| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Cellular Immunity Laboratory, Austin Research Institute, Heidelberg, Victoria, Australia; and
Department of Microbiology, University of Western Australia, Nedlands, Western Australia, Australia
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Inbred C57BL/6 and BALB/c mice were purchased from The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. C57BL/6 perforin-deficient (B6.P0)3 mice derived as described (14) and BALB/c.perforin-deficient (BALB/c.P0) mice bred by backcrossing and microsatellite analysis (n = 7) were maintained at the Austin Research Institute Biological Research Laboratories. Microsatellite analysis for production of the BALB/c.P0 mice was conducted using fluorescently labeled or 32P-labeled microsatellite PCR primers as described previously (15). C57BL/6 gld mice were obtained from the Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia. C57BL/6 RAG-1-deficient (RAG-10) mice (16) were obtained from Dr. Lynn Corcoran, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. Mice 4–8 wk of age were used according to animal experimental ethics committee guidelines.
Cell culture and reagents
The mouse lymphomas Yac-1 (H-2a), RMA-S (H-2b) (17), RMA (H-2b), and EL4 (H-2b), the mouse mastocytomas P815 (H-2d) and P388D1 (H-2d), and the DA3 (H-2d) mammary carcinoma (18) were grown in RPMI medium supplemented with additives as described (8). The mouse RM-1 (H-2b) prostate carcinoma (19) and 3T3 (H-2d) fibroblast cell line were maintained in Dulbecco’s modified Eagle’s medium and additives as above. Recombinant human IL-2 was a gift from Chiron, Emeryville, CA. IL-2-activated adherent mouse spleen NK cells were prepared as described (20).
Flow cytometry
MHC class I expression was analyzed by flow cytometry (FACScaliber, Becton Dickinson, Mountain View, CA) using the anti-mouse mAbs anti-H-2KbDb (Dr. P. Xing, Austin Research Institute, Heidelberg, Australia) or anti-H-2Dd (34-5-8S, PharMingen, San Diego, CA) and a FITC rat anti-mouse Ig (Silenus, Hawthorn, Australia) secondary.
51Cr release assays
The cytotoxicity of mouse spleen NK cells, IL-2-activated adherent NK cells, soluble Fas ligand (FasL) (provided by Dr. David Lynch, Immunex, Seattle, WA), or a combination of perforin and granzyme B were assessed by 4-h 51Cr release assays against labeled targets as described (8). Each experiment was performed at four (only 100:1 shown) different E:T ratios twice using duplicate samples.
Experimental metastases: RM-1 lung colonization
Tail vein inoculum challenges were performed to ascertain whether systemic antimetastatic activity existed after primary RM-1 tumor growth. These were conducted using the s.c tumor as a primary as described by Eastham et al. (21). Briefly, groups of five B6, B6.RAG-10, B6.gld, or B6.P0 mice were inoculated s.c. between the shoulder blades with RM-1 tumor cells (2 x 106), and tumors were allowed to establish for 9 days. At this point, under induced anesthesia, s.c tumors were surgically resected and RM-1 cells were injected via the dorsolateral tail vein. Mice were euthanized 14 days later, the lungs removed and fixed in Bouin’s solution, and individual surface lung metastases were counted with the aid of a dissecting microscope. Control experiments were performed by inoculating mice with RM-1 cells via the tail vein and 14 days later counting lung metastases. Some groups of B6 mice were depleted of T lymphocytes and/or NK cells in vivo, by treatment with mAb (100 µg): anti-CD4 (GK1.5, rat IgG2b) and anti-CD8 (53-6.7, rat IgG2a, Sigma); anti-NK1.1 (PK136, mouse IgG2a, American Type Culture Collection); anti-CD3 (KT3, rat IgG2a) with or without anti-NK1.1 on days -2, 0 (day of i.v. tumor inoculation), 2, and 9. These schedules have previously been shown to effectively deplete T cell or NK cell subsets following analysis using FITC-labeled mAbs as described (8). The data were recorded as the mean (n = 5) number of lung colonies ± SE. The excised tumor was weighed wet, and the data were recorded as the mean weight (grams) ± SE. Significance was determined by an unpaired t test to determine a two-tailed p value.
Spontaneous metastases: DA3 lung colonization
DA3 mammary tumor cells were injected s.c. on the left flank into groups of five BALB/c and BALB/c.P0 mice. Mice were euthanized 42 days later and lung metastases counted as above. Some groups of BALB/c mice were depleted of NK cells in vivo by treatment with rabbit anti-asialo-GM1 Ab (Wako Chemicals, Richmond, VA) or mAbs as above (100 µg), on days -4, day 0 (day of tumor inoculation), and weekly thereafter. The anti-asialo-GM1 antisera was shown to effectively deplete DX5+ (rat IgM, PharMingen) NK cells in BALB/c mice (data not shown). Data were recorded as above.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The levels of H-2d expression on DA3 tumor cells were
determined by flow cytometry and compared with RMA-S (TAP-2-deficient)
and P388D1 (H-2d-positive) cells (Fig. 1
A). DA3 cells displayed very
low levels of H-2d expression. RM1 prostate carcinoma cells
expressed little or no H-2b when compared with EL4
(H-2b-positive) and negative control RMA-S cells (Fig. 1B). RM-1 tumor cells were relatively sensitive to a
sublytic concentration of perforin combined with increasing
concentrations of granzyme B when compared with a classical
NK-sensitive target, RMA-S, and insensitive 3T3 cells (Fig. 1C). DA3 tumor cells were somewhat less sensitive to a
combination of perforin and granzyme B (Fig. 1C). Both DA3
and RM-1 tumor cells were lysed when exposed to soluble FasL, although
neither was as sensitive as FasL-sensitive Yac-1 target cells (Fig. 1D). Similar sensitivity of these target cells was
demonstrated using cytotoxic anti-Fas mAbs or d12S effector cells
(22) that exclusively lyse via a Fas-dependent mechanism (data not
shown). Resting (Fig. 1E) and IL-2-activated NK cells (Fig. 1F) from the spleens of B6 mice were cytolytic to RM-1 tumor
cells. As observed for many other tumor targets in vitro (8, 14), NK
cells from B6.P0 or B6 mice treated with anti-NK1.1 mAb
were poorly cytolytic (Fig. 1, E and F), whereas
those NK cells from B6.gld mice or B6 mice treated with
anti-CD3 mAb were as cytolytic toward RM-1 as NK cells from B6 mice
(Fig. 1, E and F). Resting (Fig. 1G)
and IL-2-activated NK cells (Fig. 1H) from the spleens of
BALB/c mice were cytolytic to DA3 tumor cells, while again NK cells
from BALB/c.P0 or BALB/c mice treated with
anti-asialo-GM1 mice were poorly cytolytic (Fig. 1, G and H). These data further supported a role for
NK cell perforin in direct lysis of RM-1 and DA3 in vitro.
|
Initially untreated B6 (wild-type or mutant) mice or B6 mice
treated with anti-CD3, anti-CD8, anti-CD4, or
anti-NK1.1 mAb were inoculated i.v. with increasing numbers of RM-1
tumor cells, and 14 days later the lung metastases were counted. At the
lower inoculated doses of RM-1 cells, a significantly greater number of
lesions were observed in B6.P0 mice
(p < 0.004) and, more evidently, in B6 mice
treated with anti-NK1.1 mAb (B6 anti-NK1.1 mAb-treated mice had
more metastases than B6.P0 mice, p <
0.002) than in untreated B6 mice (Fig. 2A). A combination of
anti-NK1.1 and anti-CD3 mAb did not compromise tumor control
more than anti-NK1.1 mAb alone. B6.gld mice,
B6.RAG-10 mice (lacking functional T and B cells), or B6
mice depleted of T cell subsets did not have a significantly greater
number of RM-1 tumor metastases than untreated B6 mice (all
p > 0.052) (Fig. 2A). These mice served as
controls for those prior given a s.c. tumor 9 days before resection and
systemic challenge with RM-1 tumor cells.
|
B). By contrast, in
anti-NK1.1 mAb-treated B6 mice, the number of metastases following
tail vein challenge was similar irrespective of the pregrowth of a s.c.
RM-1 tumor (compare Fig. 2A and Fig. 2B).
Significantly, again there were increased numbers of metastases in
B6.P0 mice compared with wild-type B6 mice
(p < 0.0001), but even more were again
detected in anti-NK1.1 mAb-treated mice (B6 anti-NK1.1
mAb-treated mice had more metastases than B6.P0 mice,
p < 0.0009) (Fig. 2B). Interestingly,
B6.RAG-10 mice or B6 mice treated with anti-CD3
displayed significantly more lung colonies than untreated B6 mice
(p < 0.0001), while B6.gld mice or
those B6 mice depleted of CD4+ and CD8+ cells
did not (Fig. 2B). Importantly, again a combination of
anti-NK1.1 and anti-CD3 did not display additive effects,
suggesting that CD3+ cells are not responsible for systemic
protection from lung colonization of RM-1 tumor cells over and above
NK1.1+ cells. The mean wet weight of the s.c. RM-1 tumors
excised from all mice was not significantly different (data not shown).
Overall, these data suggested that 1) prior s.c. growth of RM-1
provided some protection to further i.v. challenge with RM-1 tumor
cells, 2) CD3- NK1.1+ cells were responsible
for the protection from lung colonization by RM-1 cells, and 3)
perforin was a mediator, but not the only one, of protection to RM-1
tumor cells by NK1.1+ cells. Control of spontaneous DA3 tumor colonization in the lung by NK1.1+ cells is perforin dependent
Since the RM-1 tumor is spontaneously metastatic only in an
orthotopic setting (23), we decided to examine the general importance
of NK cell perforin in another spontaneous model of metastasis. DA3 is
a mammary carcinoma that metastasizes to the lung and lymph nodes
following inoculation of BALB/c mice with a primary s.c. tumor. A
number of different DA3 tumor doses (105 to
106) were inoculated s.c., and after 42 days lung
metastases were counted. Significantly, there were increased numbers of
metastases in BALB/c.P0 mice compared with wild-type B6
mice (p < 0.0019), but fewer than found in
anti-asialo-GM1 Ab-treated mice (Fig. 3). Although it was not practical to
accurately quantify metastasis to the lymph nodes, it was noted that
both BALB/c.P0 mice and BALB/c mice treated with
anti-asialo-GM1 Ab had more lymph node involvement.
There were an increased number of lung metastases in anti-CD3- but
not anti-CD4- and anti-CD8-treated mice, but this was not
determined to be statistically significant (Fig. 3). The mean wet
weight of the s.c. DA3 tumors excised from the mice was again not
significantly different (data not shown). These data in a spontaneous
model supported the major findings in the experimental metastasis RM-1
tumor model that 1) NK cells were responsible for the protection from
lung colonization by metastases and 2) perforin was a mediator, but not
the only effector mechanism used by NK cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A further important observation was that depletion of NK cells
compromised tumor protection significantly more than perforin
deficiency. This finding was in contrast to previous experiments with
RM-1 (unpublished data) and RMA-S (8) tumor cells inoculated into the
peritoneum, where depletion with anti-NK1.1 mAb did not further
compromise tumor protection in perforin-deficient mice. These data
suggest that additional as yet undefined effector mechanisms of NK
cells may control tumor metastasis to the lung but may not be important
in the rejection of peritoneal tumor by NK cells. This effector
mechanism could potentially involve another death-inducing TNF
superfamily molecule such as TNF-related apoptosis-inducing ligand,
which has recently been demonstrated to be used by some immature human
NK cells (25). Alternatively, the ability of NK cells to make
cytokines, such as IFN-
, that affect T cell and other leukocyte
responses may be important. The levels of class I on RM-1 was not
enhanced by prolonged in vitro culture in IFN- or TNF, although a
minor increase in class I (
2-fold) was observed in DA3 cells
cultured in IFN- (data not shown). It remains to be tested whether
these tumors up-regulate class I or Fas expression in vivo, thus making
them targets for attack by additional immune mechanisms. We have
already observed that the recruitment and accumulation of NK cells in
response to class I-deficient tumors may require TNF depending on the
site of tumor growth (8), and thus cytokine networks may also determine
the types of effector mechanisms that the NK cell eventually uses.
Supporting this notion is the apparently organ-specific effect of
perforin in viral infection (26).
Data from the RM-1 experimental metastasis model indicated that
CD3- NK1.1+ cells were responsible for
protection, but suggested that CD3+ NK1.1+
cells may play an accessory role. In particular, there was a
significant increase in RM-1 metastases in B6.RAG-10 mice,
mice depleted of CD3+ cells, or mice depleted of
Thy-1+ cells (data not shown) compared with that observed
in untreated- or anti-CD4/CD8-treated wild-type mice. It remains
difficult to accurately account for the subpopulation(s) of
CD3+ NK1.1+ cells that may be contributing to
tumor protection since NKT cells are generally heterogeneous for many
surface Ags and are found in very small proportions in most tissues
(27). Previously, Takeda et al. (28) demonstrated that IL-12-activated
NK1.1+ T cells from the liver can inhibit liver and lung
metastases following i.v. injection of tumors. In addition, V
14
NK1.1+ T cell-deficient mice were demonstrated to no longer
mediate IL-12-induced prevention of tumor metastasis (29).
NK1.1+ T cells are exquisitely sensitive to IL-12 (30), and
experiments currently in progress in V14 NK1.1+ T
cell-deficient, IL-12-deficient, and IFN--deficient mice should be
informative.
In summary, this study has highlighted that perforin plays an important role but is not totally responsible for NK cell-mediated protection from tumor metastasis. The future use of these experimental and spontaneous models of tumor metastases in various gene knockout and mutant mice will enable many new questions to be addressed. In particular, which other effector arms of innate immunity protect the host from tumor metastasis, and when and where do the these act?
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Mark Smyth, Cellular Cytotoxicity Laboratory, The Austin Research Institute, Studley Road, Heidelberg, Victoria, 3084 Australia. E-mail address:
3 Abbreviations used in this paper: B6.P0, C57BL/6 perforin-deficient; BALB/c.P0, BALB/c perforin-deficient; B6.RAG-10, C57BL/6 RAG-1-deficient; FasL, Fas ligand.
Received for publication December 28, 1998. Accepted for publication March 2, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
ß T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. J. Immunol. 156:3366.[Abstract]
14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623.
- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9:345.[Medline]
This article has been cited by other articles:
|
|
 |
|
  B. N. Alves, J. Leong, D. L. Tamang, V. Elliott, J. Edelnant, D. Redelman, C. A. Singer, A. R. Kuhn, R. Miller, M. E. Lowe, et al. Pancreatic lipase-related protein 2 (PLRP2) induction by IL-4 in cytotoxic T lymphocytes (CTLs) and reevaluation of the negative effects of its gene ablation on cytotoxicity J. Leukoc. Biol., September 1, 2009; 86(3): 701 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. KAWAGUCHI, K. KONO, Y. MIZUKAMI, K. MIMURA, and H. FUJII Mechanisms of Escape from Trastuzumab-mediated ADCC in Esophageal Squamous Cell Carcinoma: Relation to Susceptibility to Perforin-granzyme Anticancer Res, June 1, 2009; 29(6): 2137 - 2146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Engelmann, D Koczan, P Ricken, U Rimpler, J Pahnke, Z Li, and B M Putzer Transcriptome analysis in mouse tumors induced by Ret-MEN2/FMTC mutations reveals subtype-specific role in survival and interference with immune surveillance Endocr. Relat. Cancer, March 1, 2009; 16(1): 211 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Schreiber, V. V. Deyev, J. D. Rosenblatt, and E. R. Podack Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination Cancer Res., March 1, 2009; 69(5): 2026 - 2033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bolitho, S. E. A. Street, J. A. Westwood, W. Edelmann, D. MacGregor, P. Waring, W. K. Murray, D. I. Godfrey, J. A. Trapani, R. W. Johnstone, et al. Perforin-mediated suppression of B-cell lymphoma PNAS, February 24, 2009; 106(8): 2723 - 2728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. F. Werneck, G. Lugo-Villarino, E. S. Hwang, H. Cantor, and L. H. Glimcher T-Bet Plays a Key Role in NK-Mediated Control of Melanoma Metastatic Disease J. Immunol., June 15, 2008; 180(12): 8004 - 8010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Binyamin, R. K. Alpaugh, T. L. Hughes, C. T. Lutz, K. S. Campbell, and L. M. Weiner Blocking NK Cell Inhibitory Self-Recognition Promotes Antibody-Dependent Cellular Cytotoxicity in a Model of Anti-Lymphoma Therapy J. Immunol., May 1, 2008; 180(9): 6392 - 6401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, M. W.L. Teng, J. Sharkey, J. A. Westwood, N. M. Haynes, H. Yagita, K. Takeda, P. V. Sivakumar, and M. H. Kershaw Interleukin 21 Enhances Antibody-Mediated Tumor Rejection Cancer Res., April 15, 2008; 68(8): 3019 - 3025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Greeneltch, M. Schneider, S. M. Steinberg, D. J. Liewehr, T. J. Stewart, K. Liu, and S. I. Abrams Host Immunosurveillance Controls Tumor Growth via IFN Regulatory Factor-8 Dependent Mechanisms Cancer Res., November 1, 2007; 67(21): 10406 - 10416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Voskoboinik, V. R. Sutton, A. Ciccone, C. M. House, J. Chia, P. K. Darcy, H. Yagita, and J. A. Trapani Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function Blood, August 15, 2007; 110(4): 1184 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Swann, Y. Hayakawa, N. Zerafa, K. C. F. Sheehan, B. Scott, R. D. Schreiber, P. Hertzog, and M. J. Smyth Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function J. Immunol., June 15, 2007; 178(12): 7540 - 7549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E.A. Street, N. Zerafa, M. Iezzi, J. A. Westwood, J. Stagg, P. Musiani, and M. J. Smyth Host Perforin Reduces Tumor Number but Does Not Increase Survival in Oncogene-Driven Mammary Adenocarcinoma Cancer Res., June 1, 2007; 67(11): 5454 - 5460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zamai, C. Ponti, P. Mirandola, G. Gobbi, S. Papa, L. Galeotti, L. Cocco, and M. Vitale NK Cells and Cancer J. Immunol., April 1, 2007; 178(7): 4011 - 4016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Johansson, M. A. Taylor, M. Jagodic, K. Tus, J. D. Schatzle, E. K. Wakeland, and M. Bennett Mapping of Quantitative Trait Loci Determining NK Cell-Mediated Resistance to MHC Class I-Deficient Bone Marrow Grafts in Perforin-Deficient Mice J. Immunol., December 1, 2006; 177(11): 7923 - 7929. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Abdool, E. Cretney, A. D. Brooks, J. M. Kelly, J. Swann, A. Shanker, E. W. Bere Jr., W. M. Yokoyama, J. R. Ortaldo, M. J. Smyth, et al. NK Cells Use NKG2D to Recognize a Mouse Renal Cancer (Renca), yet Require Intercellular Adhesion Molecule-1 Expression on the Tumor Cells for Optimal Perforin-Dependent Effector Function J. Immunol., August 15, 2006; 177(4): 2575 - 2583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lundqvist, S. I. Abrams, D. S. Schrump, G. Alvarez, D. Suffredini, M. Berg, and R. Childs Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res., July 15, 2006; 66(14): 7317 - 7325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, Y. Hayakawa, E. Cretney, N. Zerafa, P. Sivakumar, H. Yagita, and K. Takeda IL-21 Enhances Tumor-Specific CTL Induction by Anti-DR5 Antibody Therapy J. Immunol., May 15, 2006; 176(10): 6347 - 6355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, S. Yu, K. Zinn, J. Wang, L. Zhang, Y. Jia, J. C. Kappes, S. Barnes, R. P. Kimberly, W. E. Grizzle, et al. Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function J. Immunol., February 1, 2006; 176(3): 1375 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, M. W. L. Teng, J. Swann, K. Kyparissoudis, D. I. Godfrey, and Y. Hayakawa CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer J. Immunol., February 1, 2006; 176(3): 1582 - 1587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Smyth, J. Swann, E. Cretney, N. Zerafa, W. M. Yokoyama, and Y. Hayakawa NKG2D function protects the host from tumor initiation J. Exp. Med., September 6, 2005; 202(5): 583 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. I. Pao, N. Sumaria, J. M. Kelly, S. v. Dommelen, E. Cretney, M. E. Wallace, D. A. Anthony, A. P. Uldrich, D. I. Godfrey, J. M. Papadimitriou, et al. Functional Analysis of Granzyme M and Its Role in Immunity to Infection J. Immunol., September 1, 2005; 175(5): 3235 - 3243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Takaki, Y. Hayakawa, A. Nelson, P. V. Sivakumar, S. Hughes, M. J. Smyth, and L. L. Lanier IL-21 Enhances Tumor Rejection through a NKG2D-Dependent Mechanism J. Immunol., August 15, 2005; 175(4): 2167 - 2173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, M. E. Wallace, S. L. Nutt, H. Yagita, D. I. Godfrey, and Y. Hayakawa Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer J. Exp. Med., June 20, 2005; 201(12): 1973 - 1985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Esplugues, J. Vega-Ramos, D. Cartoixa, B. N. Vazquez, I. Salaet, P. Engel, and P. Lauzurica Induction of tumor NK-cell immunity by anti-CD69 antibody therapy Blood, June 1, 2005; 105(11): 4399 - 4406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Clementi, F. Locatelli, L. Dupre, A. Garaventa, L. Emmi, M. Bregni, G. Cefalo, A. Moretta, C. Danesino, M. Comis, et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene Blood, June 1, 2005; 105(11): 4424 - 4428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liu, S. A. Caldwell, and S. I. Abrams Immune Selection and Emergence of Aggressive Tumor Variants as Negative Consequences of Fas-Mediated Cytotoxicity and Altered IFN-{gamma}-Regulated Gene Expression Cancer Res., May 15, 2005; 65(10): 4376 - 4388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, J. Swann, J. M. Kelly, E. Cretney, W. M. Yokoyama, A. Diefenbach, T. J. Sayers, and Y. Hayakawa NKG2D Recognition and Perforin Effector Function Mediate Effective Cytokine Immunotherapy of Cancer J. Exp. Med., November 15, 2004; 200(10): 1325 - 1335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Voskoboinik, M.-C. Thia, A. De Bono, K. Browne, E. Cretney, J. T. Jackson, P. K. Darcy, S. M. Jane, M. J. Smyth, and J. A. Trapani The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (PFN1) Gene J. Exp. Med., September 20, 2004; 200(6): 811 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E.A. Street, Y. Hayakawa, Y. Zhan, A. M. Lew, D. MacGregor, A. M. Jamieson, A. Diefenbach, H. Yagita, D. I. Godfrey, and M. J. Smyth Innate Immune Surveillance of Spontaneous B Cell Lymphomas by Natural Killer Cells and {gamma}{delta} T Cells J. Exp. Med., March 15, 2004; 199(6): 879 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Brady, Y. Hayakawa, M. J. Smyth, and S. L. Nutt IL-21 Induces the Functional Maturation of Murine NK Cells J. Immunol., February 15, 2004; 172(4): 2048 - 2058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hayakawa, V. Screpanti, H. Yagita, A. Grandien, H.-G. Ljunggren, M. J. Smyth, and B. J. Chambers NK Cell TRAIL Eliminates Immature Dendritic Cells In Vivo and Limits Dendritic Cell Vaccination Efficacy J. Immunol., January 1, 2004; 172(1): 123 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, S. E. A. Street, and J. A. Trapani Cutting Edge: Granzymes A and B Are Not Essential for Perforin-Mediated Tumor Rejection J. Immunol., July 15, 2003; 171(2): 515 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. H. van Dommelen, H. A. Tabarias, M. J. Smyth, and M. A. Degli-Esposti Activation of Natural Killer (NK) T Cells during Murine Cytomegalovirus Infection Enhances the Antiviral Response Mediated by NK Cells J. Virol., February 1, 2003; 77(3): 1877 - 1884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Seki, Y. Hayakawa, A. D. Brooks, J. Wine, R. H. Wiltrout, H. Yagita, J. E. Tanner, M. J. Smyth, and T. J. Sayers Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis Is an Important Endogenous Mechanism for Resistance to Liver Metastases in Murine Renal Cancer Cancer Res., January 1, 2003; 63(1): 207 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hayakawa, J. M. Kelly, J. A. Westwood, P. K. Darcy, A. Diefenbach, D. Raulet, and M. J. Smyth Cutting Edge: Tumor Rejection Mediated by NKG2D Receptor-Ligand Interaction Is Dependent upon Perforin J. Immunol., November 15, 2002; 169(10): 5377 - 5381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ogasawara, S. K. Yoshinaga, and L. L. Lanier Inducible Costimulator Costimulates Cytotoxic Activity and IFN-{gamma} Production in Activated Murine NK Cells J. Immunol., October 1, 2002; 169(7): 3676 - 3685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Pulaski, M. J. Smyth, and S. Ostrand-Rosenberg Interferon-{gamma}-dependent Phagocytic Cells Are a Critical Component of Innate Immunity against Metastatic Mammary Carcinoma Cancer Res., August 1, 2002; 62(15): 4406 - 4412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E.A. Street, J. A. Trapani, D. MacGregor, and M. J. Smyth Suppression of Lymphoma and Epithelial Malignancies Effected by Interferon {gamma} J. Exp. Med., July 1, 2002; 196(1): 129 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Kelly, K. Takeda, P. K. Darcy, H. Yagita, and M. J. Smyth A Role for IFN-{gamma} in Primary and Secondary Immunity Generated by NK Cell-Sensitive Tumor-Expressing CD80 In Vivo J. Immunol., May 1, 2002; 168(9): 4472 - 4479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Seki, A. D. Brooks, C. R. D. Carter, T. C. Back, E. M. Parsoneault, M. J. Smyth, R. H. Wiltrout, and T. J. Sayers Tumor-Specific CTL Kill Murine Renal Cancer Cells Using Both Perforin and Fas Ligand-Mediated Lysis In Vitro, But Cause Tumor Regression In Vivo in the Absence of Perforin J. Immunol., April 1, 2002; 168(7): 3484 - 3492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, N. Y. Crowe, D. G. Pellicci, K. Kyparissoudis, J. M. Kelly, K. Takeda, H. Yagita, and D. I. Godfrey Sequential production of interferon-gamma by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of alpha -galactosylceramide Blood, February 15, 2002; 99(4): 1259 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Cretney, K. Takeda, H. Yagita, M. Glaccum, J. J. Peschon, and M. J. Smyth Increased Susceptibility to Tumor Initiation and Metastasis in TNF-Related Apoptosis-Inducing Ligand-Deficient Mice J. Immunol., February 1, 2002; 168(3): 1356 - 1361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Schmaltz, O. Alpdogan, K. J. Horndasch, S. J. Muriglan, B. J. Kappel, T. Teshima, J. L. M. Ferrara, S. J. Burakoff, and M. R. M. van den Brink Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect Blood, May 1, 2001; 97(9): 2886 - 2895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Smyth, N. Y. Crowe, and D. I. Godfrey NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma Int. Immunol., April 1, 2001; 13(4): 459 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, E. Cretney, K. Takeda, R. H. Wiltrout, L. M. Sedger, N. Kayagaki, H. Yagita, and K. Okumura Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Trail) Contributes to Interferon {gamma}-Dependent Natural Killer Cell Protection from Tumor Metastasis J. Exp. Med., March 19, 2001; 193(6): 661 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. A. Street, E. Cretney, and M. J. Smyth Perforin and interferon-{gamma} activities independently control tumor initiation, growth, and metastasis Blood, January 1, 2001; 97(1): 192 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, K. Y.T. Thia, S. E.A. Street, D. MacGregor, D. I. Godfrey, and J. A. Trapani Perforin-Mediated Cytotoxicity Is Critical for Surveillance of Spontaneous Lymphoma J. Exp. Med., September 5, 2000; 192(5): 755 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, M. Taniguchi, and S. E. A. Street The Anti-Tumor Activity of IL-12: Mechanisms of Innate Immunity That Are Model and Dose Dependent J. Immunol., September 1, 2000; 165(5): 2665 - 2670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lehmann, M. Zeis, N. Schmitz, and L. Uharek Impaired binding of perforin on the surface of tumor cells is a cause of target cell resistance against cytotoxic effector cells Blood, July 15, 2000; 96(2): 594 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Prevost-Blondel, E. Roth, F. M. Rosenthal, and H. Pircher Crucial Role of TNF-{alpha} in CD8 T Cell-Mediated Elimination of 3LL-A9 Lewis Lung Carcinoma Cells In Vivo J. Immunol., April 1, 2000; 164(7): 3645 - 3651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, K. Y. T. Thia, S. E.A. Street, E. Cretney, J. A. Trapani, M. Taniguchi, T. Kawano, S. B. Pelikan, N. Y. Crowe, and D. I. Godfrey Differential Tumor Surveillance by Natural Killer (Nk) and Nkt Cells J. Exp. Med., February 21, 2000; 191(4): 661 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smyth, R. W. Johnstone, E. Cretney, N. M. Haynes, J. D. Sedgwick, H. Korner, L. D. Poulton, and A. G. Baxter Multiple Deficiencies Underlie NK Cell Inactivity in Lymphotoxin-{alpha} Gene-Targeted Mice J. Immunol., August 1, 1999; 163(3): 1350 - 1353. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
