Proliferation-based T-cell selection for immunotherapy and graft-versus-host-disease prophylaxis in the context of bone marrow transplantation.
Graft-versus-host disease (GvHD) caused by alloreactive T cells within the graft is a major drawback of allogeneic BMT, but depletion of T cells leads to higher rates of relapse, opportunistic infections and graft failure. Therefore, selective removal of GvHD-inducing alloreactive T cells might be beneficial. We describe here the separation of alloresponsive T cells, based on carboxyfluorescein succimidyl ester labeling, in vitro allostimulation and FACS-sorting. In vivo effects of the separated cell populations were investigated in the context of allogeneic BMT in murine models: in vitro resting T cells were shown to survive in the allogeneic host and retain immunoreactivity against 'third-party' antigens. As demonstrated in two different transplantation models, elimination of proliferating cells significantly reduces GvHD but offers no advantages to using T-cell-depleted bone marrow alone concerning engraftment and tumor control. Transplanting T cells that proliferate in response to tumor antigens in vitro may narrow down the spectrum of antigens recognized by T cells and therefore reduce GvHD while maintaining graft-facilitating function and tumor control. Therefore, selecting tumor-reactive T cells on the basis of their proliferative response in vitro may be beneficial for the recipient, less time consuming than T-cell cloning and still reduce the extent of GvHD.
Pachnio
A
A
II Medical Department, University of Kiel, Kiel, Germany.
Dietrich
S
S
Klapper
W
W
Humpe
A
A
Schwake
M
M
Sedlacek
R
R
Gramatzki
M
M
Beck
C
C
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001835:Body Weight; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods; D004195:Disease Models, Animal; D005452:Fluoresceins / Q000737:chemistry; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy*; D018398:Homeodomain Proteins / Q000378:metabolism; D007167:Immunotherapy; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013194:Staining and Labeling / Q000379:methods; D013388:Succinimides / Q000737:chemistry; D013601:T-Lymphocytes / Q000145:classification / Q000276:immunology*; D014407:Tumor Cells, Cultured
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D018398:Homeodomain Proteins; D013388:Succinimides; C064658:RAG-1 protein