PMID- 19400555
OWN - NLM
STAT- MEDLINE
DCOM- 20090701
LR  - 20181201
IS  - 0018-2052 (Print)
IS  - 0018-2052 (Linking)
VI  - 58
IP  - 1
DP  - 2009 Mar
TI  - Induction of gamma delta T cells using zoledronate plus interleukin-2 in patients 
      with metastatic cancer.
PG  - 37-44
AB  - A loss of human leukocyte antigen (HLA) expression in clinical tumors is one of 
      their escape mechanisms from immune attack by HLA-restricted effector cells. In 
      this study, the induction of HLA-unrestricted effector cells, gamma delta T 
      cells, using zoledronate (ZOL) and interleukin (IL)-2 in vitro was investigated 
      in patients with metastatic cancer. Peripheral blood mononuclear cells (PBMCs) 
      from 10 cancer patients (8 colorectal and 2 esophageal) with multiple metastases 
      and ascites lymphocytes from 3 cancer patients (1 gastric and 2 colorectal) were 
      stimulated with varied concentrations of ZOL plus 100 U/ml IL-2 for 48 hr 
      followed by culturing with IL-2 alone for 12 days. Lymphocyte proliferative 
      responses were determined using 3H-TdR uptakes and interferon (IFN)-gamma 
      production was evaluated using enzyme-linked immunosorbent assay. Surface 
      phenotyping was performed using flow cytometry. Cytotoxic activity of effector 
      cells was determined using 51Cr-releasing assay. It was found that proliferative 
      responses of PBMCs were significantly stimulated with ZOL plus IL-2 when compared 
      with IL-2 alone, showing 200 to 500-fold expansions for 2 weeks, although ZOL 
      alone induced no response. The optimal concentration of ZOL was 1-5 microM. 
      Ascites lymphocytes could also be stimulated with ZOL plus IL-2. The 
      proliferative responses were remarkable in patients whose PBMCs could produce 
      high levels of IFN-gamma during an initial 48-hr stimulation using ZOL plus IL-2. 
      Removal of an adherent cell fraction before the induction augmented the 
      proliferative responses in patients who otherwise had low-grade proliferative 
      responses. Generated cells comprising approximately 90 or 20% in PBMCs from 
      healthy donors or cancer patients, respectively, expressed gamma delta-type 
      T-cell receptor. Gamma delta T cells showed high cytotoxic activity against 
      CD166-positive TE12 and TE13 cancer cells but not against CD166-negative MKN45 
      cells. The cytotoxic activity against TE13 cells was augmented when target cells 
      were pre-treated overnight with ZOL. These results suggest that ZOL in the 
      presence of IL-2 can efficiently stimulate the proliferation of gamma delta T 
      cells, which have cytotoxic properties against cancer cells. The use of 
      zoledronate-activated killer (ZAK) cells should be encouraged in possible 
      adoptive immunotherapy trials for patients with incurable cancer.
FAU - Nagamine, Ichiro
AU  - Nagamine I
AD  - Department of Surgical Oncology, Research Institute for Radiation Biology and 
      Medicine, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, 
      Japan.
FAU - Yamaguchi, Yoshiyuki
AU  - Yamaguchi Y
FAU - Ohara, Masahiro
AU  - Ohara M
FAU - Ikeda, Takuhiro
AU  - Ikeda T
FAU - Okada, Morihito
AU  - Okada M
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Hiroshima J Med Sci
JT  - Hiroshima journal of medical sciences
JID - 0421060
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Diphosphonates)
RN  - 0 (Imidazoles)
RN  - 0 (Interleukin-2)
RN  - 0 (Receptors, Antigen, T-Cell, gamma-delta)
RN  - 6XC1PAD3KF (Zoledronic Acid)
SB  - IM
MH  - Antineoplastic Agents/administration & dosage
MH  - Case-Control Studies
MH  - Cell Line, Tumor
MH  - Cell Membrane/metabolism
MH  - Cell Proliferation
MH  - Colorectal Neoplasms/*drug therapy/*immunology/metabolism
MH  - Diphosphonates/*administration & dosage
MH  - Esophageal Neoplasms/*drug therapy/*immunology/metabolism
MH  - Humans
MH  - Imidazoles/*administration & dosage
MH  - Immunotherapy, Adoptive/methods
MH  - Interleukin-2/*administration & dosage
MH  - Leukocytes, Mononuclear/metabolism
MH  - Lymphocyte Activation
MH  - Neoplasm Metastasis
MH  - Receptors, Antigen, T-Cell, gamma-delta/*metabolism
MH  - T-Lymphocytes/*drug effects/*metabolism
MH  - Zoledronic Acid
EDAT- 2009/04/30 09:00
MHDA- 2009/07/02 09:00
CRDT- 2009/04/30 09:00
PHST- 2009/04/30 09:00 [entrez]
PHST- 2009/04/30 09:00 [pubmed]
PHST- 2009/07/02 09:00 [medline]
PST - ppublish
SO  - Hiroshima J Med Sci. 2009 Mar;58(1):37-44.