our during the peak response to peptide (4-6 days) laboratory for the HLA-DR4 group of alleles. but not at the peak of the PHA response. They were harvested onto filters and uptake of radio- label was determined using either an LKB Beta PEPTIDES plate system (Wallac, Turku, Finland) or PHD The amino acid sequences in brackets are given cell harvester (Cambridge Instruments Inc, as single letter codes.
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