Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor ╨Ю┬▒
код для вставкиСкачать1170 LOCALIZATION OF TUMOR NECROSIS FACTOR RECEPTORS IN THE SYNOVIAL TISSUE AND CARTILAGE-PANNUS JUNCTION IN PATIENTS WITH RHEUMATOID ARTHRITIS Implications for Local Actions of Tumor Necrosis Factor a BENT W. DELEURAN, CONG-QIU CHU. MAX FIELD, FIONULA M. BRENNAN, TRACEY MITCHELL. MARC FELDMANN, and RAVINDER N. MAIN1 Objective. We have previously described the location of tumor necrosis factor a (TNFa)-producing cells in synovial tissue and cartilage-pannus junction in rheumatoid arthritis (RA). To further understand the local actions of TNFa, we investigated the expression of TNF receptors (TNF-R) on cells in the same compartments in patients with RA. Methods. The expression of both p55 TNF-R and p75 TNF-R was determined using alkaline phosphataseconjugated mouse anti-alkaline phosphatase (APAAP) and double immunofluorescence staining techniques with monoclonal antibodies. From The Mathilda and Terence Kennedy Institute of Rheumatology. Bute Gardens and Sunley Research Centre. London. England. Supported by the Arthritis and Rheumatism Council of Britain. Dr. Deleuran's work was supported by the University of Aarhus and by the Danish Rheumatism Association. Bent W. Deleuran. MD: Research Fellow, The Mathilda and Terence Kennedy Institute of Rheumatology (current address: Department of Rheumatology. University of Aarhus, Denmark): Cong-Qiu Chu. MD. PhD: Research Scientist, The Mathilda and Terence Kennedy Institute of Rheumatology. Bute Gardens; Max Field, BSc, MD, MRCP: Senior Lecturer and Consultant Rheumatologist. The Mathilda and Terence Kennedy Institute of Rheumatology (current address: Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, Scotland): Fionula M. Brennan. BSc. PhD: Senior Research Scientist. The Mathilda and Terence Kennedy Institute of Rheumatology. Sunley Research Centre: Tracey Mitchell, BSc: Research Assistant, The Mathilda and Terence Kennedy Institute of Rheumatology, Bute Gardens: Marc Feldmann. MD, PhD. FRCPath: Professor, The Mathilda and Terence Kennedy Institute of Rheumatology. Sunley Research Centre; Ravinder N . Maini. MB, FRCP: Professor and Director. The Mathilda and Terence Kennedy Institute of Rheumatology, Bute Gardens. Address reprint requests to Ravinder N . Maini, MB. FRCP. The Mathilda and Terence Kennedy Institute of Rheumatology. 6 Bute Gardens, Hammersmith. London W6 7DW. UK. Submitted for publication February 18, 1992: accepted in revised form May 20. 1992. Arthritis and Rheumatism, Vol. 35, No. 10 (October 1992) Results. In RA synovial membrane, both p55 TNF-R and p75 TNF-R were detectable in up to 90% of the cells in the lining layer, and were demonstrated on cells in deeper layers of the membrane, including vascular endothelial cells. Cells in lymphoid aggregates expressed both TNF-R, but with a predominant expression of p75 receptor. At the cartilage-pannus junction, the majority of pannus cells, especially those invading cartilage, expressed both the p55 and the p75 TNF-R. Sequential section and double immunofluorescence staining showed that the TNF-R-expressing cells were in the vicinity of TNFa-containing cells, and some TNFacontaining cells also expressed TNF-R. TNF-Rexpressing cells were also detected in osteoarthritic and normal synovial tissue, but in smaller numbers and at a lower intensity. Conclusion. These results provide histologic evidence that both p55 TNF-R and p75 TNF-R are expressed by a variety of cell types in RA synovial tissue, reflecting the fact that a wide range of cells are potential targets for T N F a in this tissue. This study further supports the hypothesis that T N F a plays a major role in the pathogenesis of RA. Tumor necrosis factor a (TNFa) is a pleiotropic cytokine which has been implicated in the pathogenesis of rheumatoid arthritis (RA). Many of its biologic properties indicate that T N F a may be involved not only in regulation of immune and inflammatory responses in rheumatoid synovitis, but also in cartilage and bone destruction ( I ) . Elevated levels of biologically active T N F a have been detected in RA synovial fluid (2,3). Our previous studies demonstrated that T N F a is locally produced by synovial tissue cells (4-6). and it is likely that the production of T N F a is LOCALIZATION OF TNF RECEPTORS I N RA JOINTS i m p o r t a n t in v i v o f o r t h e p r o d u c t i o n o f o t h e r proinflammatory c y t o k i n e s , s u c h as interleukin-I (1L-I) a n d g r a n u l o c y t e - m a c r o p h a g e colony-stimulating f a c t o r . by synovial cells (5.7). Based on t h e s e o b s e r v a t i o n s , it w a s therefore h y p o t h e s i z e d that TNFa is a pivotal c y t o k i n e in t h e p a t h o g e n e s i s o f RA (S,7). TNFa m e d i a t e s its effects via binding t o cell surface TNF r e c e p t o r s (TNF-R). T w o T N F - R , with m o l e c u l a r weights o f 55 kd (pSS) a n d 75 k d ( ~ 7 3h,a v e been cloned recently (8-10). T N F - R are widely distribu t e d , b u t with t h e availability of specific monoclonal a n t i b o d i e s ( M A b ) , differences in t h e cellular e x p r e s s i o n of p5S T N F - R a n d p75 T N F - R h a v e become a p p a r e n t . B o t h TNF-R are p r e s e n t on lymphocytic cell lines, peripheral blood m o n o c y t e s ( I I ), a n d natural killer cells (12). Resting l y m p h o c y t e s h a v e v e r y f e w TNF r e c e p t o r s , but u p o n activation, p7S TNF-R is preferentially i n d u c e d ( I I,l3,14).TNFa ( I S ) , IL-I, phorbol 12-myristate 13-acetate (16), bacterial lipopolysaccharide (17). and a c t i v a t o r s of protein kinase C (18) d o w n - r e g u l a t e s u r f a c e TNF-R e x p r e s s i o n , w h e r e a s interferon-y (19) a n d IL-2 (20) i n c r e a s e its expression. We h a v e previously described t h e location of TNFa-producing cells in r h e u m a t o i d synovial tissue a n d a t s i t e s o f tissue d e s t r u c t i o n , s u c h as t h e cartilagep a n n u s j u n c t i o n (6). TNFa e x e r t s its a c t i o n s locally. To u n d e r s t a n d f u r t h e r t h e local effects of TNFa, w e investigated t h e presence and cellular distribution o f b o t h pS5 and p7S T N F - R in r h e u m a t o i d synovial tissue and cartilage-pannus j u n c t i o n , in an a t t e m p t to m a p t h e potential t a r g e t s of TNFa. B o t h pS5 T N F - R a n d p7S TNF-R were f o u n d to be e x p r e s s e d b y a large number of synovial cells in r h e u m a t o i d synovial memb r a n e and a t t h e cartilage-pannus j u n c t i o n . PATIENTS AND METHODS Reagents. Mouse MAb to human pS5 T N F - R (HTR-9) and p75 TNF-K (UTR-I) have been described previously ( I I ). Affinity-purified polyclonal rabbit antiT N F a antibody was generated by repeated injection of human recombinant T N F a (Genentech. South San Francisco, CA). as previously described (6). Goat anti-mouse IgG. alkaline phosphatase-conjugated mouse anti-alkaline phosphatase complex (APAAP). mouse antLCD68 antibody (EBMI 1). rabbit anti-human von Willebrand factor. and fluorescein-conjugated swine anti-rabbit IgG were all obtained from Dakopatts (Copenhagen, Denmark). Normal mouse lgGl and goat anti-mouse IgG linked to biotin were obtained from Sigma (Poole. UK). Streptavidin-linked Texas red was purchased from Amersham (Buckinghamshire, UK). Patients. Synovial tissue from the knee joint was obtained at arthroplasty o r arthroscopy in 12 patients with 1171 RA, and cartilage-pannus junction samples were obtained from 5 of the 12. All patients fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria for RA (21). Patients were treated with methotrexate ( n = 2). D-penicillamine (n = 3), sodium aurothiomalate (n = 2 ) . azathioprine (n = I ) , and corticosteroids ( n = 4): 2 patients were not receiving any second-line antirheumatic drugs. Synovial tissue was also obtained from 8 osteoarthritis (OA) patients. who had received nonsteroidal antiinflammatory drugs, acetaminophen, o r a combination of these drugs. None had received steroid treatment. Normal synovial membrane and cartilage-synovium junction samples were obtained from the knee joints of 7 patients undergoing amputation for osteogenic sarcoma at a site distant from the knee joint (samples kindly provided by Dr. M. Bayliss. Kennedy Institute). All samples were snap frozen in isopentane cooled in liquid nitrogen and stored at -80°C until use. Imrnunohistochemical techniques. Five-micrometer cryostat sections were washed in 0.05M Tris buffered saline (TBS). pH 7.36. for 1 minute at 4°C in order to remove soluble receptors, then fixed in acetonehethanol at -20°C for 10 minutes and blocked for 20 minutes with 20% normal goat serum (NGS). The sections were incubated overnight at 4°C with anti-p55 TNF-R MAb (HTR-9; I5 pg/ml), anti-p75 TNF-R MAb ( U T R - I ; 20 pg/ml), o r antLCD68 MAb ( E B M I I : 3 pg/ml). Binding was detected by 30-minute incubation of the sections at room temperature with goat anti-mouse IgG diluted in 2%) NGS. followed by APAAP, for 30 minutes. In order to amplify the signal, the incubation with goat anti-mouse IgG and APAAP was repeated once. The sections were then incubated for up to 15 minutes with I m g h l fast red (Sigma) in TBS, pH 8.2, containing 0.6M dimethylformamide. 0.02M naphthol phosphate, and 0.001M levamisole. The reaction was stopped with distilled water and the sections were counterstained in hematoxylin. Normal mouse IgGI at equivalent protein concentration was included as a control. For double immunofluorescence staining, the RA synovial membrane and cartilage-pannus junction sections were treated and incubated as above with anti-TNF-R MAb (H'IR-9 and UTR-I) and rabbit anti-TNFa o r rabbit antihuman von Willebrand factor antibodies. Binding of HTR-9 and UTR-I was detected with biotin-labeled goat anti-mouse IgG and streptavidin-linked Texas red. Rabbit anti-TNFa and rabbit anti-human von Willebrand factor antibodies were detected with fluorescein-conjugated swine anti-rabbit IgG. Statistical analysis. The numbers of TNF-R-positive and CDh8-positive cells were determined by counting up to 500 cells in each area of the tissue examined, and the results were expressed as a percentage of positive cells over the total cells. Data were analyzed using the Wilcoxon rank sum test. RESULTS Localization of p55 TNF-R-expressing cells in synovial membrane. Staining with HTR-9 antibody (p55 T N F - R ) o f t e n s h o w e d a c y t o p l a s m i c p a t t e r n , with 1172 Table 1. DELEURAN E T AL Distribution of tumor necrosis factor receptor (TNF-R)- and CD68-expressing cells in synovial membrane* p55 TNF-R CD68 RA OA C RA OA C RA OA C 92 87 86 92 87 71 100 100 100 50 5 10 50 2 21 86511 NP 35 2 22t 15 2 14t 40529t NP 85 2 21 60 2 22 9055 50 2 23 45 t 35$ 35 2 24$ 85513 NP 15 t 3 t 102 5t 15512t 70 t 12 40 2 20 0 10 2 9 55 2 12 202 7 0 NP 45 t 10 I5 2 3 0 NP % of subjects positive Mean 2 SD % of cells positive Lining layer lnterstitium Vascular endothelium Lymphoid aggregate p75 TNF-R 55 5 23 50 -t 21 85212 20 2 10 NP * The distribution of p55 TNF-R-, p75 TNF-R-, and CD68-positive cells was determined in the synovial lining layer, interstitium, blood vessels, and lymphoid aggregates of synovial tissue from patients with rheumatoid arthritis (RA) (n = 12). patients with osteoarthritis (OA) (n = 8). and healthy controls (C) (n = 7), as described in Patients and Methods. NP = lymphoid aggregates were not present in tissue sections. t P < 0.01 versus RA and OA. $ P < 0.01 versus RA. increased intensity around the nucleus. Synovial membrane samples from 1 1 of 12 RA patients, 7 of 8 OA patients, and 6 of 7 normal controls contained the TNF-R-expressing cells (Table I ) . In RA synovium, the p55 TNF-R-expressing cells were equally represented in the lining layer (mean t SD 55 t 23% positive) (Figure IA) and on cells in the interaggregate areas (mean 50 2 21% positive), whereas in lymphoid aggregates, only 20 5 10% of the cells were positive for p55 TNF-R (Figure IC). Most of vascular endothelial cells stained for p55 TNF-R (Table I). In OA synovium, the cell density was lower than that observed in RA synovium, and no cell aggregates were found. Furthermore, the staining intensity of p55 TNF-R (Figure 2A) was lower than that seen in RA samples, although a similar proportion of cells were positive and a similar cellular distribution was observed. In normal synovial membrane samples, the staining was found to be weak compared with that in RA and OA sections, and significantly fewer cells in the lining layer, interstitial layer, and vessels were positive (P < 0.01) (Table I and Figure 2B). Localization of p75 TNF-R-xpressing cells in synovial membrane. UTR- I antibody (p75 TNF-R) showed a homogeneously granular cytoplasmic staining pattern. Positive staining was identified in synovial membrane samples from 1 1 of 12 RA patients, 7 of 8 OA patients, and 5 of 7 normal subjects (Table I ) . RA samples exhibited p75 TNF-R-expressing cells in a mean 2 SD of 85 ? 21% of the lining layer cells (Figure IB), but also in 60 22% of the cells in the interaggregate areas and 50 t 23% of the lymphoid aggregate cells (Figure ID). In OA synovium, the number of p75 TNF-R-expressing cells in the lining layer and deeper layers of the membrane was signifi- * cantly reduced compared with that in RA samples ( P < O . O l ) , and the staining was less intense. As with staining for p55 TNF-R, a high level of p75 TNF-R expression was observed in association with blood vessels, in which up to 90% of the vessels were found to be positive for p75 TNF-R in both RA (Figure IE) and OA synovial membrane samples. In normal synovial membranes, the staining intensity for p75 TNF-R was very weak, and positive staining was expressed by only a few cells compared with RA and OA samples ( P < 0.01) (Table I ) . Approximately 15% of the blood vessel endothelial cells also stained for p75 TNF-R. Localization of p55 and p75 TNF-R-expressing cells at the cartilage-pannus junction. In the invasive cartilage-pannus junction samples from RA patients (n = 5 ) , most of the cells in the interface of cartilage and pannus, as well as cells invading cartilage, expressed both p55 TNF-R (mean 85% of cells positive) (Figure 3A and Table 2) and p75 TNF-R (mean 70% positive) (Figure 3B and Table 2). The chondrocytes were also positive for p55 TNF-R in a mean of 30% of the cells (range 1040%) and for p75 TNF-R (Figure 4C) in a mean of 35% of the cells (range 1045%). This was in contrast to the normal cartilage-synovium junction, where none of the cells in the junction area expressed either TNF-R, and 10% of the chondrocytes were positive for p55 TNF-R or p75 TNF-R (Table 2). Characterization of cells expressing p55 TNF-R and p75 TNF-R. The monocyte/macrophage marker, CD68, was detected in 70 2 12% (mean 5 SD) of the lining layer cells in RA synovial tissue, 55 2 12% in OA synovial tissue, and 45 t 10% in normal synovial tissue (Table I). In the cartilage-pannus junction of RA patients, 60% of the cells were CD68 positive LOCALIZATION OF TNF RECEPTORS IN RA JOINTS 1173 Figure 1. Distribution of tumor necrosis factor receptors (TNF-R) in rheumatoid synovial membrane. In the lining layer, most of the cells stain for both pSS TNF-R ( A ) and p7.5 TNF-R ( B ) . In the lymphoid aggregate. some cells stain for pS5 TNF-R (C) (arrows), and most stain for p7S TNF-R (D). Staining for p75 TNF-R is found on endothelial cells of blood vessels and on perivascular cells (E).Normal mouse IgG I failed to stain any cells (F). (Alkaline phosphatase-conjugated mouse anti-alkaline phosphatase stained, hematoxylin counterstained; original magnification x 160 in A . B. and F. and x 320 in C. D. and E . ) (Table 2). Staining of sequential sections from RA samples showed that most of the p55 TNF-R- and p75 TNF-R-expressing cells were in the areas of CD68positive cells, both in the lining layer and at the cartilage-pannus junction. Some TNF-R-expressing cells in the lining layer, the interaggregate area, and at the cartilage-pannus junction were CD68 negative and showed a fibroblast-like cell morphology. Double imrnunofluorescence staining of RA synovial membrane sections using a combination of 1174 DELEURAN ET AL Figure 2. Representative sections of osteoarthritic (A) and normal (B) synovial membrane, showing pS5 tumor necrosis factor receptor expression. The perinuclear staining pattern is particularly marked in the osteoarthritic synovium (Alkaline phosphatase-conjugated mouse anti-alkaline phosphatase stained, original magnification x 160.) Figure 3. Localization of tumor necrosis factor receptors (TNF-R) at the cartilage-pannusjunction in the rheumatoid joint. A, Cells expressing p5S TNF-R at the interface of cartilage (C) and pannus (P)and B, those expressing p75 TNF-R at the site of the cartilage lesion are seen. C. Some chondrocytes express p7S TNF-R (arrows); p55 TNF-R showed a similar staining pattern. D,Normal mouse lgGl failed to stain these cells (Alkaline phosphatase-conjugated mouse anti-alkaline phosphatase stained. hematoxylin counterstained: original magnification x 160 in A. B, and D. and x 320 in C . ) LOCALIZATION OF TNF RECEPTORS I N RA JOINTS 1175 Figure 4. Double immunofluorescence staining of rheumatoid synovial lining layer. demonstrating that cells expressing p55 tumor necrosis factor receptor (TNF-K) ( A ) are in the vicinity of TNFa-containing cell\ ( B ) . and some cells costain for T N F a and p5.5 TNF-R. (Original magnification x 2.50.) HTR-9 or UTR-I with polyclonal rabbit anti-TNFa showed that p5S TNF-R- and p75 TNF-R-expressing cells were often in the vicinity of TNFa-positive cells, and 60% of the TNFa-positive cells were also labeled with both HTR-9 and UTR-I antibodies (Figures 4 A and B). Double staining using a combination of HTR-9 or UTR-I with rabbit anti-von Willebrand factor antibodies confirmed that both receptors were also localized to the endothelium of blood vessels. DISCUSSION In the present investigation. using specific monoclonal antibodies, we have detected pS5 TNF-R and p75 TNF-R in diseased and normal synovial tissue, and demonstrated that both TNF-R are increased on cells in rheumatoid synovial membrane and at the cartilage-pannus junction. Both TNF-R were Table 2. Expression of tumor necrosis factor receptors (TNF-K) and CD68 at the cartilage-pannu\ junction and in chondrocytes of patients with rheumatoid arthritis* Cart Ilage-pan n u \ junction cell\ KA C Chondrocytes KA c * The distribution of p55 7°F-K-. p75 TNF-K-. and CD6X-positive cells was determined at the cnrtilage-pannu\ junction in patients with rheumatoid arthritis ( K A ) ( n = 5 ) and at the normal synoviumcartilage junction in healthy controls tC) ( n = 7). as described in Patients and Methods. Re\ult\ are expre\sed a\ the mean (range) percentage of cell\ po\itive. expressed by cells in the region where their ligand, TNFa, was also immunolocalized. The major site of TNF-R expression in the inflamed synovial membrane in RA is the lining layer, in which up to 90% of the lining cells expressed both pSS and p75 TNF-R. Of the 2 cell types that constitute the lining layer. macrophages are in the majority, although fibroblast-type cells are also present (22). Serial section staining indicated that TNF-Rexpressing cells are mostly CD68-positive macrophagehonocyte. TNFa is produced by 40% of the lining layer cells, most commonly macrophages (6); double staining for TNFa and TNF-R indicated that TNFa-producing cells were in the vicinity of the TNF-R-expressing cells, and a significant proportion of cells stained for both TNFa and the receptors. This would imply that these cells are subject to paracrine and autocrine stimulation. Increased expression of TNFa and TNF-R in the rheumatoid synovial lining layer would enable activation of macrophages and fibroblast growth (23), and induce the production of collagenase and prostaglandin (24). In the deeper layers of the synovial membrane (interaggregate area), the frequency of p75 TNF-Rpositive cells was decreased, whereas pS5 TNF-R expression was unchanged on cells in this area. The presence of p7S TNF-R expressed by a larger number of cells (and to a lesser degree for pS5 TNF-R) within the aggregate areas indicates that RA synovial lymphocytes predominantly express p75 TNF-R. This has been confirmed by flow cytometric analysis (25) which indicated that isolated synovial lymphocytes (mainly I176 CD3 positive) predominantly expressed p75 TNF-R. TNFa induces IL-2 receptor expression, and therefore could act as a growth factor for T cells (26). Thus, the fact that a high proportion of lymphocytes express p75 TNF-R in these aggregates suggests that TNFa may be involved in the continued T cell activation. Vascular endothelial cells play an important role in chronic rheumatoid synovitis by allowing inflammatory cell trafficking into the inflamed tissue (27). TNFa induces expression of adhesion molecules on endothelial cells (28,29), thus increasing binding of inflammatory cells such as lymphocytes and monocytes to endothelial cells and facilitating diapedesis. Repeated intraarticular injection of TNFa into experimental animals produced a massive infiltration of mononuclear cells into the synovial tissue (30). TNFa also stimulates endothelial cells to produce 1L-l (31) and IL-8 (32). which are important mediators in rheumatoid synovitis. It is likely that these TNFamediated effects on endothelial cells are involved in RA synovitis. since 90% of the blood vessel endothelial cells in synovial membrane and pannus tissue expressed both TNF-R. Furthermore, TNFa is produced by perivascular cells and by endothelial cells themselves (6); this further emphasizes its ability to participate in the many pathologic processes that can occur in the synovium. The cartilage-pannus junction is the site at which RA joint injury takes place. Cells (predominantly macrophages and fibroblasts) in erosive pannus produce proteolytic enzymes, causing degradation o f the underlying cartilage. As in the lining layer, most of those CD68-positive macrophages and cells with fibroblast morphology in the pannus showed a highly increased expression o f both pS5 TNF-R and p75 TNF-R. TNFa has been implicated in the severe joint destruction seen in RA, since it is found at the cartilage-pannus junction (6) and, in vitro, it induces cartilage and bone erosion (33,34). Thus, in RA, locally produced TNFa may act on these macrophages and fibroblast-like cells to release destructive enzymes. Administration of TNFa into rabbit knee joints causes proteoglycan degradation and cartilage injury ( 3 3 , supporting this hypothesis. In addition, the results of in vitro studies have suggested that TNFa acts directly on chondrocytes (33). Herein we provide evidence that RA chondrocytes also bear TNF-R; thus, TNFa released by pannus cells may directly cause cartilage damage. TNFa may also be involved in the pathogenesis DELEURAN ET AL of OA, but there are conflicting reports on this (36,37). In previous studies we demonstrated that TNFa can be found in OA synovial membrane cells, but at a lower quantity than in RA cells (5,6). The present studies have shown that TNF-R can be found in a similar distribution to that seen for TNFa itself in the lining layer and in the endothelial cells. However, samples from RA patients had much greater staining intensity for TNF-R compared with those from OA patients, suggesting that the number of TNF-R per cell is also smaller in OA synovial cells. This is consistent with the findings of flow cytometric analyses of isolated synovial membrane cells from RA and OA patients (25). In normal synovial membrane, the staining intensity for TNF-R was weak, and was confined to the lining layer and vessels. Only a few of the cells in normal synovium expressed p75 TNF-R, in contrast to its expression on a large number of cells in RA synovial membrane. suggesting that this TNF-R, in particular, is up-regulated during inflammation. These results showing increased expression of TNF-R in RA synovial tissue indicate that a wide variety of synovial cells are potential targets for TNFa. This reflects the wide range of involvement that TNFa appears to have in the synovitis and tissue destruction in RA, and supports the notion that TNFa is a major mediator in the pathogenesis of this disease. I t is not known at present how the expression of TNF-R on RA synovial cells is regulated. This important question is currently under investigation. ACKNOWLEDGMENT We thank Dr. M. Brockhaus (Hoffmann-La Roche. Basel. Switzerland) for providing the HTR-9 and UTR-I monoclonal antibodies. 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