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
| Autor: | Luciana Cavalheiro Marti, Michael Colvin, Joanne Kurzberg, Divinomar DeOliveria, Paul Szabolcs, Young-Ah Lee, Kyung Duk Park |
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| Rok vydání: | 2004 |
| Předmět: |
Interleukin 2
Antimetabolites Antineoplastic medicine.medical_treatment Recombinant Fusion Proteins T-Lymphocytes Hematopoietic stem cell transplantation Epitope Lymphocyte Depletion 03 medical and health sciences 0302 clinical medicine Denileukin diftitox medicine Cytotoxic T cell Humans Transplantation Homologous Diphtheria Toxin IL-2 receptor Cells Cultured 030304 developmental biology 0303 health sciences Transplantation Acute graft-versus-host disease Alloreactive T cells business.industry Hematology Fetal Blood Hematopoietic Stem Cells 3. Good health Cord blood Allogeneic hematopoietic stem cell transplantation Immunology Trimetrexate Interleukin-2 Stem cell business 030215 immunology medicine.drug |
| Zdroj: | Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 10(11) |
| ISSN: | 1083-8791 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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