Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance.
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.
Zheng
Xin Xiao
XX
Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. xzheng@bidmc.harvard.edu
Sánchez-Fueyo
Alberto
A
Sho
Masayuki
M
Domenig
Christoph
C
Sayegh
Mohamed H
MH
Strom
Terry B
TB
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D023001:Transplantation Tolerance / Q000276:immunology / Q000502:physiology*; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; C413753:Rgl3 protein, mouse; D020726:ral Guanine Nucleotide Exchange Factor