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CTLA4Ig-Induced Linked Regulation of Allogeneic T Cell Responses¹

Richard S. Lee^*, James R. Rusche, Michaella E. Maloney^*, David H. Sachs^*, Mohamed H. Sayegh and Joren C. Madsen^2,*,

^* Transplantation Biology Research Center and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114; Repligen Corporation, Needham, MA 02494; and Laboratory of Immunogenetics and Transplantation, Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

The mechanisms by which CTLA4Ig exerts its powerful immunomodulatory effects are not clear. We show here that CTLA4Ig can induce linked regulation of allogeneic porcine T cell responses in vitro. Naive miniature swine SLA^dd T cells were rendered hyporesponsive to specific allogeneic Ag after coculturing with MHC-mismatched SLA^cc stimulators in the presence of CTLA4Ig. These Ag-specific hyporesponsive T cells were subsequently able to actively inhibit the allogeneic responses of naive syngeneic T cells in an MHC-linked fashion, as the responses of naive SLA^dd responders against specific SLA^cc and (SLA^ac)F₁ stimulators were inhibited, but allogeneic responses against a 1:1 mixture of SLA^aa (I^a, II^a) and SLA^cc (I^c, II^c) were maintained. This inhibition could be generated against either class I or class II Ags, was radiosensitive, and required cell-cell contact. Furthermore, the mechanism of inhibition was not dependent upon a deletional, apoptotic pathway, but it was reversed by anti-IL-10 mAb. These data suggest that CTLA4Ig-induced inhibition of naive allogeneic T cell responses can be mediated through the generation of regulatory T cells via an IL-10-dependent mechanism.

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