Monocyte Scintigraphy in Rheumatoid Arthritis: The Dynamics of Monocyte Migration in Immune-Mediated Inflammatory Disease

Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, Noord Holland, The Netherlands.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e7865. DOI: 10.1371/journal.pone.0007865
Source: PubMed


Macrophages are principal drivers of synovial inflammation in rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disease. Conceivably, synovial macrophages are continuously replaced by circulating monocytes in RA. Animal studies from the 1960s suggested that macrophage replacement by monocytes is a slow process in chronic inflammatory lesions. Translation of these data into the human condition has been hampered by the lack of available techniques to analyze monocyte migration in man.
We developed a technique that enabled us to analyze the migration of labelled autologous monocytes in RA patients using single photon emission computer tomography (SPECT). We isolated CD14+ monocytes by CliniMACS in 8 patients and labeled these with technetium-99m (99mTc-HMPAO). Monocytes were re-infused into the same patient. Using SPECT we calculated that a very small but specific fraction of 3.4 x 10(-3) (0.95-5.1 x 10(-3)) % of re-infused monocytes migrated to the inflamed joints, being detectable within one hour after re-infusion.
The results indicate monocytes migrate continuously into the inflamed synovial tissue of RA patients, but at a slow macrophage-replacement rate. This suggests that the rapid decrease in synovial macrophages that occurs after antirheumatic treatment might rather be explained by an alteration in macrophage retention than in monocyte influx and that RA might be particularly sensitive to treatments targeting inflammatory cell retention.

Download full-text


Available from: Paul P Tak
  • Source
    • "This process increases the chance that lymphocytes will encounter the antigen and is also critical to the development of an inflammatory response. Abnormal immune cells migration is always associated with the development and progression of autoimmune diseases [1–3]. Many studies have provided strong support for this idea, and clinical studies have indicated that pharmacological inhibitors on immune cells migration can be highly effective in certain disease conditions [4, 5]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) are highly efficient antigen-presenting cells. The migratory properties of DCs give them the capacity to be a sentinel of the body and the vital role in the induction and regulation of adaptive immune responses. Therefore, it is important to understand the mechanisms in control of migration of DCs to lymphoid and nonlymphoid tissues. This may provide us novel insight into the clinical treatment of diseases such as autoimmune disease, infectious disease, and tumor. The chemotactic G protein-coupled receptors (GPCR) play a vital role in control of DCs migration. Here, we reviewed the recent advances regarding the role of GPCR in control of migration of subsets of DCs, with a focus on the chemokine receptors. Understanding subsets of DCs migration could provide a rational basis for the design of novel therapies in various clinical conditions.
    Full-text · Article · Mar 2014
  • Source
    • "In RA, the joint synovial tissue is abnormally infiltrated by a variety of specific cells such as macrophage, T cell, B cell, granulocyte, and monocyte [5]. Among these inflammatory cells, macrophages are abundantly present in the inflamed synovial membrane and at the cartilage-pannus junction, contributing to joint inflammation and cartilage destruction in the acute and chronic progression of RA [6]–[8]. The infiltration/activation of macrophages stimulates the over-expression of several proinflammatory cytokines including TNF-α, IL-1β, and IL-6 which are, at least in part, dependent on the activation of NF-κB [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis (RA) is the most common arthritis and is mainly characterized by symmetric polyarticular joint disorders. Our previous study demonstrated a novel small molecule compound (Z)-N-(3-Chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene) methyl) phenoxy) acet-amide (SKLB023) showed potently anti-arthritic effects in a rat arthritis model, however, the underlying mechanisms for this are largely unknown. Both NF-κB and macrophages were reported to play important roles in the pathologic processes of RA. The purposes of this study were to indicate whether NF-κB and macrophages contributed to anti-arthritic effects of SKLB023 in two experimental arthritis models. Our results showed that SKLB023 could significantly improve joint inflammation and cartilage destruction both in adjuvant induced arthritis (AIA) and collagen-induced arthritis (CIA) models. We further found that the binding activation of NF-κB to DNA in joint tissues and RAW264.7 macrophages were suppressed by SKLB023. SKLB023 also inhibited the NF-κB activity in peritoneal macrophages by luciferase assay. Furthermore, the number of macrophages in synovial tissues was decreased after the treatment of different doses of SKLB023. The levels of TNF-α, IL-1β, and IL-6 in plasma, and the levels of TNF-α, NO, and IL-1β in peritoneal macrophages were down-regulated by SKLB023. Finally, SKLB023 attenuated the expression of iNOS and COX-2 in vivo and suppressed the phosphorylations of components of the mitogen-activated protein kinases (MAPKs). These observations identify a novel function for SKLB023 as an inhibitor of NF-κB in macrophages of RA, highlighting that SKLB023 was a potential therapeutic strategy for RA.
    Full-text · Article · Feb 2013 · PLoS ONE
  • Source
    • "Autologous monocytes have also been successfully labeled with [ 99m Tc]HMPAO and assessed in RA [134] [137]. Thurlings and colleagues reported that [ 99m Tc]HMPAO-labeled monocyte scintigrahpic findings positively correlate with the swollen joint count and number of macrophages, as confirmed by immunohistochemical staining, in biopsied synovial tissue from 8 RA patients [138]. While it is clear that radiolabeled leukocyte joint scintigraphy allows delineation of inflammation and distribution of disease with high sensitivity, it lacks specificity for RA, ultimately limiting its clinical utility. "
    [Show abstract] [Hide abstract]
    ABSTRACT: As remission has now become a realistic therapeutic goal in the clinical management of RA due to the introduction and widespread adoption of biologic agents, there is a greater need for earlier diagnoses and objective methods for evaluating disease activity and response to treatment. In this capacity, advanced imaging strategies are assuming an expansive clinical role, particularly as they take advantage of newer imaging technologies and the shift toward imaging at the molecular level. Molecular imaging utilizes target-specific probes to non-invasively visualize molecular, cellular, and physiological perturbations in response to the underlying pathology. Probes for nuclear and MR imaging have been and are being developed that react with discrete aspects of inflammatory and destructive pathways specific to RA. These probes in addition to new MR sequences and contrast agents have the potential to provide an earlier and more reliable assessment of clinical outcome, disease activity, severity, and location, and therapeutic response. Furthermore, these imaging strategies may enable a more fundamental understanding of critical pathophysiological processes and the advent of new molecular therapies. This review will discuss these advances in both nuclear medicine and MRI strategies for imaging RA with a particular emphasis on molecular imaging.
    Full-text · Article · Nov 2012 · American Journal of Nuclear Medicine and Molecular Imaging
Show more