No abstract

The induction of tolerance in a primed immune system is a major aim for therapy in autoimmunity and transplant rejection. In this paper, we investigate the action of the nondepleting anti-CD4 Ab, YTS 177. Although this Ab is nondepleting, we have demonstrated a direct action in vivo on activated effector cells. We show that the Ab inhibits transfer of insulin-dependent diabetes mellitus by the CD4+ Th1 clone BDC2.5 to nonobese diabetic mice. Furthermore, we show that this Ab acts directly on diabetogenic effector cells because it prevented BDC2.5-induced insulin-dependent diabetes mellitus in nonobese diabetic-scid recipients in the absence of other T cells. The Ab halts the diabetic process even when it is administered after the BDC2.5 cells have infiltrated the pancreas and destruction of islets is already underway. This is accompanied by an immediate decrease in proinflammatory cytokine production with cessation of β cell destruction and disappearance of infiltrating cells from the pancreas, leaving any remaining β cells intact. These data suggest that Abs such as this may be effective not only because they induce regulatory T cells but also because they are able to directly prevent effector cell function.

No abstract

It is well established that long-term protection from insulin-dependent diabetes mellitus (IDDM) can be afforded to non-obese diabetic (NOD) mice by a short course of nondepleting (nd) anti-CD4 monoclonal antibodies (mAb). Since it is increasingly apparent that the CD8 + T cell plays a prominent role in the development of IDDM, we have investigated the effect of an anti-CD8 mAb (YTS 105) of the same isotype in both spontaneous and induced IDDM in NOD mice. Treatment with YTS 105 for 3 weeks was able to prevent the transfer of IDDM for a long period, and also substantially reduced spontaneous IDDM in female NOD mice. The role of the thymus in tolerance induction by these antibodies was studied. In the adult transfer model, thymectomized NOD mice, unlike their euthymic counterparts, were not protected long-term by treatment with YTS 105, and began to become overtly diabetic shortly after treatment. This was also true when the nd anti-CD4 mAb was used. Protection from spontaneous disease was not affected in the same way by thymectomy. The reasons for the observed effect of the thymus in the transfer model, and the differences between the two models that may explain the contrasting results are discussed.

It is well established that long-term protection from insulin-dependent diabetes mellitus (IDDM) can be afforded to non-obese diabetic (NOD) mice by a short course of non-depleting (nd) anti-CD4 monoclonal antibodies (mAb). Since it is increasingly apparent that the CD8+ T cell plays a prominent role in the development of IDDM, we have investigated the effect of an anti-CD8 mAb (YTS 105) of the same isotype in both spontaneous and induced IDDM in NOD mice. Treatment with YTS 105 for 3 weeks was able to prevent the transfer of IDDM for a long period, and also substantially reduced spontaneous IDDM in female NOD mice. The role of the thymus in tolerance induction by these antibodies was studied. In the adult transfer model, thymectomized NOD mice, unlike their euthymic counterparts, were not protected long-term by treatment with YTS 105, and began to become overtly diabetic shortly after treatment. This was also true when the nd anti-CD4 mAb was used. Protection from spontaneous disease was not affected in the same way by thymectomy. The reasons for the observed effect of the thymus in the transfer model, and the differences between the two models that may explain the contrasting results are discussed.