Innovative treatment approaches for rheumatoid arthritis. T-cell regulation.
There is considerable evidence to implicate T cells in the pathogenesis of rheumatoid arthritis (RA). They initiate and sustain inflammation and therefore are attractive targets for immunotherapy. Several strategies targeting T cells have been tried in RA. The use of monoclonal antibodies to deplete T cells have been used extensively but with little success. Studies have shown that T cell depleting antibodies produce profound peripheral blood lymphopenia but they are less effective in depleting lymphocytes in the joint. Since clinical efficacy is likely to depend on depleting almost all synovial lymphocytes, high doses of monoclonal antibodies would have to be given. However, the invariably severe peripheral blood lymphopenia induced by such a regimen is likely to result in profound immunosuppression. Therefore, this strategy has been abandoned and recent attempts have been made to induce tolerance in RA. In animal models of RA, treatment with high dose non-depleting anti-CD4 monoclonal antibody protects them from arthritis induced by injection of streptococcal cell wall. In addition, it leads to a state of anergy which protects the animals from arthritis induction without further treatment with anti-CD4 monoclonal antibody. This is currently being used in clinical trials of RA. Other tolerance inducing treatment strategies include T cell or T cell receptor vaccination and oral tolerance. The former is particularly difficult since the rheumatoid arthritogenic antigen and the pathogenic T cell remain unknown. The latter has shown promise in placebo controlled trials although the ideal dosage remains unknown. The mechanism of action of oral tolerance involves either immunosuppressive T cell cytokines, T cell anergy or depletion.
Choy
E H
EH
UMDS, Rheumatology Unit, Guy's Hospital, London, UK.
Kingsley
G H
GH
Panayi
G S
GS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007125:Immunogenetics; D007167:Immunotherapy; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014611:Vaccination
D000911:Antibodies, Monoclonal