T-cell-targeted therapies in rheumatoid arthritis.
T cells regulate the disease process in rheumatoid arthritis (RA) on multiple levels and represent a logical choice for anti-inflammatory therapy. In the inflamed joint they promote neoangiogenesis and lymphoid organogenesis, and stimulate synoviocyte proliferation and development of bone-eroding osteoclasts. The design of T-cell-targeted therapies for RA needs to take into account the uniqueness of T-cell generation, turnover and differentiation in affected patients. Patients accumulate 'old' T cells that respond to alternate regulatory signals because of an accelerated immune aging process; any therapeutic interventions that increase the replicative stress of T cells should, therefore, be avoided. Instead, therapeutic approaches that raise the threshold for T-cell activation are more promising. As a rule, antigen-derived signals synergize with co-stimulatory signals to stimulate T cells; such co-stimulatory signals are now targeted in novel immunosuppressive therapies. An example is abatacept (soluble cytotoxic-T-lymphocyte-associated protein 4-immunoglobulin), which binds with high affinity to CD80/CD86 and effectively suppresses inflammatory activity in RA. The therapeutic benefits gained by disrupting T-cell co-stimulation indicate that the pathogenesis of RA is driven by a more generalized abnormality in T-cell activation thresholds rather than a highly selective action of arthritogenic antigens.
Weyand
Cornelia M
CM
Kathleen B and Mason I Lowance Center for Human Immunology, Department of Medicine, Emory School of Medicine, Atlanta, GA 30322, USA. cweyand@emory.edu
Goronzy
Jörg J
JJ
D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
D007166:Immunosuppressive Agents