Adoptive transfer of small numbers of DX5+ cells alleviates graft-versus-host disease in a murine model of semiallogeneic bone marrow transplantation: a potential role for NKT lymphocytes.
Natural killer T (NKT) lymphocyte cells are a subset of regulatory lymphocytes with important immunemodulatory effects. Our aim was to evaluate the effect of transplantation of NKT lymphocytes on graft versus host disease (GVHD) in a murine model of semiallogeneic BMT. GVHD was generated by infusion of 2 x 107 splenocytes from C57BL/6 donor mice into irradiated (C57BL/6 x Balb/c)F1 recipient mice. Adoptive transfer of increasing numbers of DX5+ cells was performed. Recipient mice were followed for histological parameters of GVHD-associated liver, bowel, and cutaneous injury. Intrahepatic and intrasplenic lymphocytes were isolated and analyzed by FACS for CD4+ and CD8+ subpopulations. It was seen that adoptive transfer of 4.5 x 106 DX5+ cells significantly alleviated GVHD-related hepatic, bowel, and cutaneous injury, and improved survival (85% survival on day 28). In contrast, depletion of DX5+ cells led to severe GVHD-associated multiorgan injury and 100% mortality. A direct correlation with the number of transplanted DX5+ cells was noted (maximal effect with transplantation of 4.5 x 106 DX5+ cells). Tolerance induction was associated with an increased peripheral CD4/CD8 ratio, intrahepatic trapping of CD8 lymphocytes and a shift towards a Th2-type cytokine profile, manifested by decreased IL-12/IL10, IL-12/IL-4, IFNgamma/IL-10, and IFNgamma/IL-4 ratios. Transplantation of DX5+ cells holds promise as a novel therapeutic measure for GVHD.
Margalit
M
M
Liver Unit, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem IL-91120.
Ilan
Y
Y
Ohana
M
M
Safadi
R
R
Alper
R
R
Sherman
Y
Y
Doviner
V
V
Rabbani
E
E
Engelhardt
D
D
Nagler
A
A
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000379:methods; D016516:CD4-CD8 Ratio; D016207:Cytokines / Q000032:analysis; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000637:transplantation*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes; D018418:Th2 Cells; D014184:Transplantation, Homologous
D016207:Cytokines