Role of IL-7 and TSLP in immunopathology of (rheumatoid) arthritis

Translated title of the contribution: Role of IL-7 and TSLP in immunopathology of (rheumatoid) arthritis

S.A.Y. Hartgring

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

Abstract

IL-7 and TSLP as therapeutic targets for rheumatoid arthritis Interleukin (IL)-7 is a potent immunostimulatory cytokine. In this thesis we demonstrate that IL-7 and a IL-7-related cytokine thymic stromal lymphopoietin (TSLP) stimulate inflammatory responses that can aggravate rheumatoid arthritis (RA). The persistence of IL-7 activity and levels upon TNF-alpha blockade in patients with RA suggests that blockade of the IL-7 pathway is a potential target in treatment-refractory RA. IL-7 activity is dependent on signaling through the IL-7R. Increased IL-7R expression was found in RA synovial tissue. CD4 T cells from RA synovial fluid and tissue strongly expressed IL-7R, as well as a percentage of B cells and macrophages. IL-7R+ T cells lacking FoxP3-expression strongly proliferated, compared to non-proliferating IL-7R- T cells with high levels of FoxP3. In line with this, blockade of IL-7R signaling by soluble human IL-7R inhibited IFN-gamma production by cells from RA patients. To further support the importance of IL-7/IL-7R-mediated inflammatory responses in RA the role of this inflammatory pathway was studied in experimental arthritis. Increased IL-7 in serum and inflamed paws of arthritic mice was demonstrated. Comparable to RA patients, local IL-7 levels in mice correlated with arthritis severity. Neutralization of IL-7 inhibited joint inflammation, demonstrating an important role for IL-7-driven immunity in experimental arthritis. Furthermore, prophylactic and therapeutic IL-7R blockade decreased severity of experimental arthritis, associated by reduced T-cell numbers, T-cell cytokines (IFN-gamma, IL-5 and IL-17), and many proinflammatory mediators, including IL-1-beta and TNF-alpha. Since TSLP, in conjunction with the TSLP receptor, also utilizes the IL-7R for signaling, blockade of IL-7R-driven immunity might also influence TSLP-induced immune activation. Therefore, the role of TSLP in arthritis was also addressed. TSLP and IL-7 strongly increased arthritis severity, but only IL-7 increased radiological joint destruction, associated with increased intensity of cell infiltrates, cartilage damage, bone erosions, and osteoclast activity. Both IL-7 and TSLP administration induced expansion of memory T cells, associated with increased numbers of IFN-gamma- and IL-17-producing T cells by IL-7, and increased IL-4-producing T cells by TSLP. Both, IL-7 and TSLP increased several proinflammatory mediators, such as CD40L and chemokine MDC. Thus, IL-7 and TSLP enhanced arthritis by differential regulation of arthritogenic responses. In support of the role of TSLP in arthritis we documented that arthritis severity was strongly down-regulated in TSLPR-deficient mice. This was associated with unchanged thymic and splenic cellnumbers, but strongly reduced radiological joint damage, and reduced inflammation, cartilage erosions, periosteal exostosis, bone erosions and numbers of TRAP+ osteoclasts. Mediators of T-cell activation, chemokines, vascular activation and angiogenesis factors, and tissue destructive factors were all reduced in TSLPR-deficient mice. Furthermore, interruption of both IL-7R and TSLPR pathways resulted in additive disease suppression almost completely preventing immunopathology. The data presented in this thesis reveal the capacity of IL-7 and TSLP and their receptors to strongly promote arthritis and joint destruction, and demonstrates the distinct arthritogenic contributions of both cytokines. These data indicate that targeting of IL-7 and TSLP and their receptors might be new strategies to control (rheumatoid) arthritis.
Translated title of the contributionRole of IL-7 and TSLP in immunopathology of (rheumatoid) arthritis
Original languageUndefined/Unknown
QualificationDoctor of Philosophy
Awarding Institution
  • Utrecht University
Supervisors/Advisors
  • Lafeber, Floris, Primary supervisor
  • Bijlsma, JWJ, Supervisor
  • van Roon, Joel, Co-supervisor
Award date3 Dec 2009
Publisher
Print ISBNs978-90-393-52-199
Publication statusPublished - 3 Dec 2009

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