Effect of KRN7000 on induced graft-vs-host disease.
OBJECTIVE
Graft-vs-host disease (GVHD) is a serious complication of allogeneic stem cell transplantation (SCT) and donor lymphocyte infusion (DLI), for which no effective therapy exists. In our study, KRN7000, a synthetic analog of alpha-galactosylceramide, known for its ability to activate natural killer T cells, was tested for its ability to prevent onset of GVHD in a murine model of haploidentical major histocompatible (MHC) mismatched hematopoietic cells.


METHODS
Irradiated (BALB/cXC57BL/6)F1 mice were inoculated with parental C57BL/6 splenocytes with or without SCT. KRN7000 was given intraperitoneally as single or multiple doses at 100 microg/kg/dose and mice were followed up for GVHD clinical symptoms and for survival. The effect of KRN7000 treatment was also tested in vitro for the induction of suppression of alloreactivity in mixed lymphocyte reaction (MLR).


RESULTS
KRN7000 prevented development of GVHD symptoms in almost all mice and 52/53 mice maintained a healthy profile for more than 235 days. Most vehicle-treated mice or untreated controls died of GVHD within a median of 3 weeks. KRN7000 treatment did not prevent engraftment of donor cells following sublethal total-body irradiation (TBI) and allowed durable persistence of donor cells following lethal TBI and SCT. Splenocytes derived from KRN7000-treated mice suppressed efficiently mixed lymphocyte reaction (MLR) in vitro.


CONCLUSIONS
GVHD induced by alloreactive lymphocytes can be prevented by KRN7000. GVHD prevention may be accomplished by regulation of T cell function and might thus provide a new modality for safer SCT and DLI.
Morecki
Shoshana
S
Department of Bone Marrow Transplantation & Cancer Immunotherapy, Cell Therapy & Transplantation Research Center, Hadassah University Hospital, Jerusalem, Israel. morecki@hadassah.org.il
Panigrahi
Soumya
S
Pizov
Galina
G
Yacovlev
Elena
E
Gelfand
Yael
Y
Eizik
Osnat
O
Slavin
Shimon
S
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D017710:Lymphocyte Transfusion / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous / Q000276:immunology; D014916:Whole-Body Irradiation
D000276:Adjuvants, Immunologic; D005699:Galactosylceramides; C103873:KRN 7000