The role of natural killer T cells in costimulation blockade-based mixed chimerism.
Distinct lymphocyte populations have been identified that either promote or impede the establishment of chimerism and tolerance through allogeneic bone marrow transplantation (BMT). Natural killer T (NKT) cells have pleiotropic regulatory properties capable of either augmenting or downmodulating various immune responses. We investigated in this study whether NKT cells affect outcome in mixed chimerism models employing fully mismatched nonmyeloablative BMT with costimulation blockade (CB). The absence of NKT cells had no detectable effect on chimerism or skin graft tolerance after conditioning with 3Gy total body irradiation (TBI), and a limited positive effect with 1Gy TBI. Stimulation of NKT cells with alpha-galactosylceramide (alpha-gal) at the time of BMT prevented chimerism and tolerance. Activation of recipient (as opposed to donor) NKT cells was necessary and sufficient for the alpha-gal effect. The detrimental effect of NKT activation was also observed in the absence of T cells after conditioning with in vivo T-cell depletion (TCD). NKT cells triggered rejection of BM via NK cells as chimerism and tolerance were not abrogated when NKT cells were stimulated in the absence of both NK cells and T cells. Thus, activation of NKT cells at the time of BMT overcomes the effects of CB, inhibiting the establishment of chimerism and tolerance.
Nierlich
Patrick-Nikolaus
PN
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.
Klaus
Christoph
C
Bigenzahn
Sinda
S
Pilat
Nina
N
Koporc
Zvonimir
Z
Pree
Ines
I
Baranyi
Ulrike
U
Taniguchi
Masaru
M
Muehlbacher
Ferdinand
F
Wekerle
Thomas
T
D000818:Animals; D016026:Bone Marrow Transplantation; D046528:Chimerism; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D007107:Immune System; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000379:methods; D013601:T-Lymphocytes / Q000166:cytology*; D014916:Whole-Body Irradiation
D005699:Galactosylceramides; D007166:Immunosuppressive Agents; C493154:alpha-galactosylceramide