The influence of pretransplantation conditioning on graft-vs.-leukemia effect in mice.

OBJECTIVE

The therapeutic potential of allogeneic hematopoietic stem cell transplantation relies on the graft-vs.-leukemia (GVL) effect to eradicate residual tumor cells immunologically. The relationship of conditioning intensity to GVL effect was investigated.

MATERIALS AND METHODS

Lethally irradiated (either 900 or 1300 cGy) B6D2F1 (H-2(b/d)) recipients were transplanted from B6 (H-2(b)) donors. P815 or L1214 (H-2(d)) tumor cells were injected intravenously or subcutaneously on day 1 post-transplantation to generate a GVL model.

RESULTS

Tumors in allogeneic mice treated with 1300 cGy exhibited markedly delayed subcutaneous tumor growth in vivo as compared with mice treated with 900 cGy, while intravenous tumor growths were comparable between the two radiation doses. Serum levels of tumor necrosis factor-α or interferon-γ were similar and the percentages of donor T-cell proliferation or apoptosis early after hematopoietic stem cell transplantation were comparable. The numbers of CD8(+) T cells from recipients that received 1300 cGy were significantly elevated in skin and tumor tissues. CD62L(low) and CD44(high) CD8(+) T-cell fractions were also elevated in 1300 cGy. After the higher radiation dose, P815-specific interferon-γ responses of splenic CD8(+) T cells were markedly enhanced and the fractions of T cells of interferon-γ-producing T cells in tumor tissues but not in spleen were increased. The protein concentrations of chemokines in skin and tumor tissues were substantially elevated in 1300 cGy compared to 900 cGy.

CONCLUSIONS

The higher radiation dose (1300 vs. 900 cGy) resulted in significantly enhanced GVL effect against an extramedullary tumor and the alterations in effector T-cell trafficking into tumor tissue are the most likely mechanism.