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Nondepleting Anti-CD4 Has an Immediate Action on Diabetogenic Effector Cells, Halting Their Destruction of Pancreatic ß Cells¹

Jenny M. Phillips^2,*, Silvia Zusman Harach^*, Nicole M. Parish^*, Zoltan Fehervari^*, Katherine Haskins and Anne Cooke^*

^* Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262

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 ß cell destruction and disappearance of infiltrating cells from the pancreas, leaving any remaining ß 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.

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