MD Biosciences Blog

T-cells in Rheumatoid Arthritis | Where, Why & When?

Posted by MD Biosciences

on Mar 28, 2011 12:02:00 PM

The role of T-cells and their actions in rheumatoid arthritis (RA) has been the focus of a great deal of research for some time [1], mainly as a result of many observations in human patients and experimental animal models.  The association of Human Leukocyte Antigen (HLA) DR, a MHC class II cell surface receptor, in RA provides the strongest evidence that CD4+ T-cells are involved in the development of disease [2, 3, 6]. Many other types of T-cells, including CD8+, regulatory T-cells and γδ T-cells have been shown to play different roles in the progression of RA [1, 2, 3, 8]. The mechanisms of disease involved in RA are still unknown; however the main hypothesis theorizes that auto antigens are presented to auto reactive T helper cells, which then orchestrate the inflammatory processes which are characteristic of the disease [3]. The nature of the antigens involved is unknown however several candidates have been suggested, most recently, citrullinated proteins [5, 6].

Work in animal models of arthritis has provided valuable information on the role of T-cells in this complex disease [9]. The importance of T-cells can be shown in the transfer of CD4+ T-cells from an arthritic animal to a healthy animal, which leads to induction of tissue damage in the recipient [2]. Interestingly, recent research has delivered surprising results on the location of T-cells in models of arthritis [4]. In the model of proteoglycan induced arthritis (PGIA), fluorescence-labelled donor T-cells were tracked in SCID mice and the majority were found in the lymph nodes with unexpectedly few found in the joint [5]. In addition, this study also demonstrated that inhibition of T-cell movement from the lymph tissue, using the drug FTY720, did not prevent development or reduce severity of disease in the PGIA model, suggesting that T-cells do not have to be present in the joint for the induction of arthritis in this model [5].

In another study, this time using humanized DR-4 transgenic  mice in the collagen induced arthritis (CIA) model, pro-inflammatory T-cells were tracked using a tetramer and were found in the blood and joints during early stages of the disease [3]. However, as disease progressed, the T-cells became undetectable in the joint, rare in the blood and decreased in the lymph tissues. The authors of this study conclude that there may be a “threshold” of activated T-cells circulating that is required for the onset of disease, and once reached the number of active T-cells decreases in the blood, lymph nodes and synovial fluid [3]. These findings raise interesting questions on the link between the location and role of T-cells in models of arthritis.

With all of the evidence for the involvement of T-cells in the development of RA, there is potential for T-cell specific therapies to be the next line in defense against the disease [2]. The most recent T-cell targeted therapy is Abatacept (Orencia®), a fusion protein of the extracellular portion of CTLA4 and human IgG1Fc, which interrupts the “second signal” between the CD28 ligand on the T-cell by binding the CD80/86 ligand on the antigen presenting cell [6, 7, 10].  Clinical trials have shown that Abatacept improves swollen and tender joint complaints and radiological results in patients with disease reduction comarable to some present anti-TNF agents while providing a better safety profile than those drugs [7, 10]. The impressive clinical data for this drug suggests that T-cell specific therapies are promising new agents in the treatment of RA.

The importance of T-cells in RA has been highlighted through a focus of research on the subject, however many questions still remain over their exact function in the pathogenesis of disease. The questions surrounding the location of T-cells during disease, the still unidentified auto antigens that cause the disease and the failure of T-cells to function properly are all areas that demand further research to advance our knowledge of the most common inflammatory condition in humans.

Preclinical efficacy studies, rheumatoid arthritis, preclinical contract research (CRO), collagen-induced arthritis (CIA), anti-collagen antibody-induced arthritis (ACAIA)

 

References:

  1. Fournier, C. (2005). Joint Bone Spine, 72: 527-532
  2. Skapenko, A. et al (2005). Arthritis Research & Therapy, 7(Suppl 2): S4-S14 
  3. Svendsen, P. et al (2004). The Journal of Immunology, 173: 7037-7045
  4. Kamradt T, Frey O. (2010).  Arthritis Research & Therapy, 12:122
  5. Angyal, A. et al (2010).  Arthritis Research & Therapy, 12:R44
  6. Andersson, A. et al (2008). Arthritis Research & Therapy 10:204
  7. Solomon, GE (2010). Bulletin of the NYU Hospital for Joint Diseases, 68(3):162
  8. Roark, CL. et al (2007). The Journal of Immunology, 179: 5576-5583
  9. Goronzy JJ, Weyland, CM (2009). Arthritis Research & Therapy, 11:249
  10. Van Vollenhoven, R.F. (2009) Nature Reviews Rheumatology, 5: 531-541

Topics: Inflammation