A role for CD2 antibodies (BTI-322 and its humanized form) in the in vivo elimination of human T lymphocytes infiltrating an allogeneic human skin graft in SCID mice: an Fcgamma receptor-related mechanism involving co-injected human NK cells.

Snanoudj, Renaud;Rouleau, Matthieu;Bidère, Nicolas;Carmona, Sylvie;Senik, Anna;et.al.
(2004) Transplantation — Vol. 78, n° 1, p. 50-58 (2004)

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  • Snanoudj, Renaud
    Author
  • Rouleau, Matthieu
    Author
  • Bidère, Nicolas
    Author
  • Carmona, Sylvie
    Author
  • Latinne, DominiqueUCLouvain
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  • Bazin, HervéUCLouvain
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  • Senik, Anna
    Author
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Abstract
BACKGROUND: Pilot clinical studies have shown that the rat anti-human-CD2 monoclonal antibody, LoCD2a/BTI-322, can efficiently prevent and treat acute kidney rejection. However, the in vivo mechanism by which it prevents allograft rejection has not been studied. BTI-322 and its humanized form have been shown to mediate in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) against CD2 cells through the activation of monocytes or natural killer (NK) cells. METHODS: Human fetal skin samples were grafted into severe combined immunodeficient/nonobese diabetic mice. Five weeks later (day 0), the mice were injected with human allogeneic peripheral blood lymphocytes (PBL). Either on day 0 or on day 14, mice were treated with BTI-322, hu-BTI-322, or their F(ab')2 fragments. Peripheral blood mononuclear cells (PBMC) thoroughly devoid of NK cells were also assayed. RESULTS: After injection of PBL, the human skins became heavily infiltrated with activated human T lymphocytes, resulting in dermal microvascular injuries indicative of graft rejection. Early treatment with BTI-322 and hu-BTI-322 prevented all these events. These CD2 antibodies rapidly eliminated human T lymphocytes that had already infiltrated the grafts, with no evidence of recirculation toward the spleen. Their F(ab')2 fragments were, in contrast, ineffective. Elimination of NK cells from injected PBMC prevented the curative effect exerted by whole CD2 antibodies. It also abrogated their cytotoxicity potential against CD2 cells in ADCC assays. CONCLUSION: F(ab')2 fragments of the CD2 antibodies could not prevent allograft rejection, whereas whole immunoglobulin G could, and human NK cells were required for the curative effect exerted by these antibodies. The results are consistent with an FcgammaR-dependent ADCC mechanism mediated in vivo by human NK cells.
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Snanoudj, R., Rouleau, M., Bidère, N., Carmona, S., Baron, C., Latinne, D., Bazin, H., Charpentier, B., & Senik, A. (2004). A role for CD2 antibodies (BTI-322 and its humanized form) in the in vivo elimination of human T lymphocytes infiltrating an allogeneic human skin graft in SCID mice: an Fcgamma receptor-related mechanism involving co-injected human NK cells. Transplantation, 78(1), 50-58. https://hdl.handle.net/2078.5/49059 (Original work published 2004)