title: Clinical-scale selective depletion of alloreactive T cells using an anti-CD25 immunotoxin.
abstract: Allogeneic hematopoietic stem cell transplantation is the treatment of choice for many hematological malignancies. Its efficacy is limited by graft-versus-host disease (GVHD), the leading cause of post-transplant morbidity and mortality. GVHD is mediated by a subpopulation of T cells in the stem cell graft. Ex vivo T cell depletion of all T cells of the graft can prevent development of GVHD but can lead to a delay in immune reconstitution and an increase of potentially lethal opportunistic infections and leukemic relapses. Hypothetically, an approach that enables a selective depletion of the alloreactive donor T cells that cause GVHD while preserving third party (anti-leukemic and anti-microbial) reactivity would be optimal for recipients of HSCT. Our preliminary data demonstrated that an anti-CD25 immunotoxin, which reacts with a cell surface activation antigen, can selectively deplete alloreactive donor T cells activated by non-leukemic recipient white blood cells while preserving the beneficial third-party reactivity in vitro. In this report we describe a method for clinical-scale ex vivo selective depletion of alloreactive donor T cells using the anti-CD25 immunotoxin, RFT5-SMPT-dgRTA. Two logs of alloreactive T cells could be selectively depleted while preserving third party reactivity. This method was reproducible in 10 pre-clinical experiments with 8 HLA-mismatched healthy volunteer pairs and 2 HLA-matched sibling donor/patient pairs.
authors.affiliation: Cancer Immunobiology Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA. jmichal@med.muni.cz
authors.forename: J
authors.initials: J
authors.lastname: Michálek
authors.forename: R H
authors.initials: RH
authors.lastname: Collins
authors.forename: E S
authors.initials: ES
authors.lastname: Vitetta
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D005240:Feasibility Studies; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018796:Immunoconjugates; D008212:Lymphocyte Depletion / Q000379:methods*; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D015203:Reproducibility of Results; D012276:Ricin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; C114847:RFT5-SMPT-dgA immunotoxin; D015375:Receptors, Interleukin-2; D012276:Ricin