Superior depletion of alloreactive T cells from peripheral blood stem cell and umbilical cord blood grafts by the combined use of trimetrexate and interleukin-2 immunotoxin.
Acute graft-versus-host disease, a major obstacle to the overall success of allogeneic hematopoietic stem cell transplantation, is primarily induced by a subset of donor T cells. Most strategies to prevent acute graft-versus-host disease target all T cells regardless of their specificity, and this leads to prolonged posttransplantation immunodeficiency. Selective depletion of alloreactive T cells could spare protective immunity and facilitate engraftment and graft-versus-leukemia effects. Recently described depletion strategies target activation markers such as CD25 that are expressed by alloreactive T cells. However, incomplete depletion may occur when a single surface epitope or pathway of apoptosis is targeted that may not be fully and concurrently expressed among all alloreactive cells. We now report on a novel strategy effective in both cord blood and peripheral blood stem cell alloreactive T cells that simultaneously induces 2 independent pathways of apoptosis after stimulation by recipient dendritic cells or Epstein-Barr virus-transformed B cells. First, we demonstrate that the folate antagonist trimetrexate selectively depletes proliferating alloreactive precursors in vitro in a dose- and time-dependent manner. Similarly, a second agent, denileukin diftitox, kills activated alloreactive T cells expressing CD25. Most importantly, these 2 agents can exert their effects in concert with superior efficacy while sparing resting bystander T cells, which remain available to mount antimicrobial or third-party responses.
Szabolcs
Paul
P
Department of Pediatrics, Pediatric Stem Cell Transplant Program, Duke University Medical Center, Durham, North Carolina 27705, USA. szabo001@mc.duke.edu
Park
Kyung-Duk
KD
Marti
Luciana
L
Deoliveria
Divinomar
D
Lee
Young-Ah
YA
Colvin
Michael O
MO
Kurzberg
Joanne
J
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002478:Cells, Cultured; D004167:Diphtheria Toxin / Q000494:pharmacology*; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008212:Lymphocyte Depletion / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013601:T-Lymphocytes; D014184:Transplantation, Homologous; D016597:Trimetrexate / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D016597:Trimetrexate