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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-08-2480. This Article Full Text (PDF) All Versions of this Article: 2002-08-2480v1 102/2/564    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vanhove, B. Articles by Soulillou, J.-P. Search for Related Content PubMed PubMed Citation Articles by Vanhove, B. Articles by Soulillou, J.-P. Social Bookmarking                   What's this? Submitted August 13, 2002 Accepted March 9, 2003 Selective blockade of CD28 and not CTLA-4 with a single-chain Fv-alpha-1-antitrypsin fusion antibody Bernard Vanhove*, Genevieve Laflamme, Flora Coulon, Marie Mougin, Patricia Vusio, Fabienne Haspot, Jerome Tiollier, and Jean-Paul Soulillou Unite 437, INSERM, Nantes, France Unite 463, INSERM, Nantes, France Sangstat Europe, Lyon, France * Corresponding author; email: bvanhove{at}nantes .inserm.fr. B7-1 and B7-2 are costimulatory molecules expressed on antigen presenting cells. The CD28-B7 co-stimulation pathway is critical for T cell activation, proliferation and Th polarization. Blocking both CTLA-4 and CD28 interactions with a CTLA4-Ig fusion protein has been shown to inhibit various immune-mediated processes in vivo, such as allograft rejection and autoimmunity. However, selective blockade of CD28 may represent a better strategy for immunosuppression than B7 blockade, since CTLA4/B7 interactions have been shown to participate in the extinction of the T cell receptor-mediated activation signal and to be required for the induction of immunological tolerance. In addition, selective CD28 inhibition specifically decreases the activation of allo- and autoreactive T cells, but not the activation of T cells stimulated by exogenous antigens presented in the context of self-MHC molecules. CD28 blockade cannot be obtained with anti-CD28 dimeric antibodies, which cluster their target and promote T cell co-stimulation, whereas monovalent Fab fragments can block CD28 and reduce alloreactivity. In this study, we report the construction of a monovalent single-chain Fv antibody fragment from a high affinity anti-human CD28 antibody (CD28.3) that blocked adhesion of T cells to cells expressing the CD28 receptor CD80. Genetic fusion with the long-lived serum protein alpha-1-antitrypsin led to an extended half-life without altering its binding characteristics. The anti-CD28 fusion molecule showed biological activity as an immunosuppressant by inhibiting T cell activation and proliferation in a MLR. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. H. Munn, M. D. Sharma, and A. L. Mellor Ligation of B7-1/B7-2 by Human CD4+ T Cells Triggers Indoleamine 2,3-Dioxygenase Activity in Dendritic Cells J. Immunol., April 1, 2004; 172(7): 4100 - 4110. [Abstract] [Full Text] [PDF]

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