[PDF][PDF] Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance

XX Zheng, A Sánchez-Fueyo, M Sho, C Domenig… - Immunity, 2003 - cell.com
XX Zheng, A Sánchez-Fueyo, M Sho, C Domenig, MH Sayegh, TB Strom
Immunity, 2003cell.com
Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent
immunosuppression but also to profound and long-lived T cell depletion. We reasoned that
a strategy that almost exclusively targets activated cytopathic donor reactive T cells and
spares immunoregulatory networks might prove to be an exceptionally potent and highly
selective means of producing long-term engraftment and tolerance. Herein we show that the
combined administration of rapamycin and agonist IL-2-and antagonist IL-15-related …
Abstract
Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent immunosuppression but also to profound and long-lived T cell depletion. We reasoned that a strategy that almost exclusively targets activated cytopathic donor reactive T cells and spares immunoregulatory networks might prove to be an exceptionally potent and highly selective means of producing long-term engraftment and tolerance. Herein we show that the combined administration of rapamycin and agonist IL-2- and antagonist IL-15-related cytolytic fusion proteins provides for long-term engraftment/tolerance in exceptionally stringent allotransplant models by (1) limiting the early expansion of activated T cells, (2) preserving and even exaggerating their subsequent apoptotic clearance, and (3) further amplifying the depletion of these activated T cells by antibody-dependent mechanisms, while (4) preserving CD4+CD25+ T cell-dependent immunoregulatory networks.
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