Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells.
BACKGROUND
Challenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient lymphocyte infusion) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by recipient lymphocyte infusion. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants.


METHODS
We challenged C3H→AKR radiation chimeras with AKR-type splenocytes (i.e. recipient lymphocyte infusion) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flowcytometry and the mechanisms involved in antileukemic effects using in vivo antibody-mediated depletion of CD8(+) T and NK cells, and intracellular cytokine staining.


RESULTS
Whereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, recipient lymphocyte infusion chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. Recipient lymphocyte infusion chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8(+) T cells and NK cells contribute to the antileukemic effect. Consistent with a role for NK cells, the proportion of IFN-γ producing NK cells in recipient lymphocyte infusion chimeras was significantly higher than in control chimeras.


CONCLUSIONS
In the MHC-matched setting, recipient lymphocyte infusion elicits lymphohematopoietic host-versus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8(+) T cells and NK cells. The data indicate that NK cells are activated as a bystander phenomenon during lymphohematopoietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy.
Laboratory of Experimental Transplantation, University of Leuven, Belgium.
Lien
L
De Somer
Ben
B
Sprangers
Sabine
S
Fevery
Omer
O
Rutgeerts
Caroline
C
Lenaerts
Louis
L
Boon
Mark
M
Waer
An D
AD
Billiau
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D024201:Bystander Effect; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D020544:Graft vs Leukemia Effect / Q000276:immunology; D006789:Host vs Graft Reaction; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D011828:Radiation Chimera / Q000276:immunology*; D015996:Survival Rate; D014184:Transplantation, Homologous / Q000276:immunology; D014916:Whole-Body Irradiation
D016207:Cytokines