Rheumatoid Arthritis: Førre O

Førre O, Smerdel A. · No affiliation provided · Scand J Rheumatol. · Pubmed #12195624 No free full text.

Abstract: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders. Although the pathogenesis is not completely understood, many studies point to a genetic component in the susceptibility for this disease with environmental factors also contributing to the pathogenesis. The genetic component of JIA is complex, involving the effects of multiple genes at various points in the disease pathology. The best documented association is with the genes within the Human Leukocyte Antigen (HLA) complex, encoding the classical peptide-presenting molecules. JIA is associated with particular alleles at, at least, three different HLA loci: HLA-A (HLA-A*0201), -DR/DQ (DRB1*08, DRB1*11, DRB1*13) and -DP (DPB1*0201, DPB1*0301), with marked differences between the disease subtypes. Non-HLA genes may also contribute to the disease. Many of these genes encode cytokines and probably regulate their production. Examples of such cytokines involved in JIA are interleukin-1 alpha (IL-1 alpha), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), interleukin-10 (IL-10), macrophage inhibitory factor (MIF), interferon regulatory transcription factor (IFN1). Accumulated data suggest that interactions between the genes are necessary for the development of the disease. Knowledge of the genes involved would help to understand the molecular mechanisms involved in the pathogenesis of JIA and may have implications for prognosis and therapy.

Vinje O, Flatø B, Førre O. · Senter for revmatiske sykdommer, Rikshospitalet, Oslo. · Tidsskr Nor Laegeforen. · Pubmed #10833937 No free full text.

Abstract: We present a review of the criteria for the classification of juvenile arthritides. Historical aspects, the present situation and proposals for new criteria are outlined. The most commonly used classification criteria today are the European juvenile chronic arthritis criteria (JCA), the European League Against Rheumatism (EULAR) criteria, and the American juvenile rheumatoid arthritis (JRA), the American Rheumatoid Association (ARA) criteria. They differ in nomenclature and have different inclusion and exclusion demands. This has made it difficult to compare studies using different criteria. Neither of them can define homogeneous subgroups of disease. The most recent proposal for new classification criteria of juvenile arthritides is that of the International League Against Rheumatism, ILAR. They are primarily designed to define homogeneous subgroups of disease. The goal is also to obtain an international consensus. Advantages and disadvantages are discussed in this article. The criteria have not yet been validated, and should not be used by clinicians until they have been approved by the international scientific society. We also present guidelines recommended for the classification of juvenile arthritis in Norway today. We recommend using the term juvenile arthritis. Disease duration of arthritis must be at least six weeks. A diagnosis of arthritis should not be made on painful and restricted joint movement alone, as is the case in both the EULAR and ARA criteria today, but at least be based on definite swelling of joints verified by either clinical examination and/or by imaging techniques such as ultrasound, X-ray or EMR.

Førre O, Haugen M, Hassfeld WG. · Center for Rheumatic Diseases, The National Hospital, Oslo, Norway. · Scand J Rheumatol. · Pubmed #10777119 No free full text.

Abstract: It is very difficult to predict future treatment modalities especially in diseases like rheumatoid arthritis (RA) with unknown etiology and pathogenesis. In the near future, traditional disease-modifying antirheumatic drugs (DMARD) alone, in combination with each other, or together with cyclosporine, FK506, Rapamycin, or Leflunomide, will probably be the main treatment for RA. Currently biological anti-TNFalpha agents like humanized MAb and recombinant TNF-receptor constructs are now launched in the market. This therapy alone, or in combination with methotrexate is very effective in RA patients. There are, however, concerns over increase in serious infections. Autologous stem cell transplantation will probably be used in certain patient with serious autoimmune diseases.

Kvien TK, Zeidler HK, Hannonen P, Wollheim FA, Førre O, Hafström I, Kaltwasser JP, Leirisalo-Repo M, Manger B, Laasonen L, Prestele H, Kurki P. · Oslo City Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway. · Ann Rheum Dis. · Pubmed #12006323 links to  free full text

Abstract: OBJECTIVE: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. METHODS: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. RESULTS: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. CONCLUSION: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

Fraser DA, Thoen J, Djøseland O, Førre O, Kjeldsen-Kragh J. · Centre for Rheumatic Diseases, National Hospital, Oslo, Norway. · Clin Exp Rheumatol. · Pubmed #10895373 No free full text.

Abstract: OBJECTIVE: To investigate the effects of either a 7-day fast or a 7-day ketogenic diet upon serum interleukin-6 (IL-6) and dehydroepiandrosterone sulphate (DHEAS) in RA patients. METHODS: We measured serum concentrations of DHEAS and IL-6 in 23 RA patients with active disease, 10 of whom followed a 7-day sub-total fast and 13 of whom consumed a ketogenic diet (isoenergetic, carbohydrate < 40 g/day) for 7 days. Clinical and laboratory variables were measured at baseline, on day 7 and after re-feeding on day 21. Correlation analyses were used to assess the associations between serum IL-6, DHEAS and disease activity variables at each timepoint. RESULTS: Fasting, but not the ketogenic diet, decreased serum IL-6 concentrations by 37% (p < 0.03) and improved disease activity at day 7. Both fasting and the ketogenic diet increased serum DHEAS levels by 34% as compared with baseline (both p < 0.006). Levels of IL-6, but not DHEAS, correlated with several disease activity variables. CONCLUSION: Both fasting and a ketogenic diet significantly increased serum DHEAS concentrations in RA patients. Only fasting significantly decreased serum IL-6 levels and improved disease activity. As the increases in serum DHEAS were similar in response to both fasting and a ketogenic diet, it is unlikely that the fall in serum IL-6 or clinical improvements after fasting were directly related to increases in serum DHEAS. The fasting-induced fall in serum IL-6 may underlie the fall in CRP and ESR observed in RA patients in response to a 7-day fast.

Dolman KM, Brouwer N, Frakking FN, Flatø B, Tak PP, Kuijpers TW, Førre O, Smerdel-Ramoya A. · Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef, Amsterdam, 1105 AZ, The Netherlands. · Arthritis Res Ther. · Pubmed #18334024 links to  free full text

Abstract: BACKGROUND: Mannose-binding lectin (MBL) is an innate immune protein. The aim of our study was to determine whether genetically determined MBL deficiency is associated with susceptibility to juvenile rheumatoid arthritis (JRA) and whether MBL2 genotypes are associated with JRA severity. METHODS: In a retrospective cohort study of 218 patients with polyarthritis (n = 67) and oligoarthritis (n = 151), clinical and laboratory disease variables were obtained by clinical examination and chart reviews. Healthy Caucasian adults (n = 194) served as control individuals. MBL2 gene mutations were determined by Taqman analysis to identify genotypes with high, medium and low expression of MBL. Functional MBL plasma concentrations were measured using enzyme-linked immunosorbent assay. Associations between clinical and laboratory variables and MBL2 genotypes were determined by Kruskal-Wallis and chi2 tests. RESULTS: MBL2 genotype frequencies were similar in polyarthritis and oligoarthritis patients as compared with control individuals. MBL plasma concentrations were associated with the high, medium and low MBL genotype expression groups (P < 0.01). In polyarthritis patients, the presence of low-expressing (deficient) MBL2 genotypes was associated with early age at onset of disease (P = 0.03). In oligoarthritis patients, patients with low-expressing MBL2 genotypes were more often in remission (81%) than patients in the medium (54%) and high (56%) genotype groups (P = 0.02). The remaining clinical and laboratory variables, such as arthritis severity index, presence of radiographic erosions and antinuclear antibody positivity, were not associated with MBL2 genotypes. CONCLUSION: Genetically determined MBL deficiency does not increase susceptibility to JRA, but MBL deficiency is associated with a younger age at onset of juvenile polyarthritis. On the other hand, MBL-deficient children with juvenile oligoarthritis are more often in remission. Therefore, MBL appears to play a dual role in JRA.

Eike MC, Nordang GB, Karlsen TH, Boberg KM, Vatn MH, Anonymous00371, Dahl-Jørgensen K, Rønningen KS, Joner G, Flatø B, Bergquist A, Thorsby E, Førre O, Kvien TK, Undlien DE, Lie BA. · Institute of Immunology, Rikshospitalet HF, N-0027 Oslo, Norway. · Ann Rheum Dis. · Pubmed #18065500 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs. METHODS: We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests. RESULTS: RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels. CONCLUSION: We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.

Viken MK, Olsson M, Flåm ST, Førre O, Kvien TK, Thorsby E, Lie BA. · Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Sognsvannsveien 20, Oslo 0027, Norway. · Tissue Antigens. · Pubmed #17661906 No free full text.

Abstract: The protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene has, during the last 2 years, been recognized as a susceptibility gene for numerous autoimmune diseases, including rheumatoid arthritis (RA) and type 1 diabetes. An association between the exonic 1858C>T single nucleotide polymorphism (SNP) and RA has repeatedly been replicated in several Caucasian populations. The SNP is not associated with autoimmune diseases in Asian populations, as the 1858T allele is almost absent. Recently, a promoter polymorphism -1123G>C was proposed to be associated with acute-onset type 1 diabetes in Japanese and Korean populations. Furthermore, in Caucasian populations, the presence of additional PTPN22 risk variants has been suggested, indicating that the 1858C>T risk variant cannot explain the entire disease association observed in the region. In this study, we wanted to jointly address and integrate these separate findings to further elucidate the association between the PTPN22 gene and RA in a Norwegian material of 861 RA patients and 559 healthy controls. Our results revealed that the strength of the association with the PTPN22 promoter polymorphism, -1123G>C, is analogous to that observed for 1858C>T. As the -1123G>C variant is also polymorphic in Asian populations, our data underpin the need to further explore the association between this variant and autoimmune diseases in different populations.

Fraser DA, Thoen J, Selvaag AM, Djøseland O, Førre O, Kjeldsen-Kragh J. · Centre for Rheumatic Diseases, National Hospital, Oslo, Norway. · Clin Rheumatol. · Pubmed #11346236 No free full text.

Abstract: The aim of the study was to investigate the effects a 72-h fast upon serum total and free cortisol concentrations in RA patients not previously treated with glucocorticoids. Total serum cortisol and transcortin concentrations were measured in four RA patients with active disease at 4-h intervals during two 24-h periods (1200 h-1200 h), the first while eating a normal diet (fed state) and the second during the last 24 h of a 72-h water fast. Free cortisol concentrations were calculated from the total cortisol and transcortin values. The 3-day fast increased overall 24-h free and total cortisol concentrations by 50% and 35%, respectively. This was due largely to a marked increase in nocturnal serum cortisol concentrations during fasting, particularly at 0400 h, when mean total and free cortisol levels were increased by 170% and 260% compared to the fed state. Between 2000 and 0800 h overall total- and free cortisol concentrations were increased by 72% and 99%, respectively. These results suggest that an increase in nocturnal concentrations of cortisol occurs in response to fasting in RA patients not previously treated with glucocorticoids. These increases may mediate the beneficial clinical response previously found in studies of longer fasting periods in RA patients.

Helgeland M, Svendsen E, Førre O, Haugen M. · Centre for Rheumatic Diseases, National Hospital, Oslo, Norway. · Clin Exp Rheumatol. · Pubmed #11072610 No free full text.

Abstract: OBJECTIVE: Earlier studies have shown that patients suffering from juvenile arthritis (JA) have reduced serum concentrations of antioxidants compared with healthy controls. The aim of this study was to investigate whether the lower serum concentration of antioxidants found in these patients could be explained by a low dietary intake. METHODS: Serum from 14 patients and 22 healthy controls was analysed for the antioxidants retinol, beta-carotene, vitamin E, zinc and selenium. All of the participants completed a food frequency questionnaire that gave a picture of their dietary intake for the previous month. RESULTS: Compared with the healthy controls, the patients with JA had significantly reduced serum concentrations of beta-carotene (0.57 +/- 0.41 and 0.71 +/- 0.26 mmol/L respectively, p < 0.05), retinol (918 +/- 246 and 1176 +/- 300 IE/L, respectively, p < 0.01) and zinc (12.7 +/- 2.6 and 13.3 +/- 1.2 mmol/L, respectively, p < 0.05). The dietary intake was equivalent in the two groups, but the dietary intake of vitamin A, vitamin E and zinc did not reach the recommended dietary allowances. There was a statistically significant difference in serum concentrations of vitamin E and selenium between patients regularly taking a dietary supplements and patients who did not do so (p < 0.05). This difference was not found in the control group. CONCLUSION: The results of this study confirm that children suffering from JCA have reduced serum levels of beta-carotene, retinol and zinc compared with healthy controls. Patients benefited from dietary supplements of nutrients when the dietary intake did not reach the recommended dietary allowances.

Hansen MH, Dybwad A, Førre O, Sioud M. · Department of Immunology, Norwegian Radium Hospital, Montebello, Norway. · Clin Exp Rheumatol. · Pubmed #10949721 No free full text.

Abstract: OBJECTIVE: To uncover the specificities of autoantibodies to nuclear proteins (ANA) in patients with juvenile rheumatoid arthritis (JRA). METHODS: Peptide ligands for ANA were selected by panning random peptide phage display libraries on antibodies binding to HEp-2 cells. Positive phage clones were identified by the immunoscreening technique. RESULTS: Groups of peptides were identified, some of which share the core motifs of KTTTnPY, RVADnL/I or RnNSPL. Perinuclear and nuclear staining of HEp-2 cells were obtained with patient serum antibodies binding to the phage displaying the core peptide motifs. In contrast, no significant reactivity was seen with the antibodies binding to the wild type phage. Antibodies to the phage displaying peptides containing some of the core motifs were detected more frequently in ANA-positive as compared to ANA-negative JRA patients. Homology search with the selected core motifs revealed a significant homology with a number of human nuclear proteins and proteins from potential infectious agents that could serve as trigger in the breakdown of tolerance. CONCLUSION: Panning of phage display libraries on antibodies reacting with cellular structures can lead to the identification of their specificities. Thus, the peptide epitopes reported here constitute additional information that may lead to the development of diagnostic tests and the identification of the parental antigens that initiated the B cell responses in patients with JRA.

Haugen M, Lien G, Flatø B, Kvammen J, Vinje O, Sørskaar D, Førre O. · Center for Rheumatic Diseases, National Hospital, Oslo, Norway. · Arthritis Rheum. · Pubmed #10902752 links to  free full text

Abstract: OBJECTIVE: To assess the impact of disease activity on acquired peak bone mass and bone turnover in young adult patients with either persistent juvenile arthritis (JA) or a history of JA (JA in remission). METHODS: Two hundred twenty-nine patients with JA were studied after a mean +/- SD of 15.6 +/- 2.4 years in women and 14.9 +/- 2.1 years in men since disease onset. One hundred forty-five women and 84 men were over the age of 20 at the time of examination (mean +/- SD age 24.9 +/- 2.9 years for women and 25.2 +/- 3.1 years for men). Forty-one healthy women (mean +/- SD age 27.4 +/- 3.1 years) and 55 healthy men (mean +/- SD age 25.7 +/- 3.1 years) served as a reference group. Bone mineral density (BMD) was analyzed by dual x-ray absorptiometry. Serum osteocalcin concentrations and urinary concentrations of deoxypyridium (D-Pyd) were measured. Linear regression analyses were performed to evaluate the impact of disease on BMD. RESULTS: Patients with persistent disease had significantly lower BMD compared with healthy subjects (P < 0.001 for women at all measured sites and for men at the femoral neck and total body; P < 0.05 for men at the radius and lumbar spine). Of the patients with a history of JA, only women had significantly lower BMD at the femoral neck and total body (P < 0.05). Patients with persistent JA had significantly more osteopenia and osteoporosis than healthy subjects, while patients with a history of JA had more frequent osteopenia only in the total body. Weight, urinary concentration of D-Pyd, and belonging to the patient group significantly affected BMD at all measured sites in the entire study population, while analysis of all patients found that only the number of months taking corticosteroids significantly affected BMD at all measured sites. However, the impact of the variables differed from site to site. CONCLUSION: Our findings imply that most young adults with JA attain the same BMD as healthy subjects if the disease goes into remission, while young adults with active disease have increased risk for osteopenia and osteoporosis.

Fraser DA, Thoen J, Bondhus S, Haugen M, Reseland JE, Djøseland O, Førre O, Kjeldsen-Kragh J. · Centre for Rheumatic Diseases, National Hospital, Oslo, Norway. · Clin Exp Rheumatol. · Pubmed #10812493 No free full text.

Abstract: OBJECTIVE: To assess the clinical, immunological and hormonal effects of carbohydrate restriction in rheumatoid arthritis (RA) patients via the provision of a ketogenic diet. METHODS: Thirteen RA patients with active disease consumed a ketogenic diet for 7 days, providing the estimated requirements for energy and protein whilst restricting their carbohydrate intake to < 40 g/day. This was followed by a 2-week re-feeding period. Clinical and laboratory evaluations were carried out on days 0, 7 and 21. Changes in serum glucose, beta-hydroxybutyrate (beta-HB), leptin, insulin-like growth factor-1 (IGF-1) and cortisol were also measured at these time points. To study CD4+ and CD8+ lymphocyte responses, mitogen stimulated T-cell activation was assessed in heparinised whole blood via flow-cytometric analysis of CD69 expression. RESULTS: After the 7-day ketogenic diet, there were significant increases in serum beta-HB and cortisol, and significant decreases in body weight, the total lymphocyte count, serum leptin, IGF-1 and glucose. However, with the exception of morning stiffness, there were no significant changes in any of the clinical or laboratory measures of disease activity, or in early T-lymphocyte activation and the absolute numbers of CD4+ and CD8+ cells. CONCLUSION: In RA patients several of the metabolic and hormonal responses to a ketogenic diet, such as a fall in serum IGF-1 and leptin, resemble those which occur in response to acute starvation. However, the clinical and immunological changes which occur in response to acute starvation do not take place with a ketogenic diet and thus may be dependent upon energy and/or protein restriction.

Fraser DA, Thoen J, Rustan AC, Førre O, Kjeldsen-Kragh J. · Centre for Rheumatic Diseases, Akersbakken 27, Rikshospitalet, 0172 Oslo, Norway. · Rheumatology (Oxford). · Pubmed #10534544 links to  free full text

Abstract: OBJECTIVE: To measure whether changes in the concentrations of circulating free fatty acids (FFAs) after a 7 day fast in rheumatoid arthritis (RA) patients would inhibit in vitro T-lymphocyte proliferation. METHODS: The concentration and composition of plasma FFAs were measured in nine RA patients at the conclusion of a 7 day fast. A FFA mixture was made up based on these findings (20% linoleic, 43% oleic, 10% stearic, 27% palmitic acid). Mitogen-induced lymphocyte proliferative responses were measured after co-culture of peripheral blood mononuclear cells (PBMC) from healthy individuals in the presence of increasing concentrations of this FFA mixture (from 0 to 2000 microM) and in the presence of FFA mixtures where the relative proportions of fatty acids varied. RESULTS: Both the concentration of the FFA mixture and the ratio between the unsaturated and saturated fatty acids significantly influenced in vitro lymphocyte proliferation (P<0.0001). Unexpectedly, the highest concentrations of the FFA mixture increased lymphocyte proliferation. At equimolar concentrations (600 microM), manipulating the amounts of oleic and linoleic fatty acids relative to stearic and palmitic fatty acids had a potent inhibitory effect upon lymphocyte proliferation. CONCLUSION: Fasting-associated increases in total plasma FFA concentrations do not inhibit, but rather enhance, in vitro lymphocyte proliferation. An inhibitory effect could only be achieved by manipulating the balance between the unsaturated and saturated fatty acids.

Fraser DA, Thoen J, Reseland JE, Førre O, Kjeldsen-Kragh J. · Centre for Rheumatic Diseases, National Hospital, Oslo, Norway. · Clin Rheumatol. · Pubmed #10524554 No free full text.

Abstract: We investigated the effects of acute starvation on mitogen-induced T-cell activation and Th1/Th2 cytokine responses in rheumatoid arthritis (RA) patients. Ten RA patients with active disease underwent a 7-day fast followed by a 2-week refeeding period. Immunological, hormonal, laboratory and clinical evaluations were carried out on days 0, 7 and 21. Using flow cytometry, mitogen-stimulated T-cell activation was assessed in fresh heparinised blood via analysis of CD69 expression. Production of Th1 (interferon-gamma) and Th2 (interleukin-4, IL-4) cytokines was also assessed by ELISA. The 7-day fast significantly decreased the erythrocyte sedimentation rate, C-reactive protein level, joint count, morning stiffness, body weight, CD4+ and CD8+ counts and CD69+ expression on mitogen stimulated CD4+ lymphocytes. A significant increase in mitogen-induced IL-4 production after fasting was found. The fast markedly reduced serum leptin and insulin-like growth factor-1 concentrations. No significant differences occurred in serum cortisol or prolactin before and after fasting. Decreases in CD4+ lymphocyte activation during fasting correlated with decreases in body weight. Our results suggest that the clinical and laboratory improvements in fasting RA patients may be attributed to decreased CD4+ T-cell activation and an increase in the number and/or function of IL-4-producing Th2 cells. Factors associated with loss of body weight during acute starvation appear to have an inhibitory effect on CD4+ lymphocyte activation.