-
[show abstract]
[hide abstract]
ABSTRACT: To determine if the combination of radiosurgery and tumor cell vaccine would enhance the therapy of metastatic lesions of the central nervous system (CNS), the authors examined the antitumoral effects of radiosurgery and cytokine-transduced tumor cell vaccine.
Fifty-five rats underwent intracranial implantation of 5 x 10(3) MADB 106 cells. On Day 3 after tumor implantation, 34 rats were inoculated in the flank with nonirradiated MADB 106 cells that had been retrovirally transduced to express granulocyte-macrophage colony-stimulating factor or interleukin-4. Twenty-seven rats (17 animals that had received the vaccine and 10 that had not) underwent radiosurgery performed using a gamma knife at maximum doses of 32 Gy on Day 5. No animals in the untreated group or in the vaccine-alone groups survived longer than 21 days. Animals treated by ra diosurgery alone displayed prolonged survival in comparison with untreated animals (p < 0.0001), but only one of 10 animals survived longer than 55 days. In contrast, 14 of 17 animals that received the combination therapy of radiosurgery and vaccination survived longer than 55 days (p = 0.0003 compared with animals that underwent radiosurgery alone). On Day 55, the long-term survivors were challenged by parental MADB 106 cells, which were implanted in the contralateral hemisphere. All animals from the combination therapy groups survived longer than 50 days after this challenge, but the single survivor from the radiosurgery-alone group died of tumor growth in 27 days.
The combination of radiosurgery and cytokine gene-transduced tumor cell vaccine markedly prolonged animal survival and protected animals from a subsequent challenge by parental tumor cells placed in the CNS. The data provided by this study indicate that this combination therapy represents a strategy that may have clinical applicability for single and/or multiple metastatic brain tumors.
Journal of Neurosurgery 01/2002; 95(6):984-9. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon-alpha (9L-IFNalpha). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFNalpha and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors.
Gene Therapy 08/2001; 8(15):1157-66. · 3.71 Impact Factor
-
H Okada,
J Attanucci,
K M Giezeman-Smits,
C Brissette-Storkus,
W K Fellows,
A Gambotto,
L F Pollack,
K Pogue-Geile,
M T Lotze,
M E Bozik, W H Chambers
[show abstract]
[hide abstract]
ABSTRACT: We have reported previously that s.c. immunization of rats with IL-4 transduced 9L gliosarcoma cells (9L-IL-4) induced a potent antitumor immunity against intracranial, parental 9L tumors. Subcutaneous implantation of 9L-IL-4 influenced the systemic humoral response, which was demonstrated by Th2-type isotype-switching and the induction of cellular immune responses, which played a critical role in the rejection of tumors. Serological analyses of recombinant cDNA expression libraries (SEREX), has recently emerged as a powerful method for serological identification of tumor-associated antigens (TAAs) and/or tumor rejection antigens (TRAs). Because IL-4 is known to activate B cells and to promote humoral responses, and inasmuch as induction of humoral responses by central nervous system tumors has been reported to be minimal, we investigated whether the induction of a potent humoral immune response against 9L TAAs or TRAs in rats immunized s.c. with 9L-IL4 could be demonstrated. Screening of 5 x 10(5) independent clones of 9L-expression cDNA library for the presence of reactive antibodies in the serum from a 91-IL-4 immunized rat led to the identification of three different TAAs. One 9L TAA (clone 29) was demonstrated to be calcyclin, a member of the S-100 family of calcium-binding proteins. The second 9L TAA (clone 37) was demonstrated to be the rat homologue of the J6B7 mouse immunomodulatory molecule. The third TAA (clones 158 and 171) was determined to be the rat homologue of the mouse Id-associated protein 1 (MIDA1), a DNA-binding, protein-associated protein. Northern blotting demonstrated that message for calcyclin was overexpressed in 9L cells. Message encoding MIDA1 was highly expressed in parental 9L cells and thymus and, to a lesser degree, in testis, suggesting that MIDA1 was comparable with the cancer/testis category of TAAs. Sera obtained from animals bearing 9L-IL-4 were found to have a higher a frequency and titer of antibodies to these antigens when compared with sera obtained from rats bearing sham-transduced 9L (9L-neo) cells. To determine whether immunization with these TAAs induced antitumor immunity, animals were immunized by intradermal injection with expression plasmids encoding calcyclin or MIDA1. Subsequent challenge of rats with parental 9L resulted in significant suppression of tumor growth in animals immunized with MIDA1, but not with calcyclin. These results indicate that MIDA1 is an effective 9L TRA and will be useful for the investigation of specific antitumor immunity in this glioma model. Furthermore, these results suggest that this approach, termed "cytokine-assisted SEREX (CAS)," may serve as an effective strategy for identification of TRAs for in animal-glioma models of cytokine gene therapy, and potentially in humans undergoing cytokine gene therapy protocols as well.
Cancer Research 04/2001; 61(6):2625-31. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Malignant gliomas are among the most common intrinsic brain tumors of both children and adults, and, because of unique aspects of their biology and anatomic site, they are the most refractory to conventional therapeutic strategies involving surgery, radiotherapy, or chemotherapy. Given the failure of standard therapies to improve the outlook of affected patients, significant attention has been focused on development of alternative treatments, particularly immunotherapy. Attempts have been made to treat gliomas using a variety of immunologically based strategies, including passive immunization, adoptive cellular immunotherapy, local and systemic delivery of biological response modifiers, and vaccination with tumor cells. Although preclinical modeling of these therapies provided an impetus for translation of their results into clinical protocols, these therapies have failed to yield consistently promising results in initial trials. However, significant insights into the immunobiology of the central nervous system (CNS) and gliomas have been gained from these studies, and have established that a number of immunobiological features of the brain and of gliomas themselves may be critical determinants in regulating efficacious treatment of these tumors. These include the following: (1) the presence of a blood-brain barrier that, although partially disrupted by the tumor, functions to exclude elements of the immune system from the tumor or brain parenchyma; (2) a lack of organized secondary lymphatic tissues supporting efficient immune responses locally in the CNS; (3) low levels of expression of major histocompatibility complex proteins in the CNS; (4) an apparent paucity of the most efficient antigen-presenting cells; and (5) glioma-derived immunosuppressive factors, such as transforming growth factor-beta, that interfere with the induction of local as well as systemic immune responses to the tumor. Recognition of these factors, and an appreciation of the underlying need for and validity of developing immunologically based therapies for gliomas, supports continued development of novel immunotherapeutic approaches, particularly those attempting to enhance the immunogenicity of glioma cells. This review addresses the current state of knowledge regarding the immunobiology of gliomas, recent developments in immunotherapy of gliomas, and promising future directions for development and implementation of cellular immunotherapy of gliomas.
Seminars in Pediatric Neurology 07/2000; 7(2):131-43. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Tumor cells genetically modified to secrete cytokines stimulate potent immune responses against peripheral and central nervous system tumors; however, variable results on the efficacy of this strategy for therapeutic intervention against established intracranial neoplasia have been reported. We have found that vaccination with rat 9L gliosarcoma cells expressing interleukin 4 (9LmIL4) induced a specific, protective, immune response against rechallenge with parental 9L tumors. In naive rats, sham-transfected 9L (9Lneo) tumors and 9LmIL4 tumors grew at comparable rates for 12-14 days, and then 9LmIL4 tumors regressed. After regression of 9LmIL4 tumors, rats were resistant to rechallenge with parental 9L cells. To investigate the mechanism(s) responsible for 9LmIL4-induced immunity, the phenotype and function of tumor-infiltrating lymphocytes (TILs) in 9Lneo and 9LmIL4 tumors were compared. In flow cytometric analyses, it was determined that CD4+ T cells were the predominant cell type in both 9Lneo and 9LmIL4 tumors at day 10. However, at the onset of regression (day 14), 9LmIL4 tumors were infiltrated predominantly by CD8+ T cells. To investigate functional aspects of the anti-9L tumor responses, we assessed the capacity of 9LmIL4 TILs to mediate specific lytic function or production of cytokines. In response to parental 9L, TILs isolated from day 14 9LmIL4 tumors were demonstrated to produce substantially greater amounts of IFN-gamma than did TILs from 9Lneo tumors. Although freshly isolated TILs from 9LmIL4 or control tumors did not lyse 9L cells in 51Cr-release cytotoxicity assays, specific cytotoxicity was demonstrable using TILs from day 14 9LmIL4 or splenocytes from 9LmIL4-bearing rats after their restimulation for 5 days with parental 9L tumor cells in vitro. Antibody blocking studies demonstrated that cytokine production and lytic activity by TILs, or splenocytes from 9LmIL4-immunized rats, were mediated in a T-cell receptor-dependent fashion. Because interleukin-4 also promotes humoral responses, quantity and isotype of immunoglobulins in sera from 9Lneo or 9LmIL4-immunized rats were compared. The amount of IgG1 antibodies was significantly increased in sera from 9LmIL4-immunized rats compared to sera from 9Lneo-bearing rats. Experiments using sublethally irradiated, naive rats adoptively transferred with splenocytes and/or sera from 9LmIL4-immunized or naive rats demonstrated that immune cells, with or without immune sera, protected recipients from challenge with parental 9L. Immune sera provided no protection when given with lymphocytes from naive rats, and it did not enhance protection against parental 9L when given in conjunction with lymphocytes for 9LmIL4-immunized rats. In additional adoptive transfer experiments, an essential role for CD4+ T cells in immunity was observed because their depletion from among splenocytes of 9LmIL4-immunized rats eliminated the protective effective against 9L, whereas depletion of CD8+ cells resulted in a more limited effect on protection against 9L. These data suggest that strategies for inducing systemic, long-term tumor-specific reactivity among CD4+ T cells will be critical for the development of immunotherapy of gliomas.
Cancer Research 06/2000; 60(9):2449-57. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Vaccination with cytokine-transduced tumor cells represents a potentially important approach to the treatment of central nervous system tumors. We have recently demonstrated the therapeutic efficacy of tumor cell vaccines expressing the murine interleukin 4 (IL-4) and the herpes simplex virus-thymidine kinase in a rat brain tumor model in which nonirradiated vaccine cells can be eliminated by the subsequent administration of ganciclovir. In this report, we demonstrate the construction and characterization of a retroviral vector that encodes human IL-4, neomycin phosphotransferase, and herpes simplex virus-thymidine kinase genes for use in human clinical trials. An MFG-based retroviral vector was used to generate the recombinant retrovirus, TFG-hIL4-Neo-Tk, in which a long terminal repeat-driven polycistronic transcript encodes three cDNAs that are linked and coexpressed using two intervening internal ribosome entry site fragments from the encephalomyocarditis virus. The amphotropic retroviral vector TFG-hIL4-Neo-Tk was then used to infect human primary glioma cultures and skin-derived fibroblasts. After infection and G418 selection, cells produced 89-131 ng/10(6) cells/48 hours of human IL-4, which was determined to be biologically active. Transduced glioma cells were highly sensitive to the cytotoxic effect of ganciclovir. These data demonstrate the suitability of the TFG-hIL4-Neo-Tk vector for therapeutic studies of cytokine-transduced autologous tumor vaccination in patients with malignant gliomas.
Cancer Gene Therapy 04/2000; 7(3):486-94. · 2.80 Impact Factor
-
Methods in molecular biology (Clifton, N.J.) 02/2000; 121:95-114.
-
[show abstract]
[hide abstract]
ABSTRACT: Using a nonhuman primate model, we examined the mechanisms by which acute social stress inhibits the ability of NK cells to form conjugates with, and lyse target cells. We examined the expression and role of the primary NK cell adhesion molecules, CD2 and LFA-1, in mediating conjugation to target cells. Acute stress induced a decrease in NK cell expression of CD2 (17+/-3%); and to a lesser degree induced a decrease in expression of LFA-1 (CD11a: 8+/-3%; CD18: 7+/-3%). Antibody blocking studies indicated that anti-LFA-1 significantly inhibited NK cell conjugate formation and cytotoxicity in both control (approximately 40% and approximately 50%, respectively) and stressed (approximately 20% and approximately 45%, respectively) conditions. However, anti-CD2 blocked conjugation and cytotoxicity in the control condition by approximately 50%, but had no capacity to further affect the inhibition of conjugation or cytotoxicity of NK cells induced by acute stress. These data indicate that there are differential effects of acute stress on the expression and function of LFA-1 and CD2, and that the stress-induced inhibition of NK cell adhesion and cytotoxicity is dependent upon modulation of adhesion and/or signalling through CD2.
Journal of Neuroimmunology 11/1999; 99(2):230-41. · 2.96 Impact Factor
-
D Metes,
M Manciulea,
D Pretrusca,
H Rabinowich,
L K Ernst,
I Popescu,
A Calugaru,
A Sulica, W H Chambers,
R B Herberman,
P A Morel
[show abstract]
[hide abstract]
ABSTRACT: We recently reported that human NK cells express, in addition to CD16 [Fcgamma receptor (FcgammaR) IIIA], a second type of FcgammaR, namely CD32 (FcgammaRII). Molecular characterization of CD32 transcripts expressed by highly purified NK cells revealed that they predominantly express products of the FcgammaRIIC gene. Using stable Jurkat transfectants we have analyzed the functional properties of two FcgammaRIIc-specific isoforms isolated from NK cells, namely FcgammaRIIc1 and FcgammaRIIc3, which differ in their cytoplasmic tails. The ligand binding specificity for both murine and human IgG isotypes was found to be similar to that observed for FcgammaRIIb isoforms. Immunoprecipitation studies of FcgammaRIIc isoforms expressed in Jurkat cells revealed a protein of around 40 kDa for FcgammaRIIc1, and a protein of around 32 kDa for FcgammaRIIc3. Signal transduction studies performed on FcgammaRIIc1-expressing Jurkat cells indicated that this molecule is functional, i. e. capable of Ca2+ mobilization and activation of Lck, Zap-70 and Syk protein tyrosine kinases, although the CD3 zeta chain was not found to functionally associate with FcgammaRIIc1. In contrast, FcgammaRIIc3 transfectants showed an impaired ability of this molecule to mobilize Ca2+, but activation of Lck was detected following activation via FcgammaRIIc3. These studies demonstrate the functional activity of FcgammaRIIc isoforms and suggest that the presence of CD32, in addition to CD16, on NK cells may have functional relevance.
European Journal of Immunology 10/1999; 29(9):2842-52. · 5.10 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mixed allogeneic bone marrow chimerism induces tolerance to solid organ grafts. Although we previously reported that partially ablative conditioning with 700 cGy of total body irradiation (TBI) is sufficient to allow for bone marrow engraftment in mice, we determined that a minimum of 1000 cGy was required in the rat. Because T cells and NK cells are critical in bone marrow graft rejection, our purpose was to examine whether targeting of radioresistant NK cells and/or T cells in the recipient hematopoietic microenvironment would reduce the TBI dose required for engraftment of allogeneic rat bone marrow.
Wistar Furth rats received either anti-NK3.2.3 monoclonal antibodies on days -3 and -2, anti-lymphocyte serum on day -5, a combination of both or no pretreatment. TBI was performed on day 0 and rats were reconstituted with 100x10(6) T cell-depleted bone marrow cells from ACI donors.
Engraftment of T cell-depleted rat bone marrow was readily achieved in animals conditioned with 1000 cGy TBI alone (12/12) and the level of donor chimerism averaged 89%. At 900 cGy TBI alone only one of eight recipients engrafted. In striking contrast, 11 of 12 animals pretreated with anti-NK monoclonal antibodies and irradiated with 900 cGy showed donor chimerism at a mean level of 41%. No further enhancement of bone marrow engraftment could be achieved when recipients were pretreated with antilymphocyte serum alone or antilymphocyte serum plus anti-NK monoclonal antibodies. Mixed allogeneic chimeras exhibited stable multilineage chimerism and donor-specific tolerance to subsequent cardiac allografts.
Specific targeting of radioresistant host NK cells allows for a significant reduction of the TBI dose required for allogeneic bone marrow engraftment.
Transplantation 09/1999; 68(3):369-78. · 4.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To explore the potential for molecular immunotherapies in the treatment of malignant gliomas, we evaluated the efficacy of subcutaneous tumor cell vaccines in the treatment of intracranial 9L tumors, using 9L gliosarcoma cell lines stably transduced with the murine interleukin-4 cDNA (9L-IL4), the herpes simplex virus-thymidine kinase cDNA (9L-Tk) or both (9L-IL4-Tk). The expression of multiple genes from a single transcript was achieved by incorporating internal ribosomal entry site (IRES) cassettes in the retroviral constructs. Subcutaneous immunization of rats with nonirradiated 9L-IL4 cells or 9L-IL4-Tk cells followed by treatment with ganciclovir (GCV) completely protected the animals from a subsequent intracranial challenge with wild-type 9L cells. In contrast, only 50% of animals immunized with 9L-Tk cells and 0% of 9L-neo immunized animals rejected the same challenge with wild-type 9L. More importantly, treatment of established (day 3) intracranial 9L tumors with genetically engineered tumor cells resulted in long-term survival (> 100 days) for 25-43% of 9L-IL4-Tk immunized animals and for 27% of nonirradiated 9L-IL4 immunized animals. In striking contrast, no 9L-Tk, 9L-neo or irradiated 9L-IL4 immunized animals survived for more than 33 days. As a marker of a cellular immune response, splenocytes from nonirradiated 9L-IL4, 9L-Tk or 9L-IL4-Tk immunized animals produced interferon-gamma (IFN-gamma) in greater amounts than those from 9L-neo immunized or Hank's balanced salts solution (HBSS) treated animals when stimulated with wild-type 9L in vitro. Our findings support the use of tumor cell vaccines expressing the IL-4 and HSVtk genes for the treatment of malignant gliomas.
Gene Therapy 03/1999; 6(2):219-26. · 3.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In order to improve the therapeutic efficacy of adoptive immunotherapy of cancer using IL-2-activated NK (A-NK) cells, we developed a bi-specific monoclonal antibody (BimAb) 3.2.3xCC52. One specificity of the BimAb (mAb 3.2.3) was directed against rat CD161A (NKR-P1A) which has been shown to be an activation structure on rat NK cells involved in lysis of target cells and cytokine secretion. The other specificity (mAb CC52) was directed against a tumor associated antigen on the rat colon adenocarcinoma cell line CC531. The hybridomas producing 3.2.3 and CC52 were fused, resulting in a quadroma producing the desired 3.2.3xCC52 BimAb. The hybridomas produced antibodies of different isotypes (IgG2b and IgG1 respectively) which enabled us to pre-select quadromas with a high likelihood for production of BimAb, through testing for the production of bi-isotypic antibodies. Production of functional BimAb by the selected quadromas was demonstrated in an assay showing enhanced conjugate formation between CD161A+ cells and CC531 tumor cells. We also tested the 3.2.3xCC52 BimAb for its capacity to enhance NK cell-mediated lysis of CC531 tumor cells in 4 h and 19 h 51Cr release assays; in a prolonged (2 day) tumor neutralization assay using a tetrazolium salt (MTT)-based assay; and in tests for apoptosis using Annexin V-FITC. Although this BimAb was not demonstrated to cause enhanced lysis of CC531 cells by CD161A+ effector cells in vitro, it might be a useful tool to enhance the number of NK cells at the tumor site and/or prolong contact between tumor cells and NK cells in vivo, thereby probably enhancing the therapeutic efficacy of NK cells.
Immunobiology 03/1999; 200(1):31-48. · 3.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although the central nervous system (CNS) is often regarded as an immunologically privileged site, it is well established that specific CNS immunoreactivity can be generated through peripheral vaccination with CNS antigens. Dendritic cells (DC) are potent antigen presenting cells of hematopoietic origin that have emerged as a promising tool for cancer immunotherapy capable of evoking significant anti-tumor immunity when pulsed with tumor-associated peptides. To explore a role for DC-based immunization strategies for the treatment of CNS tumors, we developed a brain tumor model using the C3 sarcoma cell line which expresses the tumor-specific, major histocompatibility complex (MHC) class I-restricted peptide epitope E7(49-57). Syngeneic C57Bl/6 mice receiving intravenous (i.v.) injections of bone marrow-derived DCs pulsed with E7 peptide were effectively protected against a subsequent intracerebral challenge with C3 tumor cells. More importantly, this systemic immunization strategy was effective in a therapy model as 67% of animals (10 of 15) with established (day 7) intracerebral C3 tumors treated with 3 weekly injections of E7 peptide-pulsed DCs achieved a long-term survival (>90 days) while no control animals survived beyond day 41. In vivo depletion of CD8+ cells, but not CD4+ or asialo-GM1+ cells, abrogated the efficacy of E7 peptide-pulsed DC therapy of established tumors, indicating a pivotal role of specific CD8+ T-cell responses in mediating the anti-tumor effect. Our findings support the hypothesis that effective CNS anti-tumor immunoreactivity can be generated with DC-based tumor vaccines.
International Journal of Cancer 11/1998; 78(2):196-201. · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Numerous reports have demonstrated a link between stressful stimuli and immune suppression. However, the cellular mechanisms by which stress impairs immune function are largely unknown. We have examined the effects of an acute stressor on the T cell population, specifically, the number and phenotype of T cells in a nonhuman primate model. In nonstressed adult monkeys, we found differences in the level of expression of CD2 on T cells, revealing two distinct subsets of T cells, CD2dim and CD2bright cells, with CD2bright cells predominately coexpressing CD8. In response to acute stress, we observed a significant loss in the number and percent of CD2bright/CD8+ cells, with percent of CD2bright cells returning to pre-stress values within 24 h.
Journal of Neuroimmunology 07/1998; 86(1):63-73. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human natural killer (NK) cells were thought to express only FcgammaRIIIA (CD16), but recent reports have indicated that NK cells also express a second type of FcgammaR, ie, FcgammaRII (CD32). We have isolated, cloned, and sequenced full-length cDNAs of FcgammaRII from NK cells derived from several normal individuals that may represent four different products of the FcgammaRIIC gene. One transcript (IIc1) is identical with the already described FcgammaRIIc form. The other three (IIc2-IIc4) appear to represent unique, alternatively spliced products of the same gene, and include a possible soluble form. Analyses of the full-length clones have revealed an allelic polymorphism in the first extracellular exon, resulting in either a functional open reading frame isoform or a null allele. Stable transfection experiments enabled us to determine a unique binding pattern of anti-CD32 monoclonal antibodies to FcgammaRIIc. Further analyses of NK-cell preparations revealed heterogeneity in CD32 expression, ranging from donors lacking CD32 expression to donors expressing high levels of CD32 that were capable of triggering cytotoxicity. Differences in expression were correlated with the presence or absence of null alleles. These data show that certain individuals express high levels of functional FcgammaRIIc isoforms on their NK cells.
Blood 04/1998; 91(7):2369-80. · 9.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Interleukin-2 (IL-2)-activated natural killer (NK) cells are known to mediate specific functions such as cytolytic activity and tumor infiltration more efficiently than nonactivated NK cells. To investigate whether these characteristics are associated with induction or up-regulation of expression of membrane structures after IL-2 activation, we selected four hybridomas (mAbs ANK44, ANK66, ANK7, and ANK123) derived from mice immunized with rat IL-2-activated NK cells and compared the expression of the epitopes recognized on IL-2-activated NK cells versus unstimulated NK cells. We found that ANK44-expression was induced after activation with IL-2. The antigens recognized by ANK66, ANK7, and ANK123 were expressed selectively on subsets of nonactivated NK cells. After activation with IL-2 the level of expression of these antigens was increased. Moreover, the majority of NK cells then expressed these antigens after IL-2 activation. Biochemical characterization of the membrane structures recognized on IL-2-activated NK cells showed that they have not previously been described. The precise function of these membrane structures is not yet known, however, the selective nature of their expression implies their involvement in the specific functions of IL-2-activated NK cells.
Journal of Leukocyte Biology 03/1998; 63(2):209-15. · 4.99 Impact Factor
-
Transplantation Proceedings 06/1997; 29(3):1730-1. · 1.00 Impact Factor
-
Transplantation Proceedings 01/1997; 28(6):3267-8. · 1.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have recently demonstrated that cocaine administration has a limited effect on mitogen-stimulated T lymphocyte proliferation. The present study investigated the effect of cocaine on splenic T cell response to alloantigens. Rats received intraperitoneal injections of cocaine HCI, and splenocytes were isolated either thirty minutes or three hours post-administration. In the thirty minute exposure group, cocaine at 10.0 and 25.0 mg/Kg/B.Wt. suppressed (p<0.05) T cell proliferation in mixed lymphocyte cultures. Compared to control data, proliferation was decreased by 46.6% and 56.4%, respectively. However, this effect was not as pronounced in cells isolated three hours post-administration, indicating a transient inhibition of T cell function by cocaine. The decrease in splenic T cell proliferation in response to alloantigens in the thirty minute exposure group did not reflect alterations in calcium influx or IL-2 production. Although this study did not ascertain the exact mechanism of inhibition, these results demonstrate that short-term cocaine exposure can alter T cell reactivity to alloantigens, suggesting a reduction in the functional status of these cells.
Life Sciences 01/1997; 61(10):967-76. · 2.53 Impact Factor
-
Transplantation Proceedings 11/1996; 28(5):2465-6. · 1.00 Impact Factor
