Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses.
Selective elimination of alloreactive cells was carried out in the set-up of T-cell-mediated immunotherapy in an effort to gain the benefits of hematopoietic allogeneic transplantation while reducing the risk of GVHD. Low MW chemical compounds were screened for their effect on T-cell-mediated immune responses of murine- and human-derived lymphocytes. Selected compounds were further tested in secondary MLR assays in which sensitization to alloantigens was carried out in vitro, in the presence or absence of a given compound, followed by exposure to related and unrelated alloantigens or T-cell mitogenic stimulation. At a low concentration of <1 μM, a quinazoline derivative named AO#349 [2-(3,4,5-trimethoxyphenyl)-N-p-tolylquinazolin-4-amine], was able to induce 78-90% inhibition of a selective allogeneic response while retaining >92% immune reactivity to unrelated alloantigens and mitogenic stimuli in vitro. Following allogeneic sensitization in the presence of AO#349, elimination of alloreactivity to the priming alloantigens was also proved in a murine model of GVHD: 10 out of 15 sub-lethally irradiated mice inoculated with these sensitized cells were GVHD-free for >200 days. AO#349 was efficient in induction of a selective elimination of alloreactivity and should be considered for clinical application in allogeneic cell-mediated immunotherapy.
Department of Bone Marrow Transplantation and Cancer Immunotherapy, Cell Therapy and Transplantation Research Laboratory, Hadassah University Hospital, Jerusalem, Israel. morecki@hadassah.org.il
S
S
Morecki
Y
Y
Gelfand
E
E
Yacovlev
O
O
Eizik
Y
Y
Shabat
I
I
Sagiv
S
S
Slavin
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D007519:Isoantigens; D011799:Quinazolines