Requirement for NK cells in CD40 ligand-mediated rejection of Philadelphia chromosome-positive acute lymphoblastic leukemia cells.
We have previously developed a murine model of Philadelphia chromosome-positive acute lymphoblastic leukemia by i.v. injection of a pre-B ALL cell line (BM185) derived from Bcr-Abl-transformed BALB/c bone marrow. We are studying the potential to elicit autologous antileukemic immune responses by introducing genes encoding immunomodulators (CD40 ligand (CD40L), CD80, and GM-CSF) into leukemia cells. BM185 cells expressing CD40L or CD80 alone, when injected into BALB/c mice, were rejected in approximately 25% of mice, whereas cohorts receiving BM185 cells expressing two or more immunomodulator genes rejected challenge 50-76% of the time. The greatest protection was conferred in mice receiving BM185 cells expressing all three immunomodulators. Addition of murine rIL-12 treatments in conjunction with BM185/CD80/CD40L/GM-CSF vaccination allowed rejection of preestablished leukemia. BM185 cell lines expressing CD40L were rejected in BALB/c nu/nu (nude) mice, in contrast to cell lines expressing CD80 and/or GM-CSF. Nude mice depleted of NK cells were no longer protected when challenged with BM185/CD40L, demonstrating a requirement for NK cells. Similarly, NK cell depletion in immunocompetent BALB/c mice resulted in a loss of protection when challenged with BM185/CD40L, confirming the data seen in nude mice. The ability of CD40L to act in a T cell-independent manner may be important for clinical applications in patients with depressed cellular immunity following chemotherapy.
Gruber
Tanja A
TA
Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
Skelton
Dianne C
DC
Kohn
Donald B
DB
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D019496:Cancer Vaccines; D003131:Combined Modality Therapy; D003601:Cytotoxicity Tests, Immunologic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology; D007156:Immunologic Memory; D018664:Interleukin-12 / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D019496:Cancer Vaccines; D023201:CD40 Ligand; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor