Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4(+) T-cells.
This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG1 simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG1 was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG1 short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG1 before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG1 anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).
Fraunhofer Institute for Cell Therapy and Immunology (IZI), 04109, Leipzig, Germany, stephan.fricke@izi.fraunhofer.de.
Stephan
S
Fricke
Nadja
N
Hilger
Christian
C
Fricke
Uta
U
Schönfelder
Gerhard
G
Behre
Peter
P
Ruschpler
Andreas
A
Boldt
Christopher
C
Oelkrug
Ulrich
U
Sack
Frank
F
Emmrich
D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000494:pharmacology*; D056747:Immunomodulation; D007938:Leukemia / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D016019:Survival Analysis; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D000961:Antilymphocyte Serum; D007074:Immunoglobulin G