IL-1 Was Measured by a Commercially Available Quantitative Sandwich Enzyme Immunoassay

Synovial tissue acquisition and preparation

Multiple synovial tissue biopsies (at least 6) were obtained throughout the joint under local anaesthesia using a 2.7mm arthroscope and 2.8mm biopsy forceps (Storz & Co., Germany). The biopsies were prepared and stored by immersion in methylbutane (-70 0C) as previously described.[1] After thawing, sections were stained with the followingmonoclonal antibodies (mAbs): anti-CD3, anti-CD4, anti-CD8, anti-CD68, anti-factor VIII (M0756, M0716, M0707, M018, M0616, respectively, Dako, Denmark), anti-VEGF, anti-IL-1α, anti-IL-1β, anti-TNFα (sc-7269, sc-9983, sc-1250, sc-8301, respectively, Santa Cruz Biotechnology, USA), anti-TGFβ, anti-MMP-1 (MAB240, MAB901, R&D Systems, USA), anti-MMP-3, anti-TIMP-1 (IM70 and IM62, respectively, Oncogene Research Products, USA), anti-e-selectin (NCL-CD62E, Novocastra Laboratories, UK). A standard three-stage immunoperoxidase method was used for each antibody, followed by counterstaining with haematoxylin. Monoclonal antibodies were replaced with isotype-matched irrelevant primary antibodies as negative controls.

Serum biomarkers

IL-1 was measured by a commercially available quantitative sandwich enzyme immunoassay (Immunotech, France). The measurement of IL-1Ra, sIL-6R and sTNF RI were performed using Quantikine enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, USA). IL-6, TNF and IL-8 were assayed by solid-phase, two site chemiluminescent assays with an IMMULITE analyser (DPC, USA). IL-18 was measured by a commercially available quantitative sandwich enzyme immunoassay (Medical and Biological Laboratories, Japan). MMP-1 and MMP-3 were measured using commercially available enzyme immunoassays (Bindazyme ProMMP-1 and Bindazyme ProMMP-3; The Binding Site, UK). TIMP-1 was measured using a commercially available sandwich enzyme immunoassay (Quantikine TIMP-1; R&D Systems, USA). Cartilage oligomeric matrix protein (COMP) was measured by a solid phase two-site enzyme immunoassay (AnaMar Medical, Sweden). Apolipoprotein A1 (Apo-A1) was measured by nephelometry using an IMMAGE nephelometer (Beckman Coulter, USA).

The potency of patient sera to inhibit the production of IL-1 in monocytes activated by membranes isolated from T cells (HUT-78 cell line) was carried out as previously described.[2] This in vitro assay was performed to evaluate whether measurable functional decreases in the pro-inflammatory phenotype of patients’ sera could be detected following therapy.

Patient characteristics at baseline
Treatment group
Total group / Anakinra / Anakinra + pegsunercept
(n = 22) / (n = 11) / (n = 11)
Demographics
Age, years / 52 (41, 56) / 49 (41, 57) / 53 (41, 56)
Number (%) female / 18 (82) / 9 (82) / 9 (82)
Disease duration
Months since symptom onset / 23 (5, 52) / 27 (4, 59) / 8 (5, 41)
Number (%) with symptoms < 1 year / 10 (45) / 4 (36) / 6 (55)
Rheumatoid factor
Serum concentration, U/ml (normal < 25) / 147 (21, 614) / 99 (13, 809) / 183 (37, 549)
Number (%) positive / 16 (73) / 7 (64) / 9 (82)
DMARD therapy,
No. of previous DMARDs / 1 (0, 2) / 1 (0, 2) / 0 (0, 2)
Number (%) DMARD naïve / 11 (50) / 5 (46) / 6 (55)
ACR core set
Swollen joint count (0-66 scale) / 16 (12, 32) / 19 (13, 33) / 12 (10, 28)
Tender joint count (0-68 scale) / 20 (13, 32) / 21 (15, 38) / 19 (13, 30)
Patients' assessment of disease activity, mm (0-100mm VAS) / 72 (51, 81) / 68 (58, 80) / 73 (46, 82)
Physicians' assessment of disease activity, mm (0-100mm VAS) / 69 (58, 75) / 72 (60, 74) / 59 (45, 82)
Patients' assessment of pain, mm (0-100mm VAS) / 70 (47, 83) / 66 (47, 78) / 77 (47, 86)
ESR, mm/h / 50 (33, 80) / 62 (28, 83) / 39 (35, 75)
CRP, mg/l / 58 (28, 108) / 65 (25, 101) / 54 (29, 127)
HAQ score (0-3 scale) / 1.75 (1.50, 2.00) / 1.88 (1.63, 2.00) / 1.63 (1.50, 1.75)
Values are the median (interquartile range). See text for further definitions.
ACR response criteria and radiographic progression over 1 year
Treatment group / Final clinical response
Total Group / Anakinra / Anakinra + pegsunercept / ACR20 / ACR50 / ACR70 / No response
n = 22 (15) / n = 11 (7) / n = 11 (8) / n = 11 (10) / n = 8 (7) / n = 5 (4) / n = 11 (5)
ACR response, number (%) patients
ACR20
Week 4 / 11 (50) / 3 (27) / 8 (72) / - / - / - / -
Final / 11 (50) / 4 (36) / 7 (63) / - / - / - / -
ACR50
Week 4 / 3 (4) / 0 (0) / 3 (27) / - / - / - / -
Final / 8 (36) / 1 (9) / 7 (63)‡‡ / - / - / - / -
ACR70
Week 4 / 1 (5) / 0 (0) / 1 (9) / - / - / - / -
Final / 5 (23) / 0 (0) / 5 (45)‡ / - / - / - / -
Swollen joint count (0-66 scale)
Week 4 % change / -48.1 (-69.8, -27.1)** / -42.4 (-51.7, -17.6) / -53.8 (-81.0, -40.0)** / - / - / - / -
Final % change / -56.9 (-94.2, -12.5)** / -44.4 (-71.4, -21.2)* / -92.3 (-100.0, 9.5) / - / - / - / -
Tender joint count (0-68 scale)
Week 4 % change / -35.7 (-62.6, -13.8)** / -20.0 (-45.1, 0.0)* / -46.7 (-77.8, -28.1)** / - / - / - / -
Final % change / -65.4 (-91.5, -21.0)** / -40.0 (-78.9, 11.1)* / -90.9 (-100.0, -26.9)* / - / - / - / -
Patients' assessment of disease activity, mm (0-100mm VAS)
Week 4 % change / -29.9 (-61.8, -13.4)** / -26.1 (-58.5, -17.3) / -41.1 (-72.2, -6.5)** / - / - / - / -
Final % change / -61.7 (-83.4, -1.1)** / -44.5 (-68.3, -0.2)* / -75.8 (-90.0, 13.8)* / - / - / - / -
Physicians' assessment of disease activity, mm (0-100mm VAS)
Week 4 % change / -41.6 (-67.8, -8.8)** / -24.3 (-43.4, 11.7)** / -67.8 (-80.0, -25.6)** / - / - / - / -
Final % change / -58.4 (-93.6, -9.6)** / -36.8 (-79.4, -6.7)* / -93.2 (-98.3, -26.3)** / - / - / - / -
Patients' assessment of pain, mm (0-100mm VAS)
Week 4 % change / -26.9 (-64.6, -4.3)** / -28.2 (-58.2, 9.4) / -25.0 (-86.1, -7.3)* / - / - / - / -
Final % change / -59.8 (-73.7, -4.8)** / -25.5 (-61.9, -3.7)* / -68.5 (-86.2, -4.8)** / - / - / - / -
ESR, mm/h
Week 4 % change / -34.5 (-53.4, -5.1)** / -25.3 (-36.8, -6.5)** / -51.9 (-77.3, -1.1)** / - / - / - / -
Final % change / -15.1 (-51.0, 6.6) / -15.8 (-50.0, 17.9) / -14.4 (-71.8, 2.8) / - / - / - / -
CRP, mg/l
Week 4 % change / -37.9 (-77.7, -3.8)** / -21.8 (-56.3, 20.8) / -68.8 (-86.2, -29.1)** / - / - / - / -
Final % change / -53.7 (-65.9, 6.7)* / -1.4 (-56.3, 13.8) / -65.9 (-82.9, -41.7)*‡ / - / - / - / -
HAQ score (0-3 scale)
Week 4 absolute change / -34.5 (-50.0, -5.4)** / -0.50 (-0.75, -0.13)* / -0.38 (-0.88, 0.00)* / - / - / - / -
Week 4 % change / -38.9 (-80.4, 0.0)** / -33.3 (-38.9, -11.1)* / -41.7(-50.0, 0.0)* / - / - / - / -
Final absolute change / -0.44 (-0.78, -0.09)** / -0.31 (-0.94, 0.31)* / -0.81 (-1.31, -0.09)* / - / - / - / -
Final % change / -0.38 (-1.25, 0.00)** / -23.3 (-61.7, 1.3)* / -66.7 (-100.0, -9.6)* / - / - / - / -
Total Sharp score
Baseline / 8.5 (3.5,28.5) / 20.0 (7.0, 35.0) / 7.5 (1.5, 12.0) / 10.3 (7.0,29.6) / 8.5 (7.0,12.0) / 12.0 (9.4,37.5) / 3.5 (2.3,53.8)
Change at 6 months / 1.5 (0.0,5.0)** / 1.5 (0.0, 6.0) / 1.3 (0.0, 5.0)* / 1.5 (0.0,5.3)* / 1.5 (0.0,5.0)* / 2.0 (0.8,4.4) / 3.5 (0.0,5.5)
Change at 12 months / 2.0 (0.5,8.0)** / 2.0 (0.0, 8.50)* / 2.3 (1.1, 6.9)* / 2.0 (0.4,7.4)** / 2.0 (0.0,6.5)** / 2.3 (1.6,5.5) / 7.0 (0.5,8.3)
Significant progression, number (%) patients
6 months / 5 (33) / 2 (29) / 3 (30) / 3 (30) / 2 (29) / 1 (25) / 2 (40)
12 months / 6 (40) / 3 (43) / 3 (38) / 3 (30) / 2 (29) / 1 (25) / 3 (60)
Erosion score
Baseline / 3.0 (0.5,18.5) / 4.0 (1.5, 23.0) / 3.5 (0.5, 4.5) / 3.8 (1.5,19.0) / 3.5 (1.5,4.5) / 4.3 (3.6,16.5) / 0.5 (0.3,25.8)
Change at 6 months / 1.0 (0.0,2.0)** / 1.0 (0.0, 2.0) / 0.5 (0.0, 1.3)* / 0.8 (0.0,2.3)* / 0.5 (0.0,2.0)* / 0.8 (0.5,2.5) / 1.0 (0.0,1.5)
Change at 12 months / 1.0 (0.0,3.0)** / 2.0 (0.0, 5.0) / 1.0 (0.6, 2.6)* / 1.3 (0.0,3.1)* / 1.0 (0.0,3.0)* / 1.3 (0.6,2.6) / 1.0 (0.5,3.8)
Significant progression, number (%) patients
6 months / 2 (13) / 1 (14) / 1 (11) / 2 (20) / 1 (14) / 1 (25) / 0 (0)
12 months / 4 (27) / 2 (29) / 2 (25) / 3 (30) / 2 (29) / 1 (25) / 1 (20)
Narrowing score
Baseline / 5.5 (3.0,10.0) / 10.0 (5.0, 25.0) / 4.0 (1.0, 8.50) / 6.8 (4.8,10.0) / 5.5 (4.0,8.5) / 8.3 (5.0,21.3) / 3.0 (2.0,28.0)
Change at 6 months / 0.5 (0.0,2.0)** / 0.0 (0.0, 1.5) / 0.8 (0.0, 2.5)* / 0.3 (0.0,2.0) / 0.5 (0.0,2.0) / 1.3 (0.1,2.0) / 1.5 (0.0,4.5)
Change at 12 months / 1.0 (0.0,3.5)** / 0.5 (0.0, 3.0) / 1.5 (0.0, 5.4)* / 0.8 (0.0,3.1)* / 1.0 (0.0,3.5)* / 1.5 (0.3,3.1) / 3.0 (0.0,6.0)
Significant progression, number (%) patients
6 months / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0) / 0 (0)
12 months / 3 (20) / 1 (14) / 2 (25) / 1 (10) / 1 (14) / 0 (0) / 2 (40)
Values are the median (interquartile range), unless otherwise stated. A negative change indicates a decrease in that measure. Group numbers in brackets refer to patients included in radiographic analysis.* P < 0.05, ** P < 0.01 for change from baseline. ‡ P < 0.05, ‡‡ P < 0.01 vs. non-responders or between therapeutic subgroups.For radiographic data, total group refers to all patients with radiographic data at 0, 6 and 12 months.Minimally clinically important progression was calculated separately for each radiographic measure at each timepoint. See text for further definitions.
Synovial tissue biomarkers and disease activity
ESR / CRP / DAS28
Cross-section / Change / Cross-section / Change / Cross-section / Change
CD3
Baseline / 0.19 / - / 0.50* / - / 0.15 / -
Week 4 / 0.34 / -0.04 / 0.32 / 0.17 / 0.49* / 0.40
Final / 0.30 / 0.52* / 0.40 / 0.57* / 0.51* / 0.46
CD4
Baseline / 0.00 / - / 0.28 / - / -0.15 / -
Week 4 / 0.27 / 0.03 / 0.28 / 0.41 / 0.41 / 0.48*
Final / 0.40 / 0.43 / 0.62* / 0.09 / 0.17 / 0.34
CD8
Baseline / 0.21 / - / 0.44* / - / 0.21 / -
Week 4 / 0.37 / -0.06 / 0.28 / 0.04 / 0.44* / 0.36
Final / 0.31 / 0.51 / 0.35 / 0.32 / 0.59* / 0.44
CD68
Total tissue
Baseline / -0.03 / - / 0.36 / - / 0.07 / -
Week 4 / 0.05 / 0.18 / 0.00 / 0.23 / 0.01 / 0.40
Final / 0.19 / 0.47 / 0.34 / 0.19 / 0.27 / 0.37
Sublining layer
Baseline / -0.01 / - / 0.34 / - / 0.07 / -
Week 4 / 0.11 / 0.12 / 0.03 / 0.39 / 0.02 / 0.27
Final / 0.24 / 0.38 / 0.32 / 0.18 / 0.29 / 0.32
Factor VIII
Baseline / -0.02 / - / 0.04 / - / -0.19 / -
Week 4 / 0.33 / -0.15 / 0.46* / -0.08 / 0.03 / -0.07
Final / 0.54* / 0.65** / 0.34 / 0.49 / 0.57* / 0.65**
VEGF
Baseline / 0.52* / - / 0.29 / - / 0.53* / -
Week 4 / 0.22 / 0.08 / 0.03 / 0.34 / 0.12 / 0.02
Final / -0.28 / 0.26 / 0.14 / 0.03 / -0.29 / -0.15
TGFb
Baseline / 0.37 / - / 0.39 / - / -0.05 / -
Week 4 / 0.23 / 0.38 / 0.41 / 0.32 / 0.32 / 0.43*
Final / 0.28 / 0.51* / 0.16 / 0.44 / 0.24 / 0.50*
E-selectin
Baseline / 0.16 / - / 0.23 / - / 0.20 / -
Week 4 / 0.07 / -0.20 / 0.03 / 0.46* / 0.07 / 0.08
Final / -0.18 / -0.38 / 0.20 / 0.13 / -0.16 / -0.32
IL-1
Baseline / -0.31 / - / -0.04 / - / -0.36 / -
Week 4 / 0.14 / -0.03 / 0.33 / 0.02 / 0.02 / 0.39
Final / 0.15 / 0.86** / 0.01 / 0.44 / 0.59* / 0.52*
IL-1
Baseline / -0.07 / - / 0.19 / - / 0.06 / -
Week 4 / 0.05 / 0.25 / 0.35 / 0.06 / 0.09 / -0.23
Final / 0.07 / 0.15 / -0.10 / 0.02 / 0.03 / 0.00
TNFa
Baseline / 0.13 / - / 0.50* / - / 0.07 / -
Week 4 / 0.24 / 0.30 / 0.52 / 0.49* / 0.32 / 0.59**
Final / -0.02 / 0.10 / 0.00 / 0.30 / -0.12 / -0.08
OPG
Baseline / 0.13 / - / 0.28 / - / 0.08 / -
Week 4 / 0.07 / 0.04 / 0.24 / 0.20 / 0.17 / 0.45*
Final / 0.10 / 0.60* / 0.24 / 0.50 / 0.23 / 0.59*
RANK Ligand
Baseline / 0.44* / - / 0.61** / - / 0.39 / -
Week 4 / 0.36 / 0.03 / 0.59** / 0.10 / 0.45* / 0.30
Final / -0.05 / 0.46 / 0.03 / 0.33 / -0.16 / 0.11
MMP-1
Baseline / 0.12 / - / 0.19 / - / 0.16 / -
Week 4 / 0.61** / -0.10 / 0.51* / 0.23 / 0.38 / 0.45*
Final / -0.10 / 0.38 / 0.35 / 0.40 / 0.22 / 0.50
MMP-3
Baseline / 0.11 / - / 0.15 / - / 0.26 / -
Week 4 / 0.11 / -0.02 / 0.11 / 0.07 / 0.10 / -0.02
Final / 0.22 / 0.12 / 0.37 / 0.19 / 0.19 / -0.11
TIMP
Baseline / -0.19 / - / 0.03 / - / 0.07 / -
Week 4 / 0.36 / 0.28 / 0.14 / 0.42 / 0.31 / -0.49*
Final / -0.23 / 0.19 / -0.13 / 0.00 / -0.05 / 0.20
Values are Spearman's Rho. * P < 0.05, ** P < 0.01.
Serum biomarkers and disease activity
Spearman's rho
ESR, mm/h / CRP, mg/l / DAS28
Cross-section / Change / Cross-section / Change / Cross-section / Change
IL-1, pg/ml
Baseline / 0.48* / - / 0.45* / - / 0.44* / -
Week 4 / 0.24 / -0.13 / 0.19 / -0.36 / 0.37 / -0.25
Final / 0.52* / 0.05 / 0.35 / 0.06 / 0.44* / 0.29
sIL-1 RII
Baseline / -0.46* / - / -0.33 / - / -0.49* / -
Week 4 / -0.28 / -0.08 / -0.32 / 0.05 / -0.07 / 0.14
Final / 0.16 / -0.15 / 0.14 / 0.16 / -0.17 / -0.04
IL-6, pg/ml
Baseline / 0.55** / - / 0.60** / - / 0.47** / -
Week 4 / 0.41 / -0.36 / 0.49* / -0.22 / 0.35 / -0.29
Final / 0.77** / 0.72** / 0.62** / 0.54* / 0.79** / 0.56**
sIL-6 R
Baseline / -0.11 / - / -0.16 / - / -0.14 / -
Week 4 / 0.29 / 0.21 / 0.30 / 0.15 / 0.34 / 0.14
Final / 0.17 / 0.07 / -0.07 / 0.12 / 0.11 / 0.11
IL-8
Baseline / 0.25 / - / 0.18 / - / 0.14 / -
Week 4 / 0.21 / -0.15 / 0.11 / -0.36 / 0.13 / -0.13
Final / 0.31 / 0.48* / 0.20 / 0.17 / 0.17 / 0.22
IL-18
Baseline / -0.08 / - / -0.04 / - / 0.02 / -
Week 4 / -0.26 / -0.33 / -0.34 / -0.49* / -0.17 / -0.12
Final / -0.01 / -0.12 / -0.15 / 0.23 / -0.04 / -0.22
TNF
Baseline / 0.26 / - / 0.35 / - / 0.20 / -
Week 4 / -0.24 / -0.12 / 0.02 / 0.05 / -0.25 / -0.61**
Final / -0.07 / -0.16 / -0.34 / -0.38 / -0.25 / -0.46*
sTNF RII
Baseline / 0.25 / - / 0.42 / - / 0.20 / -
Week 4 / 0.43 / 0.11 / 0.42 / 0.25 / 0.29 / 0.03
Final / 0.32 / -0.01 / 0.28 / 0.19 / 0.10 / -0.11
MMP-1
Baseline / 0.47* / - / 0.64** / - / 0.22 / -
Week 4 / 0.44* / 0.20 / 0.42 / 0.51* / 0.32 / 0.31
Final / 0.73** / 0.56** / 0.60** / 0.47* / 0.68** / 0.38
MMP-3
Baseline / 0.49* / - / 0.52* / - / 0.57** / -
Week 4 / 0.52* / 0.41 / 0.74** / 0.52* / 0.60** / 0.36
Final / 0.64** / 0.70** / 0.66** / 0.40 / 0.71** / 0.36
TIMP-1
Baseline / 0.34 / - / 0.55** / - / 0.23 / -
Week 4 / 0.41 / 0.55** / 0.49* / 0.60** / 0.26 / 0.42*
Final / 0.52* / 0.53* / 0.73** / 0.68** / 0.49* / 0.47*
MMP-3:TIMP-1 ratio
Baseline / 0.40 / - / 0.42 / - / 0.53* / -
Week 4 / 0.54* / 0.41 / 0.67** / 0.41 / 0.64** / 0.30
Final / 0.62** / 0.40 / 0.61** / 0.09 / 0.71* / 0.35
COMP
Baseline / 0.18 / - / -0.04 / - / 0.09 / -
Week 4 / 0.28 / 0.29 / 0.09 / 0.31 / 0.12 / 0.33
Final / 0.32 / 0.11 / 0.31 / 0.10 / 0.42 / 0.33
Apo-A1
Baseline / -0.31 / - / -0.43* / - / -0.22 / -
Week 4 / 0.19 / 0.09 / -0.11 / -0.07 / 0.04 / -0.02
Final / 0.01 / -0.59** / -0.01 / -0.47** / -0.05 / -0.28
Inhibitory assay
5% serum
Baseline / -0.51* / - / -0.32 / - / -0.39 / -
Final / -0.21 / -0.53* / -0.26 / -0.37 / -0.26 / -0.14
10% serum
Baseline / -0.46* / - / -0.21 / - / -0.36 / -
Final / -0.11 / -0.25 / -0.15 / -0.04 / -0.10 / -0.11
* P < 0.05, ** P < 0.01.
Changes in selected biomarkers following treatment can predict and reflect final
clinical responses.
Area under ROC curve of test for final
clinical response
ACR20 / ACR50 / ACR70
Serum biomarker
IL-6
Week 4 % change / 0.52 / 0.58 / 0.60
Final % change / 0.87** / 0.85** / 0.87*
MMP-1
Week 4 % change / 0.76* / 0.65 / 0.75
Final % change / 0.84** / 0.81* / 0.85*
MMP-3
Week 4 % change / 0.69 / 0.59 / 0.71
Final % change / 0.84** / 0.88** / 0.95**
TIMP-1
Week 4 % change / 0.72 / 0.77* / 0.91**
Final % change / 0.91** / 0.86** / 0.92**
Core set measure
Swollen joint count
Week 4 % change / 0.74 / 0.92** / 0.87*
Final % change / 0.91** / 0.97** / 0.97**
Tender joint count
Week 4 % change / 0.84** / 0.74 / 0.69
Final % change / 0.99** / 0.98** / 0.96**
Patients' assessment of disease activity
Week 4 % change / 0.70 / 0.60 / 0.60
Final % change / 0.73 / 0.76 / 0.93**
Physicians' assessment of disease activity
Week 4 % change / 0.74 / 0.75 / 0.74
Final % change / 0.95** / 0.99** / 0.98**
Patients' assessment of pain
Week 4 % change / 0.63 / 0.5 / 0.45
Final % change / 0.83* / 0.80* / 0.94**
ESR
Week 4 % change / 0.73 / 0.67 / 0.75
Final % change / 0.93 / 0.84 / 0.78
CRP
Week 4 % change / 0.65 / 0.63 / 0.66
Final % change / 0.97** / 1.00** / 0.93**
HAQ score
Week 4 % change / 0.76* / 0.67 / 0.72
Final % change / 0.88** / 0.83* / 1.00**
Week 4 ACR20 response / 0.82* / 0.80* / 0.82*
ROC curves were constructed using final % decreases in serum biomarkers or ACR core set
components as test variables and final ACR responses as outcome variables. All values are
areas under the relevant ROC curve. Values near 0 or 1 indicate a good test, while values
near 0.5 indicate a poor test for final clinical outcome. * P < 0.05, ** P < 0.01.

REFERENCES

[1]Rooney T, Murphy E, Benito M, Roux-Lombard P, FitzGerald O, Dayer JM, et al. Synovial tissue interleukin-18 expression and the response to treatment in patients with inflammatory arthritis. Ann Rheum Dis 2004;63(11):1393-8.

[2]Hyka N, Dayer JM, Modoux C, Kohno T, Edwards CK, 3rd, Roux-Lombard P, et al. Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood 2001;97(8):2381-9.