BACKGROUND

Surprisingly, some patients who reject donor marrow grafts following nonmyeloablative HCT sustain remissions of advanced hematologic malignancies (

Br J Haematol 2005, 128:351
). In murine mixed chimeras prepared with nonmyeloablative conditioning, we previously showed that recipient leukocyte infusions (RLI) induced loss of donor chimerism and anti-tumor responses against host-type tumors (
Blood 2003, 102:2300
) and that both CD4+ and CD8+ T cells are necessary to achieve maximum anti-tumor effects (
J Immunol 2005, 175:665
). We now examined whether or not NK and/or NKT cells are required in the anti-tumor effect.

METHODS

Mixed chimerism was achieved in BALB/c (H-2d) mice conditioned with depleting anti-CD4 and CD8 mAbs on Day -5, cyclophosphamide 200 mg/kg on Day -1 and 7 Gy thymic irradiation on Day 0 prior to transplantation of 25x106 B10.BR (H-2k) or B10.RIII (H-2r) bone marrow cells. Some groups received RLI (3x107 BALB/c spleen cells) seven weeks post-BMT. A20 cells (5x105) were given i.v. one week after RLI. Some groups included Jα281-deficient BALB/c (Jα281 KO) mice that lack invariant NKT (iNKT) cells or NK1.1+ BALB/c mice whose NK and NKT cells can be depleted by anti-NK1.1 Ab, PK136. Some groups received a depleting dose of anti-NK1.1 antibody before and after RLI administration.

RESULTS

Untreated recipients of NK1.1-depleted RLI (n=9) showed similar tumor survival compared to recipients of NK1.1-sufficient RLI (n=9) (median survival time [MST] 52 versus 52 days respectively, p=0.68). NK1.1-depleted (with mAb in vivo) chimeras that received RLI (n=8) had shorter survival (MST 35.5 days) than NK1.1-sufficient chimeras that received RLI (n=10) (MST 68 days, P<0.01) and no anti-tumor effect was observed in the depleted group. Jα281 KO chimeric recipients receiving with Jα281 KO-derived RLI (n=12) had shorter survival than wild-type chimeric mice receiving wild-type RLI (n=11) (MST 41.0 vs 67.0 days, p<0.01) and no survival benefit of RLI was observed in Jα281 KO recipients (p=0.93).

CONCLUSION

When NK and NKT cells were depleted from NK1.1+ BALB/c recipients, no anti-tumor effect was observed. In contrast, no reduction in anti-tumor effect was observed in chimeras given NK1.1-depleted RLI. Invariant NKT cells are required to achieve anti-tumor effects in this model. Therefore, NKT cells and possibly NK cells in the recipient are essential for the anti-tumor effect of RLI, but NK and NKT cells in the RLI do not play a role. The requirement for both T cells and NK/NKT cells suggests an essential interaction between the innate and acquired immune systems.

Topics:
bone marrow, chimera organism, donors, neoplasms, immunity, rejection (psychology), antibodies, cyclophosphamide, disease remission, hematologic neoplasms

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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