Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor.
Graft-versus-host disease (GVHD), due to the presence of recipient-reactive T cells, limits the usefulness of bone marrow transplantation (BMT) and is a major contributor to patient mortality. To prevent GVHD, murine and human T cells were activated by antigen or mitogens and treated with a genetically engineered form of Pseudomonas exotoxin A (PE) directed against the IL-2 receptor. Treatment with the chimeric toxin eliminated alloreactive cytotoxic T lymphocytes (CTL) as determined by cytotoxicity and mixed lymphocyte culture assays. Precursor frequencies of alloreactive cytotoxic T cells and proliferative T cells were reduced up to 100-fold as shown by limiting dilution assays. Flow cytometric analyses revealed that treatment with the chimeric toxin completely eliminated CD25+ cells from the cultures. Toxin treatment had no significant effect on hematopoietic stem and progenitor cells as determined in vitro by colony-forming assays and in vivo by long-term hematopoietic recovery after 950 rad irradiation. Toxin treatment decreased GVHD in transplanted mice to less than 10% (as compared to 88% in untreated controls). Thus, it is possible to prevent life-threatening GVHD after BMT by using a CD25 receptor-directed toxin to eliminate host-reactive T cells from bone marrow grafts.
Harris
D T
DT
Department Microbiology and Immunology, University of Arizona, Tucson 85721, USA.
Sakiestewa
D
D
Lyons
C
C
Kreitman
R J
RJ
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology; D002452:Cell Count; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology; D051379:Mice; D010641:Phenotype; D011247:Pregnancy; D011550:Pseudomonas aeruginosa; D015375:Receptors, Interleukin-2 / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects*; D014019:Tissue Donors; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D007518:Isoantibodies; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A