HUMANIZED ANTIBODIES AGAINST THE ALPHA-CHAIN OF THE IL-2 RECEPTOR ANDAGAINST THE BETA-CHAIN SHARED BY THE IL-2 AND IL-15 RECEPTORS IN A MONKEY UVEITIS MODEL OF AUTOIMMUNE-DISEASES

We studied the efficacy and tolerance of humanized Ab interfering with the signal of the IL-2 and IL-15 receptors in a primate model of expe rimental autoimmune uveoretinitis. The inhibitory effects of humanized anti-Tac (HAT), an anti-IL-2R alpha-chain Ab, and HuMik beta 1, an Ab directed at the beta-chain shared by the receptors of IL-2 and IL-15, were tested in culture on the proliferative response of monkey Con A- blast lymphocytes stimulated with IL-2 or IL-15, Uveitis was induced i n cynomolgus monkeys by immunization with human recombinant retinal S- antigen, Treatment was initiated at the first sign of disease and cons isted of HAT and HuMik beta 1, alone or in combination, or vehicle con trol given by i.v, injection twice a week for 4 wk, Disease was evalua ted by ocular funduscopy, The results in culture showed a significant dose-dependent inhibition of the IL-2-driven proliferation of lymphocy tes by HAT, HuMik beta 1 alone was ineffective against IL-2 stimulatio n, but had a marked potentiating effect in combination with HAT, indep endent of IL-15 signaling, IL-15-driven proliferation was inhibited by HuMik beta 1, but not by HAT alone or in combination. In monkeys, exp erimental autoimmune uveoretinitis evolution was significantly inhibit ed by HAT treatment. HuMik beta 1 alone had no effect on the disease, However, when used in combination, the two Ab markedly reduced the sev erity of ocular inflammation. The Ab were well tolerated. Only three m onkeys, treated with HAT alone, made an Ab response against the inject ed Ab.