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1.
Øystein Bruserud Laila Mentzoni Brynjar Foss Jann Bergheim Sigbjørn Berentsen Ingerid Nesthus 《Cancer immunology, immunotherapy : CII》1997,43(5):275-282
Normal peripheral blood mononuclear cells (PBMC responders) were cultured together with non-irradiated allogeneic PBMC (more
than 95% leukaemia blasts) derived from patients with acute leukaemia (referred to as leukaemic PBMC stimulators). Cytokine
secretion was determined as cytokine concentrations in supernatants. Both normal PBMC and enriched CD4+ and CD8+ T cells responded to allostimulation with interferon (IFNγ) secretion. Interleukin-1 (IL-1) receptor antagonist and IL-2-neutralizing
antibodies decreased IFNγ secretion. Exogenous IL-1β, IL-2 and IL-7 increased allostimulated IFNγ secretion, whereas decreased
levels were seen in the presence of IL-6, IL-10 and granulocyte-colony-stimulating factor (G-CSF). During allorecognition
IFNγ -neutralizing antibodies decreased acute myelogenous leukaemia (AML) blast secretion of G-CSF. We conclude that (i) both
CD4+ and CD8+ T cells show allostimulated cytokine secretion in response to allogeneic stimulator cells containing a dominating population
of native, cytokine-secreting leukaemia blasts, and (ii) IFNγ released during this response can modulate the function of allogeneic
AML blasts.
Received: 4 June 1996 / Accepted: 15 October 1996 相似文献
2.
Intracellular cytokine profile of T cells from children with acute lymphoblastic leukemia 总被引:12,自引:0,他引:12
Zhang XL Komada Y Chipeta J Li QS Inaba H Azuma E Yamamoto H Sakurai M 《Cancer immunology, immunotherapy : CII》2000,49(3):165-172
Purpose: During an ongoing immune response, cytokines produced by T helper types 1 (Th1) and 2 (Th2) together with T cytotoxic types
1 (Tc1) and 2 (Tc2) are critical to the effectiveness of that response. Dysregulated expansion of one or the other subset
may contribute to the impaired function of the T-cell-mediated immune system in cancer patients. In the present study we have
investigated whether such dysregulation might exist in children with acute lymphoblastic leukemia (ALL). Methods: We analyzed 61 blood samples from 45 children with B cell precursor ALL and 16 healthy children. Interleukin(IL)-2, IL-4,
and interferon γ (IFNγ) production of their respective purified CD4+ and CD8+ T cells were assessed at the single-cell level by intracellular-cytokine-staining flow cytometry. Results: At the time of diagnosis, IL-2-producing cell populations in CD4+ and CD8+ T cells were reduced below the normal range in 31 of 44 (70.5%) and 23 of 38 (60.5%) cases respectively. Similarly, IFNγ-producing
cell populations in CD4+ and CD8+ T cells decreased in 17 of 44 (38.6%) and 18 of 38 (47.4%) cases respectively. Conversely cell populations capable of IL-4
production in CD4+ and CD8+ T cell subsets were increased in 13 of 30 (43.3%) and 15 of 30 (50.0%) cases respectively. Therefore, the Th1-to-Th2 and
Tc1-to-Tc2 ratios (1.6 ± 2.2 and 7.7 ± 6.7 respectively) were significantly lower in peripheral blood T cells of ALL patients
(n = 30) than those (6.0 ± 2.9 and 20.1 ± 10.3 respectively) in 15 healthy controls (P < 0.0001). Although both CD45RA+/CD4+ and CD45RA+/CD8+ cells significantly increased in 43 ALL patients (P < 0.05), there existed no apparent correlation between CD45 isoform expression and cytokine (IL-2 and IFNγ) production. Interestingly,
the ability to produce both IL-2 and IFNγ was recovered in 8 cases examined, after complete remission had been achieved. Conclusion: These observations suggest that, in both CD4+ and CD8+ T cells of ALL patients, there is a dysregulation in the functionality of Th1 (Tc1) and Th2 (Tc2) cells with a gross reduction
of Th1 (Tc1) cell populations and an expansion in Th2 (Tc2).
Received: 12 November 1999 / Accepted: 2 January 2000 相似文献
3.
Anja ten Brinke Gijs van Schijndel Remco Visser Tanja D. de Gruijl Jaap Jan Zwaginga S. Marieke van Ham 《Cancer immunology, immunotherapy : CII》2010,59(8):1185-1195
Dendritic cells (DCs) are promising antigen presenting cells for cancer treatment. Previously, we showed that the combination
of monophosphoryl lipid A (MPLA) with IFNγ generates mature DCs that produce IL-12 and polarize CD4+ T cells towards a Th1 phenotype. Here, we extended these observations by showing that the DCs generated with the clinical
grade maturation cocktail of MPLA/IFNγ induce superior tumour antigen-specific CD8+ CTL responses compared to the cytokine cocktail matured DCs that are currently used in the clinic. MPLA/IFNγ DCs can induce
CTL responses in healthy individuals as well as in melanoma patients. The CTL induction was mainly dependent on the IL-12
produced by the MPLA/IFNγ DCs. The high amounts of induced CTLs are functional as they produce IFNγ and lyse target cells
and this cytolytic activity is antigen specific and HLA restricted. Furthermore, the CTLs proved to kill tumour cells expressing
endogenous tumour antigen in vitro. Therefore, MPLA/IFNγ DCs are very promising for the use in future cancer immunotherapy. 相似文献
4.
We previously reported [Chakrabarti et al. (1992) Cell Immunol 142:54; 144:455] that, in a murine B lymphoma model 2C3, idiotype
(Id)-specific CD8+ cytotoxic T lymphocytes (CTL) are generated in mice following hyperimmunization with irradiated tumor cells, and that they
are effective in tumor rejection. The present study reveals that 2C3-specific CTL are also induced in spleens during tumor
progression, but are not sustained. At the early stage of tumor growth, the splenic T cells following a 5-day incubation in
vitro with killed 2C3 tumor targets, produce high levels of cytokines, namely interleukin-4 (IL-4), IL-10 and interferon γ
(IFNγ). Their cytotoxic T lymphocyte (CTL) activity and cytokine levels, except IL-2, sharply decline at the late stage when
the mice are increasingly moribund. Although the decline in cytokine level is also evident with CD4+ T cells, a precipitous and concurrent decrease occurs primarily in the IL-4 level with both CD4+ and CD8+ T cells of late-tumor-bearing animals (TBA). Study with the unseparated splenocytes also reveals that sevenfold less IL-4
is produced at the late stage. Furthermore, the cytotoxicity of CTL from late TBA can be effectively restored by addition
of supernatants from the splenocyte culture of early TBA, or by IL-4, but not by IFNγ and IL-10. In addition, only IL-4-activated
CD8+ T cells from the late TBA are found, by Winn assay, to be protective in vivo. Thus it appears that IL-4, required to sustain
antitumor CTL activity, is consumed by T and possibly other cells at the late stage of tumor growth, thereby compromising
host immunity against the tumor. We contend that induction or maintenance of protective immunity depends not only on the tumor
antigen but also on the specific cytokine milieu in a tumor-bearing host.
Received: 8 February 1997 / Accepted: 24 April 1997 相似文献
5.
Øystein Bruserud 《Cancer immunology, immunotherapy : CII》1998,46(4):221-228
T lymphocytes are important both for the host defence against infections and probably also as antileukaemic effector cells
in patients with acute leukaemia. To investigate the T lymphocyte cytokine repertoire of clonogenic T lymphocytes, CD4+ and CD8+ T lymphocyte clones were prepared from acute leukaemia patients with chemotherapy-induced cytopenia (leucocytes <0.5×109/l). A majority of both CD4+ and CD8+ clones secreted detectable interleukin-2 (IL-2), IL-10, IL-13, granulocyte/macrophage-colony-stimulating factor and interferon
γ (IFNγ) in response to phytohaemagglutinin + accessory cells (Epstein-Barr-virus-transformed B cell line, 80-Gy-irradiated).
The CD4+ clones showed significantly higher levels of IL-10 secretion than the CD8+ clones. Decreased levels of IL-2, IL-13 and IFNγ were observed when acute myelogenous leukaemia (AML) blasts were used instead
of cells from the B cell line as accessory cells during phytohaemagglutinin activation, but the differences in IL-13 and IFNγ
levels were reversed by addition of exogenous IL-2. On the basis of these results we conclude: (i) the remaining clonogenic
T lymphocytes derived from acute leukaemia patients with therapy-induced leucopenia can respond to activation with a broad
cytokine response, and T-cell-derived cytokines may then contribute to cytokine responses during complicating infections in
these patients; (ii) although T cells can modulate AML blast functions and mediate antileukaemic effects, the leukaemia blasts
will also modulate T cell functions and alter the cytokine profile of activated T lymphocytes.
Received: 6 November 1997 / Accepted: 5 March 1998 相似文献
6.
Ursula Elsässer-Beile Ulrich Wetterauer Wolfgang Schultze-Seemann Harald Gallati Jürgen Schulte Mönting Sabine von Kleist 《Cancer immunology, immunotherapy : CII》1996,42(2):93-98
The immunological properties of tumor-infiltrating (TIL) and peripheral blood lymphocytes (PBL) from 29 patients with renal
cell carcinomas were characterized with respect to their phenotypic expression and cytokine production. TIL were isolated
from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation. To eliminate all
non-lymphoid cells, CD3-positive cells were specifically separated from these cell fractions with anti-CD3 magnetic beads.
These pure CD3-positive PBL (CD3+PBL) and TIL (CD3+TIL) were cultured with pokeweed mitogen and the levels of the cytokines interleukin-1α (IL-1α), IL-1β, IL-2, interferon γ
(IFNγ), and tumor necrosis factor α (TNFα) measured in the 4-day post-inductional cell culture supernatants. In all cell cultures
a wide range of cytokine values was found, indicating a large variation in the immunological activity of the lymphocytes of
each individual. When the cell cultures of the CD3+TIL and CD3+PBL were compared in each patient similar values for IL-1α, IL-1β, IFNγ and TNFα were found. However CD3+TIL produced significantly lower levels of IL-2 than CD3+PBL upon mitogenic stimulation. This may be due to a lower CD4/CD8 ratio in the CD3+TIL as compared to the CD3+PBL. These results suggest that there are no fundamental qualitative and quantitative differences in the lymphokine-producing
capacity of CD3+TIL and CD3+PBL derived from patients with renal cell carcinomas.
Received: 8 August 1995 / Accepted: 23 January 1996 相似文献
7.
The presence of a relatively mature CD4+ CD8− (SP) T cell subset in mouse thymus has been demonstrated. Composing of 10% of total CD4SP thymocytes, this subset is defined
by the absence of 3G11 and 6C10 expression with a phenotype of CD69+/−, HSAmed/lo and heterogeneous for Qa-2 expression. The proliferation capability of TCRαβ+ 3Gl l− 6C10− CD4+ CD8− thymocytes was high while using Con A stimulus. And Con A stimulation could result in secretion of IL4, IL-10, IL-6 and a
little amount of IFNγ. IL-2 was barely detectable. This is distinct from typical Th0 type cytokines. The cells of this subset
were NK1.1 negative, but strongly expressed GATA-3 mRNA. The results suggest that the CD4+ subset of 3G11− 6C10− NK1.1− phenotype possesses immunocompetent cells with functions characteristic of Th2-like cytokines, which may indicate the cells
at transitional status from Th0 to Th2, with a propensity to Th2.
Project supported by the National Natural Science Foundation of China (Grant No. 39730410). 相似文献
8.
The presence of a relatively mature CD4+ CD8− (SP) T cell subset in mouse thymus has been demonstrated. Composing of 10% of total CD4SP thymocytes, this subset is defined by the absence of 3G11 and 6C10 expression with a phenotype of CD69+/−, HSAmed/lo and heterogeneous for Qa-2 expression. The proliferation capability of TCRαβ+ 3Gl l− 6C10− CD4+ CD8− thymocytes was high while using Con A stimulus. And Con A stimulation could result in secretion of IL4, IL-10, IL-6 and a little amount of IFNγ. IL-2 was barely detectable. This is distinct from typical Th0 type cytokines. The cells of this subset were NK1.1 negative, but strongly expressed GATA-3 mRNA. The results suggest that the CD4+ subset of 3G11− 6C10− NK1.1− phenotype possesses immunocompetent cells with functions characteristic of Th2-like cytokines, which may indicate the cells at transitional status from Th0 to Th2, with a propensity to Th2. 相似文献
9.
T cell clones (CD4+CD8–TCRαβ+γδ–) derived from bone marrow transplant recipients were stimulated with phytohaemagglutinin (PHA) +interleukin-2 (IL-2) in the
presence of irradiated (50 Gy) peripheral blood mononuclear cells (PBMC) derived from acute leukaemia patients(leukaemic PBMC
containing more than 95% blast cells). Leukaemic PBMC could function as accessory cells during mitogenic T cell activation
resulting in both T cell proliferation and a broad T cell cytokine response [IL-3, IL-4, IL-10, granulocyte/macrophage-colony-stimulating
factor (GM-CSF) tumour necrosis factor α (TNFα) and interferon γ (IFNγ) secretion]. Blockade of IL-1 effects by adding IL-1
receptor antagonist together with PHA+IL-2+leukaemia blasts increased T cell proliferation, whereas IL-6-neutralizing antibodies
did not alter T cell proliferation. A qualitatively similar T cell cytokine response and a similar cytokine profile (highest
levels detected for GM-CSF and IFNγ) were detected when normal polyclonal T cell lines were stimulated with PHA in the presence
of non-irradiated leukaemic PBMC. When leukaemic PBMC derived from 18 acute myelogenous leukaemia patients were cultured with
PHA and cells from a polyclonal T cell line, increased concentrations of the T cell cytokines IFNγ and IL-4 were detected
for all patients. We conclude that T cell activation resulting in proliferation and a broad cytokine response can take place
in the presence of excess acute myelogenous leukaemia blasts.
Received: 30 November 1995 / Accepted: 9 January 1996 相似文献
10.
Ankathatti Munegowda M Deng Y Mulligan SJ Xiang J 《Cancer immunology, immunotherapy : CII》2011,60(10):1473-1484
CD4+ Th17 cells induce antitumor immunity leading to the eradication of established tumors. However, the mechanism of antitumour
immunity and CTL activation by Th17 cells and the distinct role of Th17 and Th17-activated CTLs in antitumor immunity are
still elusive. In this study, we generated ovalbumin (OVA)-specific Th17 cells by cultivating OVA-pulsed dendritic cells with
CD4+ T cells derived from transgenic OTII mice in the presence of IL-6, IL-23, TGF-β, and anti-IFN-γ antibody. We demonstrated
that Th17 cells acquired major histocompatibility complex/peptide (pMHC)-I and expressed RORγt, IL-17, and IL-2. Th17 cells
did not have any direct in vitro tumor cell–killing activity. However, Th17 cells were able to stimulate CD8+ CTL responses via IL-2 and pMHC I, but not IL-17 signaling, which play a major role in Th17-induced preventive immunity against
OVA-expressing B16 melanoma. Th17 cells stimulated the expression of CCL2 and CCL20 in lung tumor microenvironments promoting
the recruitment of various inflammatory leukocytes (DCs, CD4+, and CD8+ T cells) stimulating more pronounced therapeutic immunity for early-stage (5-day lung metastases or 3 mm, s.c.) tumor than
for well-established (6 mm, s.c.) tumor. The therapeutic effect of Th17 cells is associated with IL-17 and is mediated by
Th17-stimulated CD8+ CTLs and other inflammatory leukocytes recruited into B16 melanoma via Th17-stimulated CCL20 chemoattraction. Taken together,
our data elucidate a distinct role of Th17 and Th17-stimulated CD8+ CTLs in the induction of preventive and therapeutic antitumor immunity, which may greatly impact the development of Th17-based
cancer immunotherapy. 相似文献
11.
Brady MS Lee F Petrie H Eckels DD Lee JS 《Cancer immunology, immunotherapy : CII》2000,48(11):621-626
Purpose: Most melanoma cell lines express HLA class II antigens constitutively or can be induced to do so with interferon γ (IFNγ).
We have previously demonstrated that peptide-specific CD4+ T cells proliferate in response to HLA-class-II-antigen-mediated peptide presentation by melanoma cells in vitro and produce
interleukin-10 (IL-10) and (IFNγ). We asked whether the responding T cells kill the tumor cells and, if so, whether direct
cell contact was required. Methods: Two HLA class II+ melanoma cell lines derived from metastases were co-cultured with a human CD4+ T cell clone specific for influenza hemagglutinin peptide (HA). T cells, melanoma, and HA were co-cultured for 48 h. Melanoma
cells with and without HA and/or T cells served as controls. After 36 h, the medium was removed for cytokine analysis by enzyme-linked
immunosorbent assay (ELISA). Twelve hours later non-adherent cells were washed away and the adherent melanoma cells were trypsinized
and counted. Dual-chamber culture plates were used to determine whether cell contact and/or exposure to cytokine were required
for tumor cell death. Results: Melanoma cell counts were over 80% lower in wells containing T cells than in wells with melanoma and peptide alone (P < 0.05). ELISA of supernatants revealed production of IFNγ and IL-10 by the responding T cells. Direct T cell contact with
tumor cells was not required for tumor cell death, as melanoma cells were killed when they shared medium but had no contact
with T cells responding to peptide presentation by HLA-class-II-antigen-positive melanoma cells in a separate chamber. Blocking
antibody to IFNγ but not IL-10 prevented melanoma cell death at levels of cytokine similar to that present in co-culture assays.
Conclusions: Peptide-specific CD4+ T cells kill melanoma cells in vitro when they recognize peptide presented by the tumor cell in the context of HLA class
II antigen. Direct cell contact is not required, suggesting that it is a cytokine-mediated event. Immunotherapy, using primed
CD4+ T cells and peptide, may be beneficial in patients whose tumors express HLA class II antigens or can be induced to do so
with IFNγ.
Received: 1 July 1999 / Accepted: 17 September 1999 相似文献
12.
Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model 总被引:2,自引:0,他引:2
Kazuki Yamanaka Isao Hara Hiroshi Nagai Hideaki Miyake Kazuo Gohji Mark J. Micallef Masashi Kurimoto Soichi Arakawa Sadao Kamidono 《Cancer immunology, immunotherapy : CII》1999,48(6):297-302
We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete
bioactive IL-12. IL-12-secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcutaneously implanted into immunocompetent
syngeneic C3H mice. Although this antitumor effect did not change when IL-12-secreting cells were injected into immunodeficient
mice whose CD8+ T or CD4+ T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells were depleted by anti-asialoGM1
antibody. In addition, when parental MBT2 cells mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admixed
MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration.
This synergism was abrogated when the mice were treated with interferon-γ-neutralizing antibody in vivo. In conclusion, local
secretion of IL-12 led to effective antitumor activity that was enhanced by systemic administration of IL-18. Interferon-γ
plays an important role in the synergism of IL-12 gene transduction and systemic administration of IL-18.
Received: 7 May 1998 / Accepted: 27 May 1999 相似文献
13.
Ursula Elsässer-Beile Thomas Grussenmeyer Dorothee Gierschner Barbara Schmoll Wolfgang Schultze-Seemann Ulrich Wetterauer Jürgen Schulte Mönting 《Cancer immunology, immunotherapy : CII》1999,48(4):204-208
The mRNA expression of Th1 and Th2 cytokines was compared in freshly isolated CD3+ tumor-infiltrating lymphocytes (CD3+ TIL) and in autologous CD3+ peripheral blood lymphocytes (CD3+ PBL) obtained simultaneously from 20 patients with renal cell carcinomas (RCC). In addition cytokine expression was compared
in CD4+ TIL and CD8+ TIL from another group of 20 patients with RCC. TIL were isolated from mechanically disaggregated tumor material and PBL
from peripheral blood by gradient centrifugation and subsequent selection with anti-CD3, anti-CD4 or anti-CD8 magnetic beads.
In these pure lymphocyte preparations the constitutive expression of interleukin-1 (IL-1), IL-2, IL-10, interferon γ (IFN),
and tumor necrosis factor α (TNF) was determined by using a polymerase-chain-reaction-assisted mRNA amplification assay. In
the CD3+ TIL, levels of mRNA for IFN, IL-10, IL-1 and TNF were significantly higher than in the autologous CD3+ PBL whereas IL-2 expression was rather low and did not differ in the two populations. Comparison of cytokine mRNA expression
in CD4+ TIL and simultaneously obtained CD8+ TIL revealed a significantly higher expression of IFN in the CD8+ cells. These data reflect an in vivo activation of RCC-infiltrating lymphocytes at the mRNA level with respect to the Th1
as well as the Th2 immune response. Th1 activation seems to be most evident in the CD8+ TIL.
Received: 14 January 1999 / Accepted: 30 April 1999 相似文献
14.
Flieger D Kufer P Beier I Sauerbruch T Schmidt-Wolf IG 《Cancer immunology, immunotherapy : CII》2000,49(8):441-448
Cytokine-induced killer cells (CIK), generated in vitro from peripheral blood mononuclear cells (PBMC) by addition of interferon
γ (IFNγ), interleukin-2 (IL-2), IL-1 and a monoclonal antibody (mAb) against CD3, are highly efficient cytotoxic effector
cells with the CD3+CD56+ phenotype. In this study, we evaluated whether the cytotoxicity of these natural-killer-like T lymphocytes against the colorectal
tumor cell line HT29 can be enhanced by the addition of a bispecific single-chain antibody (bsAb) directed against EpCAM/CD3.
For determination of bsAb-redirected cellular cytotoxicity we used a new flow-cytometric assay, which directly counts viable
tumor cells and can assess long-term cytotoxicity. We found that this bsAb induced distinct cytotoxicity at a concentration
above 100 ng/ml with both PBMC and CIK at an effector-to-target cell ratio as low as 1:1. CIK cells revealed higher bsAb-redirected
cytotoxicity than PBMC. Cellular cytotoxicity appeared after 24 h whereas PBMC showed the highest bsAb-redirected cytotoxicity
after 72 h. The addition of the cytokines IL-2 and IFNα but not granulocyte/macrophage-colony-stimulating factor enhanced
bsAb-redirected cytotoxicity of both PBMC and CIK. When the bsAb was combined with the murine mAb BR55-2, which recognizes
the Lewisy antigen, bsAb-redirected cytotoxicity was partly augmented, whereas murine mAb 17-1A, which binds to EpCAM as well, slightly
suppressed bsAb-redirected cytotoxicity induced by the bsAb. We conclude that CIK generated in vitro or in vivo combined with
this new EpCAM/CD3 bsAb and the cytokine IL-2 should be evaluated for the treatment of EpCAM-expressing tumors.
Received: 9 December 1999 / Accepted: 18 May 2000 相似文献
15.
16.
Lodge A Yu P Nicholl MB Brown IE Jackson CC Schreiber K Sugg SL Schreiber H Shilyansky J 《Cancer immunology, immunotherapy : CII》2006,55(12):1542-1552
Absence of CD4+ T cell help has been suggested as a mechanism for failed anti-tumor cytotoxic T lymphocytes (CTL) response. We examined the requirement for CD4+ T cells to eliminate an immunogenic murine fibrosarcoma (6132A) inoculated into the peritoneal cavity. Immunocompetent C3H mice eliminated both single and repeat intraperitoneal (IP) inoculums, and developed high frequency of 6132A-specific interferon-γ (IFNγ)-producing CTL in the peritoneal cavity. Adoptive transfer of peritoneal exudate cells (PEC) isolated from control mice, protected SCID mice from challenge with 6132A. In contrast, CD4 depleted mice had diminished ability to eliminate tumor and succumbed to repeat IP challenges. Mice depleted of CD4+ T cells lacked tumor-specific IFNγ producing CTL in the peritoneal cavity. Adoptive transfer of PEC from CD4 depleted mice failed to protect SCID mice from 6132A. However, splenocytes isolated from same CD4 depleted mice prevented tumor growth in SCID mice, suggesting that 6132A-specific CTL response was generated, but was not sustained in the peritoneum. Treating CD4 depleted mice with agonist anti-CD40 antibody, starting on days 3 or 8 after initiating tumor challenge, led to persistence of 6132A-specific IFNγ producing CTL in the peritoneum, and eliminated 6132A tumor. The findings suggest that CTL can be activated in the absence of CD4+ T cells, but CD4+ T cells are required for a persistent CTL response at the tumor site. Exogenous stimulation through CD40 can restore tumor-specific CTL activity to the peritoneum and promote tumor clearance in the absence of CD4+ T cells.Supported in part by grants from Children’s Hospital of Wisconsin Foundation, Society of University Surgeons Foundation, Florence and Marshall Schwid Foundation, Elsa Pardee Foundation, Kathy Duffy Fogarty Fund of the Greater Milwaukee Foundation (JS) and NIH grant RO1-CA-37156 (HS); Andrew Lodge and Ping Yu have contributed equally to this work. 相似文献
17.
T lymphocyte secretion of interleukin-13 (IL-13) in response to different activation signals was characterized in vitro. IL-13
release was investigated when virus transformed B lymphocytes or acute myelogenous leukaemia (AML) blasts were used as accessory
cells during T cell activation. First, a majority of both CD4+ and CD8+ TCRαβ+ T lymphocyte clones, derived from normal individuals and bone marrow transplant recipients, secreted IL-13 in response to
a standardized mitogenic activation signal (phytohaemagglutinin+IL-2+ B lymphocyte accessory cells). The CD4+ cells showed significantly higher IL-13 levels than the CD8+ subsets. Second, when leukaemic accessory cells (more than 95% AML blasts) were used during T cell activation, IL-13 was
released both during alloactivation of normal T lymphocytes and during mitogen activation of posttransplant T cells. Third,
when normal T lymphocytes were stimulated with allogeneic AML blasts, addition of IL-13-neutralizing monoclonal antibodies
decreased interferon γ levels. Although addition of IL-13-neutralizing antibodies did not alter granulocyte-colony-stimulating
factor secretion by allostimulating AML blasts, altered blast proliferation was detected for certain patients. Thus, most
T cell clones can release IL-13, and IL-13 can modulate cytokine responses during T cell recognition of allogeneic AML cells.
Received: 24 April 1997 / Accepted: 24 July 1997 相似文献
18.
There has been a recent interest in using IL-15 to enhance antitumor activity in several models because of its ability to
stimulate CD8+ T cell expansion, inhibit apoptosis and promote memory T cell survival and maintenance. Previously, we reported that C6VL
tumor lysate-pulsed dendritic cell vaccines significantly enhanced the survival of tumor-bearing mice by stimulating a potent
tumor-specific CD8+ T cell response. In this study, we determined whether IL-15 used as immunologic adjuvant would augment vaccine-primed CD8+ T cell immunity against C6VL and further improve the survival of tumor-bearing mice. We report that IL-15 given after C6VL
lysate-pulsed dendritic cell vaccines stimulated local and systemic expansion of NK, NKT and CD8+ CD44hi T cells. IL-15 did not, however, augment innate or cellular responses against the tumor. T cells from mice infused with IL-15
following vaccination did not secrete increased levels of tumor-specific TNF-α or IFN-γ or have enhanced C6VL-specific CTL
activity compared to T cells from recipients of the vaccine alone. Lastly, IL-15 did not enhance the survival of tumor-bearing
vaccinated mice. Thus, while activated- and memory-phenotype CD8+ T cells were dramatically expanded by IL-15 infusion, vaccine-primed CD8+ T cell specific for C6VL were not significantly expanded. This is the first account of using IL-15 as an adjuvant in a therapeutic
model of active immunotherapy where there was not a preexisting pool of tumor-specific CD8+ T cells. Our results contrast the recent studies where IL-15 was successfully used to augment tumor-reactivity of adoptively
transferred transgenic CD8+ T cells. This suggests that the adjuvant potential of IL-15 may be greatest in settings where it can augment the number and
activity of preexisting tumor-specific CD8+ T cells. 相似文献
19.
20.
C57B1/6 female mice were infected with an intrapulmonary dose of 2.5 × 104 BCG(Mycobacterium bovis Bacillus Calmette-Guerin). Lymphocyte populations in lung interstitium and lung-associated tracheal lymph nodes (LN) were
examined at 1,2, 4, 5, 6, 8 and 12 weeks after infection. BCG load in lungs peaked between 4–6 weeks post-infection and declined to very
low levels by the 12th week of infection. Lung leukocytes were obtained over the course of infection by enzyme digestion of
lung tissue followed by centrifugation over Percoll discontinuous density gradients. By 4 to 6 weeks after infection, numbers
of lung leukocytes had more than doubled but the proportions of lymphocytes (about 70%), macrophages (about 18%) and granulocytes
(about 12%) remained essentially unaltered. Flow cytometric studies indicated: (i) the total number of CD3+ T cells in lungs increased by 3-fold relative to uninfected controls at 5 to 6 weeks post-infection, but the relative proportions
of CD4 and CD8 cells within the T cell compartment remained unaltered; (ii) relative proportion of NK cells in lungs declined
by 30% but the total number of NK cells (NK1.1+) per lung increased by about 50%, 5–6 weeks post infection; (iii) tracheal LN underwent marked increase in size and cell
recoveries (6-10-fold increase) beginning 4 weeks after infection. While both T and B cells contributed to the increase in
cell recoveries from infected tracheal LNs, the T/B ratio declined significantly but CD4/CD8 ratio remained unaltered. In
control mice, IFNγ producing non-T cells outnumbered T cells producing IFNγ. However, as the adaptive response to infection
evolves, marked increase occur in the number of IFNγ producing T cells, but not NK cells in the lungs. Thus, T cells are the
primary cell type responsible for the adaptive IFNγ response to pulmonary BCG infection. Few T cells in tracheal LN of BCG
infected mice produce IFNγ, suggesting that maturational changes associated with migration to the lungs or residence in the
lungs enhance the capability of some T cells to produce this cytokine 相似文献