研究者詳細 - 河上　裕

論文 - 河上　裕

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Differential expression of MAGE-1, -2, and -3 messenger RNA in transformed and normal human cell lines

Zakut Rina, Topalian Suzanne L., Kawakami Yutaka, Mancini Marie, Eliyahu Siona, Rosenberg Steven A.

Cancer Research 53 （ 1 ） 5 - 8 1993年01月

ISSN 0008-5472

The MAGE-1 gene codes for a tumor-specific antigen, MZ2-E, that elicited a cytotoxic T-lymphocyte response in the melanoma patient from whom it was derived. We have developed a simplified method, using polymerase chain reaction amplification of exon 3 followed by restriction enzyme pattern analysis, to distinguish expression of the MAGE-1 gene from MAGE-2 and MAGE-3, other members of this gene family. MAGE-1 mRNA was expressed in 53% of 17 melanoma lines, two of seven Epstein-Barr virus-transformed B-cell lines, and 2 of 5 breast cell lines including a line established from normal breast epithelium. MAGE-1 is not likely to be the common melanoma antigen recognized by the other HLA-A1- or HLA-A2-restricted cytotoxic T-lymphocytes examined in this study, but the fact that it is expressed in about 50% of melanoma cell lines makes it a reasonable target for the immunotherapy of patients bearing HLA-A1.

T-cell recognition of human melanoma antigens

Kawakami Y., Nishimura M. I., Restifo N. P., Topalian S. L., O'Neil B. H., Shilyansky J., Yannelli J. R., Rosenberg S. A.

Journal of Immunotherapy 14 （ 2 ） 88 - 93 1993年

ISSN 1053-8550

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) with interleukin-2 (IL-2) has antitumor activity in some patients with metastatic melanoma. We have analyzed molecular mechanisms of TIL recognition of human melanoma. Some cultured TILs specifically lysed autologous and some allogeneic melanomas sharing a variety of class I major histocompatibility complex (MHC) molecules. HLA-A2-restricted melanoma-specific TILs lysed many HLA-A2⁺ melanoma cell lines from different patients but failed to lyse HLA- A2^- melanoma and HLA-A2⁺ nonmelanoma cell lines. However, these TILs were capable of lysing many naturally HLA-A2^- melanomas after introduction of the HLA-A2.1 gene by vaccinia virus. These results indicate that shared melanoma antigens (Ag) are expressed in melanomas regardless of their human leukocyte antigen types. In order to identify these shared melanoma Ags, we have tested some known proteins expressed in melanoma. Expression of tyrosinase or HMB45 Ag correlated with lysis of TILs. We are also attempting to isolate antigenic peptides by high performance liquid chromatography separation and genes encoding melanoma Ag by cDNA expression cloning. The T-cell component of the antimelanoma response was also analyzed by determining the genetic structure of the T-cell receptor (TCR) used by melanoma TILs. However, we did not observe common TCR variable region usage by different melanoma TILs. We could establish melanoma cell clones and lines resistant to TIL lysis due to the absence of or defects in the expression of Ag, MHC, or β₂-microglobulin molecules. These data indicate multiple mechanisms for melanoma escape from T-cell immunosurveillance. These findings have important implications for the development of immunotherapies for melanoma.

Expansion of tumor-infiltrating lymphocytes from human tumors using the T- cell growth factors interleukin-2 and interleukin-4

Kawakami Y., Haas G. P., Lotze M. T.

Journal of Immunotherapy 14 （ 4 ） 336 - 347 1993年

ISSN 1053-8550

We examined the role of two T cell-growth factors, interleukin (IL)-2 and IL-4, in expansion of tumor-infiltrating lymphocytes (TILs) from human tumors. In sarcoma, IL-4 (1,000 U/ml) with IL-2 (10 or 1,000 U/ml) grew TILs better than did IL-2 alone in six of 10 cases during 6 weeks of culture. IL- 4 decreased the relative number of CD56⁺ cells, which correlated with a decrease in cytolysis against Daudi in six of 10 cases. The addition of IL-4 with 1,000 U of IL-2 maintained or increased cytolysis against autologous sarcoma, while decreasing nonspecific cytolysis against Daudi or allogeneic sarcoma in three of eight cases. IL-4 decreased cytolysis against both autologous sarcoma and Daudi in four of 10 cases, suggesting nonspecific activity in these instances. In renal cell cancer (RCC), IL-4 with IL-2 (10 or 1,000 U/ml) augmented TIL growth in six of eight cases, especially during the first 2-3 weeks of culture. IL-4 with 10 U of IL-2 increased cytolysis against both autologous RCC and Daudi in six of eight cases, suggesting possible prior cell activation. In contrast, IL-4 addition with 1,000 U of IL-2 maintained or increased cytolysis against autologous RCC, while decreasing cytolysis against Daudi or allogeneic RCC in four of eight cases. In cases of bladder and of prostate cancer, IL-4 with 1,000 U of IL-2 grew TILs slightly better in five of seven cases for the first 2-3 weeks. Bladder TILs grown with IL-2 and/or IL-4 were CD⁺ T cell predominant (three of five) and rarely lytic for autologous tumor. In colon cancer and hepatoma, TILs grown with IL-2 and/or IL-4 were nonlytic for the autologous tumor. IL-4 in conjunction with IL-2 could therefore augment growth of some TILs especially for the first 2-3 weeks from various human tumors.

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Molecular mechanisms used by tumors to escape immune recognition

Restifo N. P., Kawakami Y., Marincola F., Shamamian P., Taggarse A., Esquivel F., Rosenberg S. A.

Journal of Immunotherapy 14 （ 3 ） 182 - 190 1993年

ISSN 1053-8550

In this article, we explore the hypothesis that tumor cells can escape recognition by CD8⁺ T cells via deficiencies in antigen processing and presentation. Aspects of the molecular and cellular biology of major histocompatibility complex class I are reviewed. Evidence for histology- specific molecular mechanisms in the antigen-processing and -presentation deficiencies observed in some human and murine tumors is presented. Mechanisms identified include down-regulation of antigen processing, loss of functional β₂-microglobulin, and deletion of specific α-chain alleles. Finally, we discuss studies using an antigen-presentation-deficient mouse tumor as a model for the immunogenetherapy of an antigen-presentation deficiency.

Shared human melanoma antigens

Kawakami Yutaka, Zakut Rina, Topalian Suzanne L., Stötter Hans, Rosenberg Steven A.

Journal of Immunology 148 （ 2 ） 638 - 643 1992年01月

ISSN 0022-1767

Three predominantly CD8⁺ CTL lines, TIL 501, TIL 620, and TIL 660, were generated from three HLA-A2⁺ melanoma patients by culturing tumor-infiltrating lymphocytes in 1000 U/ml IL-2. These tumor-infiltrating lymphocytes lysed 12 of 18 HLA-A2⁺ autologous and allogeneic melanomas, but none of 20 HLA-A2-negative melanomas. They also did not lyse the MHC class I negative lymphoma-leukemia cell lines, Daudi, K562, or HLA-A2⁺ non-melanoma cell lines including PHA or Con A-induced lymphoblast, fibroblast, EBV-transformed B cell, Burkitt's B cell lymphoma, and colon cancer cell lines. Autologous and allogeneic melanoma lysis was inhibited by anti-CD3, by anti-MHC class I, and by anti-HLA-A2 mAb, indicating recognition of shared tumor Ag among melanoma cell lines in a TCR-dependent, HLA-A2-restricted manner. Six HLA-A2-negative melanoma cell lines obtained from five HLA-A2-negative patients were co-transfected with the HLA-A2.1 gene and pSV2neo. All 17 cloned transfectants expressing cell surface HLA-A2 molecules, but none of 12 transfectants lacking HLA-A2 expression, were lysed by these three HLA-A2-restricted, melanoma-specific CTL. Lysis of the HLA-A2⁺ transfectants was inhibited by anti-CD3, by anti-MHC class I, and by anti-HLA-A2 mAb, indicating recognition of shared tumor Ag on transfectants in a TCR-dependent, HLA-A2-restricted manner. These results identify the HLA-A2.1 molecule as an Ag-presenting molecule for melanoma Ag. They also suggest that common melanoma Ag are expressed among melanoma patients regardless of HLA type. These findings have implications for the development of melanoma vaccines that would induce antitumor T cell responses.

Recognition of shared melanoma antigens by human tumor-infiltrating lymphocytes

Topalian S. L., Hom S. S., Kawakami Y., Mancini M., Schwartzentruber D. J., Zakut R., Rosenberg S. A.

Journal of Immunotherapy 12 （ 3 ） 203 - 206 1992年

ISSN 1053-8550

We have established that melanomas express shared tumor antigens (Ags) that can be recognized by T cells if presented in the context of self-MHC molecules. Tumor-infiltrating lymphocytes (TILs) from six melanoma patients were tested for lysis of large panels of HLA-matched or unmatched targets representing a variety of tissue types. Lysis was specific for allogeneic melanomas sharing at least one HLA-A, -B, or -C Ag with TILs, and demonstrated commonly expressed tumor Ags. Similar findings were obtained when cytokine secretion by TILs was used to indicate specific Ag recognition. Transfection of the HLA-A2.1 gene into HLA-A2 melanoma lines conferred susceptibility to lysis by HLA-A2 restricted melanoma TILs, demonstrating expression of common tumor Ags among patients of diverse HLA types. These findings have important implications for developing broadly applicable cancer immunotherapies such as vaccines.

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Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo

Klein T. W., Kawakami Y., Newton C., Friedman H.

Journal of Toxicology and Environmental Health 32 （ 4 ） 465 - 477 1991年

ISSN 0098-4108

Killer lymphocytes play a major role in host defense against tumors and infectious diseases. Previously, we reported that delta-9-tetrahydrocannabinol (THC) and Il-hydroxy-delta-9-tetrahydrocannabinol (Il-hydroxy-THC) suppressed the cytolytic activity of cultured natural killer (NK) cells. Also, we showed that the drugs appeared to be affecting a stage in the killing process subsequent to the binding of the killer cell to the target cell. In the present report, we have extended these studies to an examination of the effect of cannabinoids on the activity of cytotoxic T lymphocytes (CTLs). The cytolytic activity of CTLs generated by cocultivation with either allospecific stimulators or TNP-modified-self stimulators were suppressed by both THC and Il-hydroxy-THC treatment. Allospecific CTLs generated in vivo were also inhibited by an in vitro exposure to either THC or Il-hydroxy-THC, and the sensitivity of these cells to drug effects appeared to be greater than the sensitivity of the in vitro generated CTLs. Suppression of cytolytic function by THC and Il-hydroxy-THC ws maximal after a 4-h drug treatment, suggesting that the drug effects were inducible and therefore required a finite period of time to develop maximally. As seen in previous studies involving NK cells, drug treatment of mature CTLs appears to have little effect on the binding capacity of these cells for the target. However, the maximal killing capacity of the cells and the frequency of CTLs were significantly reduced by drug treatment. In addition to suppressing the cytolytic activity of mature effector CTLs, we also show that drug treatment inhibits both the proliferation of lymphocytes responding to an allogeneic stimulus and the maturation of these lymphocytes to mature CTLs. Similarly, CTL activity developing in vivo could be inhibited by THC injection. These results suggest that CTLs are inhibited by cannabinoids by at least two mechanisms. First, the cytolytic activity of mature killers is suppressed at some point beyond the binding to the target cell. Second, the cannabinoids appear to suppress the normal development of these mature effector cells from less mature precursor cells.

Interleukin-3 induces proliferation but not lymphokine activated killer activity from human and murine mononuclear cells.

Jablons D. M., Donohue R., Kawakami Y., Young J. D., Lotze M. T.

European Cytokine Network 1 （ 2 ） 91 - 98 1990年05月

ISSN 1148-5493

Recombinant IL-3 (rIL-3) is a potent colony stimulating factor capable of stimulating early hematopoietic pluripotential progenitor cells and of supporting the differentiation of multiple cells. IL-3 has also been shown to have effects on mature, differentiated circulating cells including eosinophils and T cells. We evaluated the role of exogenous rIL-3 in the generation of cells with LAK activity from murine splenocytes and human bone marrow, spleen, unseparated PBMC and purified null cell preparations. rIL-3 was unable to generate lytic activity from any of these populations by itself and appeared to decrease LAK activity in bone marrow cultures containing high dose IL-2, (bone marrow derived cells (n = 3) with LAK activity for fresh tumor, mean lytic units(LU) 94.6 +/- 63.5 vs 32.8 +/- 44.8 for IL-2 and IL-2 plus IL-3 cultures, respectively p2 less than 0.05). Unlike previous reports testing murine cells, IL-3 priming and subsequent culture in IL-2 of human unseparated bone marrow cells or human or murine splenocytes, failed to generate long-term cultures with lytic activity. IL-3 did, however, induce a dose dependent stimulation of bone marrow and null cell preparations (mean null cell stimulation (3H Thymidine incorporation) with IL-3, 436 +/- 168 cpm vs 9802 +/- 9799 cpm, for 0 vs 10(3) units of IL-3, respectively n = 4, p2 less than 0.05). Furthermore, in bone marrow, unseparated PBMC and null cell cultures, the addition of rIL-3 generated characteristic large blastic appearing cells with prominent basophilic granules.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of immunologic antitumor therapy

Lotze Michael T., Custer Mary C., Bolton Ellen S., Wiebke Eric A., Kawakami Yutaka, Rosenberg Steven A.

Human Immunology 28 （ 2 ） 198 - 207 1990年

ISSN 0198-8859

The use of interleukin 2-based immunotherapies for cancer has been associated with significant resonses in tumor models in both mouse and humans. Further definition of the elements responsible for response is now possible. It appears that the respnse is associated with T-cell infiltration of the tumor, and transfer of tumor-infiltrating lymphocytes expanded in tissue culture with interleukin 2 is associated with significant antitumor effects. Further expansion of cultured human melanoma tumor-infiltrating lymphocytes with suppression of lymphokine-activated killer activity as well as the modulation of monocyte activity by interleukin 4 suggests that this cytokine may be clinically useful alone or in combination with interleukin 2. Other means of enhancing the activity of interleukin 2-based immunotheraphy are suggested by the finding that tumor cell susceptibility to lysis by natural killer cells is depressed following treatment with interferon γ and tumor necrosis factor, but susceptibility to lysis by tumor-infiltrating lymphocytes is markedly enhanced. Further development of these therapies will require innovative interpretation and application of findings related to the processing and presentation of human tumor antigens and the nature of tumor antigens and careful analysis of they T-cell receptor in antitumor effectors.

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Prevention and reversal of delta-9-tetrahydrocannabinol induced depression of natural killer cell activity by interleukin-2

Specter Steven, Rivenbark Melodie, Newton Catherine, Kawakami Yutaka, Lancz Gerald

International Journal of Immunopharmacology 11 （ 1 ） 63 - 69 1989年

ISSN 0192-0561

The effects of delta-9-tetrahydrocannabinol (THC) on NK cell activity were studied. Previously, we reported that incubation of human peripheral blood mononuclear cells in THC resulted in an inhibition of natural killer (NK) cell activity. The present study examined the mechanism(s) of the decrease in NK cell activity. The inhibition of killing by NK cells was not due to a failure of NK cells to bind to K562 target cells. Furthermore, indomethacin did not abrogate the THC-mediated effect, suggesting that prostaglandins are not involved in the process leading to suppression of NK cell activity. However, NK activity was partially restored if cells, pretreated with THC, were washed to remove excess drug and then incubated overnight in fresh medium before assay. Addition of 1 - 100 U IL-2, either during pretreatment with THC or during overnight incubation, precluded or promoted the reversal of the inhibition of NK cell cytotoxicity. We conclude that the regulatory mechanism(s) involved in depression of NK cell cytotoxicity by THC is significantly influenced by IL-2.

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IL-4 regulates IL-2 induction of lymphokine-activated killer activity from human lymphocytes

Kawakami Y., Custer M. C., Rosenberg S. A., Lotze M. T.

Journal of Immunology 142 （ 10 ） 3452 - 3461 1989年

ISSN 0022-1767

IL-4 is a pluripotent lymphokine acting on various cell types. We investigated the role of human IL-4 on the generation of lymphokine-activated killer (LAK) activity. Human IL-4 alone did not induce LAK activity and inhibited IL-2 induction of LAK activity from unstimulated PBMC, peripheral blood null cells, spleen cells, and lymph node cells in a dose-dependent manner. IL-4 also inhibited several phenomena induced by IL-2 such as cell proliferation, augmentation of NK activity, increase of Leu-19⁺ cells, and expression of IL-2R(p55) on either CD3⁺ or Leu-19⁺ cells. IL-4, however, augmented cell proliferation with other T cell mitogens including PHA, Con A, PMA, or allo-MHC Ag with or without IL-2. In contrast to unstimulated cells, IL-4 alone induced marked cell proliferation and LAK activity as well as Leu-19⁺ cells from in vitro IL-2 preactivated PBMC or null cells, and did not inhibit IL-2 induced cell proliferation, LAK activity, Leu-19⁺ cells and IL-2R(p55) expression, but rather augmented them with low doses of IL-2. Although IL-4 alone induced LAK activity from peripheral blood of some patients previously given IL-2, IL-4 inhibited in vitro LAK generation with IL-2 from these cells in most cases. Therefore, IL-4 appears to directly inhibit the IL-2 activation pathway via IL-2R(p70) and prevent resting LAK precursors from proliferating and differentiating into final effector cells. However, once cells were sufficiently preactivated by IL-2, IL-4 induced LAK activity and did not inhibit IL-2 activation of these cells. These data suggest an immunoregulatory role of IL-4 on human null cells and T cells.

Suppression by cannabinoids of the induction and function of murine cytotoxic T lymphocytes

Y. Kawakami Kawakami, Klein T. W., Newton C. A., Young J., Friedman H.

International Journal of Immunopharmacology 10 （ SUPPL. 1 ） 147 1988年

ISSN 0192-0561

Suppression by cannabinoids of a cloned cell line with natural killer cell activity

Kawakami Y., Klein T. W., Newton C., Djeu J. Y., Dennert G., Specter S., Friedman H.

Proceedings of the Society for Experimental Biology and Medicine 187 （ 3 ） 355 - 359 1988年

ISSN 0037-9727

Preincubation of a cloned cell line with natural killer (NK) cell activity, as well as splenic mononuclear cells with either Δ⁹-tetrahydrocannabinol (THC) or 11-hydroxy-Δ⁹-tetrahydrocannabinol (11-OH-THC) suppressed NK cytolytic activity against YAC-1 target cells in a dose-dependent manner. THC was more inhibitory for cloned cells than 11-OH-THC and suppressed the lytic activity of these cells without reducing cell viability in the concentration range of 5 μg/ml (16 μM) to 10 μg/ml (32 μM). THC also inhibited proliferation of cloned NK cells, but this inhibitory effect was reversible in that extensive washing of cells following cannabinoid pretreatment eliminated the suppressive effect. Single-cell analysis revealed that THC did not inhibit the binding of cloned NK cells to target cells and further showed that NK cells freshly isolated from mouse spleen were restricted in killing capacity following binding to target cells. Therefore, THC and 11-OH-THC appear to directly inhibit NK cell cytolytic activity in a postbinding stage.

Suppression by delta-9-tetrahydrocannabinol of interleukin 2-induced lymphocyte proliferation and lymphokine-activated killer cell activity

Kawakami Yutaka, Klein Thomas W., Newton Catherin, Djeu Julie Y., Specter Steven, Friedman Herman

International Journal of Immunopharmacology 10 （ 4 ） 485 - 488 1988年

ISSN 0192-0561

The major psychoactive marijuana component, delta-9-tetrahydrocannabinol (THC), suppressed proliferation of murine spleen cells stimulated with recombinant human interleukin 2 (IL-2) and also suppressed the appearance of the lymphokine-activated killer (LAK) cell phenomenon in IL-2-treated spleen cell preparations. Cell function was depressed in a dose-dependent manner with as little as 2.5 μg/ml THC (8μM). In addition, spleen cells previously stimulated in culture with IL-2 and then incubated with THC for 4 h prior to target cell addition, displayed suppressed cytolytic activity against both YAC-1 and EL-4 tumor targets. Killing of EL 4 cells was suppressd at lower drug doses than the killing of YAC-1 targets. These results suggest that THC can suppress several important functions of IL-2 including clonal expansion of lymphocytes, expansion of killer cell populations and stimulation of killer cell cytotoxic activity.

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Interleukin 4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic for human autologous melanoma

Kawakami Y., Rosenberg S. A., Lotze M. T.

Journal of Experimental Medicine 168 （ 6 ） 2183 - 2191 1988年

ISSN 0022-1007

Addition of IL-4 (1,000 U/ml) to either high or low concentrations of IL-2 augmented tumor-infiltrating (TIL) growth from human melanoma. Weekly restimulation with irradiated tumor cells in conjunction with IL-4 allowed enhanced growth of TIL. With low-dose IL-2 (10 U/ml) and IL-4, expanded TIL had little cytolytic activity against Daudi or allogeneic tumors. Further, IL-4 augmented the total lytic activity against autologous tumors in most cases. With high-dose IL-2 (1,000 U/ml), IL-4 addition decreased nonspecific killing activity against Daudi or allogeneic melanomas in many cases, and reciprocally augmented cytolytic activity against the autologous melanoma in many cases. This suggests the possible use of IL-4 in cancer therapy, especially in adoptive cellular immunotherapy using TIL or in conjunction with IL-2 administration.

Ultrastructural study of megakaryocyte maturation

Ogawa T., Miyake K., Kawakami Y., Kizaki M.

Journal of Clinical Electron Microscopy 17 （ 5-6 ） 938 - 939 1984年

ISSN 0021-4981

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