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1.
J Leukoc Biol ; 69(1): 129-37, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11200057

RESUMO

Paclitaxel (TAXOL) activates in vitro macrophage (Mø) expression of proinflammatory and cytotoxic mediators, including IL-12, tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO). However, tumors dysregulate Mø through soluble suppressor molecules, and it is possible that tumors evade paclitaxel-mediated immune effector function through the production of immunomodulatory molecules and inhibition of Mø function in situ. Because Mø activation in the tumor microenviroment is a desirable goal of anti-tumor immunotherapy, we evaluated whether tumor-derived immunomodulatory factors dysregulate paclitaxel-mediated Mø activation. Tumor cell-derived supernatant suppressed paclitaxel's capacity to induce IL-12, TNF-alpha, and NO production by RAW264.7 Mø. Tumor factors also dysregulated paclitaxel-induced expression of a HIV-LTR, promoter-driven luciferase construct in RAW264.7 Mø, suggesting that tumors may inhibit a broad range of Mø functionality. Depletion studies revealed that IL-10 and transforming growth factor-beta1 (TGF-beta1), but not prostaglandin E2 (PGE2), impaired paclitaxel-mediated activation, suggesting that abrogation of these factors in situ might restore paclitaxel's activating capacity and enhance anti-tumor efficacy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Interleucina-10/imunologia , Interleucina-10/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Paclitaxel/farmacologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/farmacologia , Animais , Antineoplásicos Fitogênicos/imunologia , Regulação para Baixo , Interações Medicamentosas , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/metabolismo , Paclitaxel/imunologia
2.
J Immunol ; 162(11): 6811-8, 1999 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-10352302

RESUMO

Tumor-induced macrophages (Mphis) mediate immunosuppression, in part, through increased production of factors that suppress T cell responsiveness and underproduction of positive regulatory cytokines. Pretreatment of tumor-bearing host (TBH) Mphis with the anticancer agent paclitaxel (Taxol) partially reverses tumor-induced Mphi suppressor activity, suggesting that paclitaxel may restore TBH Mphi production of proimmune factors. Because paclitaxel demonstrates LPS-mimetic capabilities and increased production of the LPS-induced immunostimulatory cytokine IL-12 could account for enhanced T cell responsiveness, we investigated whether paclitaxel induces Mphi IL-12 production. Tumor growth significantly down-regulated Mphi IL-12 p70 production through selective dysregulation of IL-12 p40 expression. LPS stimulation failed to overcome tumor-induced dysregulation of p40 expression. In contrast, paclitaxel significantly enhanced both normal host and TBH Mphi IL-12 p70 production in vitro, although TBH Mphi IL-12 production was lower than that of similarly treated normal host Mphis. Paclitaxel enhanced p40 expression in a dose-dependent manner. Through reconstituted Mphi IL-12 expression, paclitaxel pretreatment relieved tumor-induced Mphi suppression of T cell alloreactivity. Blocking Mphi NO suppressed paclitaxel's ability to induce IL-12 production. This suggests that paclitaxel-induced activities may involve a NO-mediated autocrine induction pathway. Collectively, these data demonstrate that paclitaxel restores IL-12 production in the TBH and ascribe a novel immunotherapeutic component to the pleiotropic activities of NO. Through its capacity to induce IL-12 production, paclitaxel may contribute to the correction of tumor-induced immune dysfunction.


Assuntos
Adjuvantes Imunológicos/farmacologia , Interleucina-12/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Óxido Nítrico/fisiologia , Paclitaxel/farmacologia , Sarcoma Experimental/imunologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Dimerização , Tolerância Imunológica/efeitos dos fármacos , Interleucina-12/antagonistas & inibidores , Interleucina-12/química , Interleucina-12/fisiologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
3.
Int J Immunopharmacol ; 20(10): 537-51, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9839658

RESUMO

The antineoplastic agent paclitaxel (Taxol) mimics bacterial lipopolysaccharide (LPS) in normal host macrophages (Mphis), enhancing antitumor cytotoxicity in vitro. Because paclitaxel is used as an antitumor chemotherapeutic agent and tumor growth alters Mphi phenotype and function, we assessed effector molecule production and cytotoxic activity by normal host and tumor-bearing host (TBH) Mphis following paclitaxel administration. Paclitaxel treatment, duplicating human chemotherapeutic regimens, primed normal host splenic Mphis for enhanced production of the cytotoxic mediator nitric oxide (NO); in contrast, paclitaxel's NO-inducing activity was significantly suppressed in TBHs. In contrast to NO regulation, Mphi capacity for tumor necrosis factor-alpha (TNF-alpha) production in both normal hosts and TBHs was enhanced by paclitaxel administration. Although tumor growth modulated paclitaxel-induced Mphi NO production, paclitaxel administration enhanced both normal host and TBH Mphi cytotoxic antitumor activity. Blocking NO with a competitive inhibitor abrogated Mphi cytotoxicity, suggesting paclitaxel-induced TBH Mphi NO production, although suboptimal, remains sufficient to mediate antitumor activity. These data demonstrate that paclitaxel's in vivo immune activities are differentially regulated during tumor burden and suggest that paclitaxel's immunotherapeutic functions may contribute to its success as an anticancer agent.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Macrófagos/efeitos dos fármacos , Óxido Nítrico/biossíntese , Paclitaxel/uso terapêutico , Sarcoma Experimental/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Interferon gama/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/farmacologia , Sarcoma Experimental/imunologia , Sarcoma Experimental/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
4.
Immunopharmacol Immunotoxicol ; 20(4): 473-92, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9805229

RESUMO

The antineoplastic agent paclitaxel (TAXOL) is a potent inhibitor of tumor cell division and a useful chemotherapeutic for the treatment of refractory ovarian and breast carcinoma. Multiple immune system actions have been ascribed to paclitaxel, including the capacity to induce macrophage antitumor cytotoxic molecule production. However, T-cells are susceptible to paclitaxel's cytostatic functions, and no studies have investigated the effects of direct paclitaxel administration on lymphocyte function in the tumor-bearing host (TBH). Because paclitaxel is currently used as an antitumor chemotherapeutic agent and tumor growth alters leukocyte functions, we assessed T-cell function following chemotherapeutic-type paclitaxel treatment. Paclitaxel administration significantly compromised the proliferative capacity of both normal host and TBH lymphocytes in vitro. Although tumor growth impaired T-cell interferon-gamma (IFN-gamma) production, paclitaxel treatment did not alter IFN-gamma. We speculate that the immunostimulatory cytokine interleukin-12 (IL-12), which promoted T-cell activation and proliferation, was capable of reversing paclitaxel-mediated immunosuppression. Exogenous IL-12 fully reconstituted proliferative reactivity and enhanced IFN-gamma production by both normal host and TBH lymphocytes in vitro. Collectively, these data suggest that chemotherapeutic paclitaxel regimens impart significant but reversible inhibition of lymphocyte populations, and IL-12 may be a useful ancillary immunotherapeutic to overcome paclitaxel-induced modulation of lymphocyte activities.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Imunossupressores/farmacologia , Interleucina-12/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Paclitaxel/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Antineoplásicos Fitogênicos/antagonistas & inibidores , Interações Medicamentosas , Imunossupressores/antagonistas & inibidores , Interferon gama/biossíntese , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/antagonistas & inibidores
5.
Cancer Immunol Immunother ; 45(1): 20-8, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9353423

RESUMO

The anticancer drug taxol (paclitaxel) inhibits tumors through multiple cytotoxic and cytostatic mechanisms. Independently of these mechanisms, taxol induces distinct immunological efficacy when it acts as a second signal for activation of tumoricidal activity by interferon gamma (IFN gamma)-primed murine normal host macrophages. We reported that tumor-distal macrophages, which mediate immunosuppression through dysregulated nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) production, are differentially regulated by taxol. Because taxol influences tumor cell growth dynamics and activates immune cell populations, we assessed the ex vivo immunosuppressive and antitumor activities of taxol-treated normal host and tumor-bearing host (TBH) macrophages. Pretreatment of such cells with taxol partly reconstituted T cell alloantigen reactivity, suggesting that taxol mediates a limited reversal of TBH macrophage immunosuppressive activity. Taxol-treated TBH macrophages significantly suppressed the growth of fibrosarcoma cells (Meth-KDE) through soluble effector molecules and promoted direct cell-mediated cytotoxicity, indicating that taxol enhanced tumor-induced macrophage antitumor activities. Tumor-induced helper T cells, however, showed a higher sensitivity to direct taxol-induced suppression. These data demonstrate that taxol exerts pleiotropic effects on antitumor immune responses with the capacity to abate the immunosuppressive activities of macrophages and promote macrophage-mediated antitumor activities simultaneously, but also directly modulating T cell reactivity. Collectively, these studies suggest that the antineoplastic drug taxol may impart antitumor activity through an immunotherapeutic capacity.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Paclitaxel/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Divisão Celular/fisiologia , Citotoxicidade Imunológica , Tolerância Imunológica/efeitos dos fármacos , Isoantígenos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese
6.
Immunopharmacology ; 37(1): 63-73, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9285245

RESUMO

Taxol, a potent antitumor chemotherapeutic, promotes in vitro cytotoxic antitumor activities by normal host macrophage (M phi s). Because tumor growth induces functional changes among M phi populations, we determined whether fibrosarcoma growth (Meth-KDE) modified M phi responsiveness to the activating agent taxol. Tumors induce tumor-distal M phi populations to become immune suppressor cells, partially through overproduction of the cytotoxic and proinflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Beneficial to the tumor-bearing host (TBH) when released by tumor-proximal M phi s, NO and TNF-alpha suppress lymphoproliferation and fail to impart antitumor activity when expressed in tumor-distal compartments. We report that taxol differentially regulated normal host and TBH M phi production of the immunosuppressive molecule NO by tumor-distal M phi populations. In response to IFN-gamma-priming and taxol triggering, TBH M phi s increase their production of NO as compared to resting M phi s; however, unlike normal host M phi s, taxol-induced TBH M phi NO production was significantly suboptimal. Modulation of TBH M phi NO production in tumor-distal compartments may alleviate M phi-mediated suppression of T-cell proliferative responses, yet promote sufficient NO production by tumor-associated M phi s to affect cytotoxicity. Collectively, these data leave implications for immunotherapeutic activities by the anticancer drug taxol.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fibrossarcoma/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Óxido Nítrico/biossíntese , Paclitaxel/farmacologia , Animais , Antineoplásicos/farmacologia , Fibrossarcoma/tratamento farmacológico , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microtúbulos/efeitos dos fármacos , Transplante de Neoplasias , Proteínas Recombinantes , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos
7.
Immunol Invest ; 23(6-7): 457-72, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7851963

RESUMO

Macrophages (M phi)3 function by a two-step process that includes priming (induction of cytokine and enzyme mRNA) and activation (production of effector molecules). The initial steps in M phi priming involve the expression of certain proto-oncogenes that regulate expression of other genes. Because tumor growth primes M phi to produce several suppressor monokines, we determined if cancer induced M phi expression of these proto-oncogenes. Unstimulated peritoneal M phi from tumor-bearing hosts (TBH) constitutively expressed the proto-oncogenes c-fms, c-fos, c-myc, and c-myb, whereas normal host (NH) M phi had little or no expression of these proto-oncogenes. When M phi were given a 24-h adherence priming stimulus, NH M phi expressed c-fms and c-fos at levels equivalent to TBH M phi constitutive expression. Adherence had little or no effect on c-fms and c-fos expression in TBH M phi or on NH and TBH M phi c-myc expression. c-myb expression was not induced in NH M phi during adherence and was strongly decreased in TBH M phi. Activation with a 1-h lipopolysaccharide-treatment increased NH and TBH M phi expression of c-fms, c-fos, and c-myc, with higher expression of these proto-oncogenes in TBH M phi. Activation failed to induce c-myb expression in NH M phi and completely inhibited expression in TBH M phi. Because c-fms, c-fos, and c-myc are normally expressed early during M phi activation, our results suggest that tumor growth primes M phi by inducing expression of these proto-oncogenes. c-myb is expressed in immature M phi and is downregulated during M phi activation. These observations explain why NH M phi expression of c-myb was not induced and are consistent with reports that suggest TBH M phi have not reached full developmental maturity. The induction of M phi proto-oncogene expression during cancer may put M phi in a primed state, which leads to earlier and stronger production of adverse suppressor and cytotoxic molecules.


Assuntos
Fibrossarcoma/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Peritoneais/imunologia , Proteínas Proto-Oncogênicas/biossíntese , Proto-Oncogenes/genética , Animais , Fibrossarcoma/patologia , Expressão Gênica , Genes fms/genética , Genes fos/genética , Genes myc/genética , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myb , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
8.
J Immunol ; 153(4): 1674-86, 1994 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-8046239

RESUMO

In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.


Assuntos
Dinoprostona/fisiologia , Interleucina-10/fisiologia , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Sarcoma Experimental/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citotoxicidade Imunológica , Imunidade Celular , Imunossupressores , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Linfócitos T/imunologia
9.
Cell Immunol ; 154(1): 342-57, 1994 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-8131207

RESUMO

Tumor growth induces phenotypic and functional changes among splenic T cells and macrophages (M phi) that contribute to the immunosuppression observed in tumor-bearing hosts (TBH). These changes partly arise through alterations in immune cell production of and responsiveness to cytokines. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important T cell- and M phi-derived cytokine that is produced during normal host immunogenic challenge, but it's involvement during cancer is poorly defined. In contrast, interleukin-10 (IL-10) is an inhibitory cytokine that is produced by immune cells as a deactivation factor. IL-10 can disrupt GM-CSF synthesis and may be associated with tumor-induced changes in cytokine synthesis. We determined if tumor growth alters T-cell and M phi synthesis of and responsiveness to GM-CSF, and if these alterations occur because tumor growth heightens immune cell sensitivity to IL-10. Tumor growth significantly decreased T-cell synthesis of GM-CSF during activation by concanavalin A, and TBH T cells were more susceptible to GM-CSF synthesis inhibition by IL-10 than their normal host (NH) counterparts. This suppression was observed using both unseparated splenic lymphocyte preparations and purified CD4+ and CD8+ T cells. Similarly, TBH M phi (both splenic and peritoneal) produced less GM-CSF than NH M phi during activation by lipopolysaccharide. Tumor growth also altered major histocompatibility complex (MHC) class II- M phi GM-CSF synthesis. TBH M phi were more susceptible to GM-CSF synthesis inhibition by IL-10 than their NH counterparts. Although TBH T cells demonstrate less proliferation than NH T cells during activation, tumor growth did not compromise T-cell responsiveness to GM-CSF. However, tumor growth did increase TBH T-cell susceptibility to inhibition of proliferation by IL-10. Tumor growth suppressed M phi responsiveness to GM-CSF, and IL-10 further decreased M phi responsiveness to GM-CSF. Collectively, these results suggest that T cell and M phi production of and responsiveness to GM-CSF is disrupted during tumor growth, and that TBH T cells and M phi are more susceptible to the suppressor activity of IL-10 than their NH counterparts.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interleucina-10/farmacologia , Macrófagos/metabolismo , Sarcoma Experimental/metabolismo , Linfócitos T/metabolismo , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/efeitos dos fármacos
10.
Oncol Res ; 6(4-5): 219-28, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7841545

RESUMO

Tumor growth causes macrophages (M phi) to suppress T-cell proliferation by inducing M phi production of soluble suppressor molecules. Because interleukin (IL)-10 inhibits production of most M phi-derived molecules, we investigated the effects of IL-10 on murine M phi suppressor function during tumor growth. When acting as accessory cells during alloantigen-induced CD4+ T-cell proliferation, syngeneic tumor-bearing host (TBH) peritoneal M phi suppressed normal host (NH) T-cell proliferation more than their normal counterparts. Exogenous IL-10 suppressed alloantigen-stimulated CD4+ T-cell proliferation in the absence of accessory M phi, but it blocked TBH M phi-mediated suppression. IL-10 pretreatment of M phi reversed suppression mediated by TBH M phi but did not affect NH M phi activity. Supernatant transfer experiments showed that IL-10 blocked TBH M phi-mediated suppression by inhibiting soluble suppressor molecule production. Activated TBH M phi produced greater quantities of the suppressor molecules tumor necrosis factor-alpha, nitric oxide, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor than NH M phi did. Exogenous IL-10 reduced production of these molecules by TBH M phi more than by NH M phi. Activated TBH M phi produced more IL-10 than NH M phi, suggesting that endogenous IL-10 contributes to increased TBH M phi sensitivity to exogenous IL-10's inhibitory action. The antibody-mediated neutralization of endogenous IL-10 activity relieved NH, but not TBH, M phi-mediated suppression of T-cell proliferation. This result supports the idea that TBH M phi are more sensitive to the inhibitory action of IL-10 on suppressor molecule production. IL-10 is known to inhibit M phi antigen-presenting cell-dependent helper T-cell proliferation. We report here that IL-10 restores TBH helper T-cell functions by blocking accessory M phi production of inhibitory molecules. This restoration suggests that IL-10's M phi deactivating activity provides an upregulatory role in immunocompromised individuals where suppressor M phi are abundant.


Assuntos
Fibrossarcoma/imunologia , Interleucina-10/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Divisão Celular/fisiologia , Dinoprostona/biossíntese , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Tolerância Imunológica , Interleucina-10/biossíntese , Isoantígenos/imunologia , Isoantígenos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Óxido Nítrico/biossíntese , Sensibilidade e Especificidade , Estimulação Química , Fator de Necrose Tumoral alfa/biossíntese
11.
Scand J Immunol ; 39(1): 31-8, 1994 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-7904773

RESUMO

Normal immune homeostasis is regulated partly by a small population of CD4+ T cells that react to autologous major histocompatibility complex class-II molecules on self-cells. Decreased autoreactive T-cell responses are associated with cancer. Tumour growth causes syngeneic macrophages (M phi) to suppress autoreactive T-cell proliferation by decreasing M phi class-II expression and increasing M phi production of the suppressor molecule prostaglandin E2 (PGE2). Because interferon-gamma (IFN-gamma) is a potent M phi activation molecule which regulates both M phi PGE2 and class-II expression, the effects of IFN-gamma on tumour-induced suppression of autoreactive T-cell proliferation were investigated. Exogenous IFN-gamma increased normal host (NH) CD4+ autoreactive T-cell proliferation stimulated by syngeneic NH M phi but decreased proliferation stimulated by tumour-bearing host (TBH) M phi. Antibody (Ab) neutralization of endogenous IFN-gamma activity reduced TBH M phi-mediated suppression. Kinetic studies showed that endogenous IFN-gamma suppressor activity was not exclusive during T-cell activation. Indomethacin treatment blocked IFN-gamma-induced suppression in TBH M phi-T cell cultures. TBH M phi-T cell cultures contained significantly more PGE2 than those containing NH M phi. Exogenous IFN-gamma increased early PGE2 production in TBH M phi cultures but decreased production in NH M phi cultures. The Ab-mediated neutralization of endogenous transforming growth factor-beta or tumour necrosis factor-alpha reduced TBH M phi-mediated suppression and blocked IFN-gamma-induced suppression. Short-term treatment of M phi with IFN-gamma before their addition to T cells caused TBH M phi to stimulate T-cell proliferation, which suggests that early suppressor molecule production by TBH M phi inhibits synthesis or activity of IFN-gamma-induced stimulatory monokines. These results show that tumour growth causes M phi to suppress autoreactive T-cell responses by allowing IFN-gamma to induce M phi suppressor molecules, which block production or activity of stimulatory monokines.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interferon gama/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Animais , Células Cultivadas , Dinoprostona/imunologia , Terapia de Imunossupressão , Ativação de Macrófagos/imunologia , Masculino , Metilcolantreno , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/induzido quimicamente , Proteínas Recombinantes , Baço/imunologia
12.
Immunol Invest ; 22(6-7): 463-76, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8262568

RESUMO

Tumor-induced changes in macrophage (M phi)2 accessory activities significantly suppress T-cell recognition of allogeneic and syngeneic major histocompatibility complex (MHC) class II molecules. Because these changes are often associated with altered responses to stimulatory and inhibitory cytokines, we investigated the possibility that tumor growth alters the contribution of a macrophage regulatory cytokine, macrophage colony-stimulating factor (M-CSF), during reactivity against allogeneic and syngeneic MHC class II molecules. T-cell reactivity against allogeneic MHC class II molecules was significantly suppressed by tumor-bearing host (TBH) M phi in the presence of M-CSF. M-CSF-induced suppression was independent of TBH M phi prostaglandin E2 (PGE2) synthesis. T-cell reactivity against syngeneic MHC class II molecules increased in the presence of M-CSF when normal host (NH) M phi served as the source of syngeneic molecules. However, T-cell reactivity against syngeneic MHC class II molecules in the presence of M-CSF did not change when TBH M phi served as stimulator/accessory cells. Although T-cell reactivity against NH syngeneic MHC class II molecules was additively increased by M-CSF and indomethacin (a PGE2 synthesis inhibitor) treatment, reactivity against TBH syngeneic MHC class II molecules increased solely through PGE2 synthesis inhibition. Admixtures of both NH and TBH M phi in the absence or presence of M-CSF suggest that tumor-induced suppression was not strictly due to decreased expression of MHC class II molecules. Collectively, these data suggest that TBH M phi are partly suppressive through altered responsiveness to M-CSF.


Assuntos
Fibrossarcoma/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Isoantígenos/imunologia , Fator Estimulador de Colônias de Macrófagos/imunologia , Macrófagos/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Animais , Autoantígenos/imunologia , Indometacina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia , Células Tumorais Cultivadas
13.
Immunobiology ; 188(4-5): 430-45, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8244447

RESUMO

T cells can react to self-cells bearing the syngenic major histocompatibility complex class II molecule Ia. Decreased autoreactive T cell responses are associated with cancer. Tumor growth causes syngeneic macrophages (M phi) to suppress autoreactive T cell proliferation by decreasing M phi Ia expression and increasing M phi production of the suppressor molecule prostaglandin E2 (PGE2). Because M phi produce tumor necrosis factor-alpha (TNF-alpha) during cancer, and TNF-alpha stimulates M phi PGE2 synthesis, we determined if TNF-alpha mediates tumor-induced suppression of autoreactive T cell proliferation stimulated by syngeneic M phi. We showed that tumor growth increases TNF-alpha production because tumor-bearing host (TBH) M phi synthesized more TNF-alpha than normal host (NH) M phi when cultured with lipopolysaccharide. Exogenous TNF-alpha increased NH CD4+ autoreactive T cell proliferation stimulated by syngeneic NH M phi but not by TBH M phi. When endogenous TNF-alpha activity was neutralized by anti-TNF-alpha antibody addition, T cell proliferation decreased when stimulated by NH M phi but increased when stimulated by TBH M phi. Kinetic studies showed that TNF-alpha affected M phi-stimulated T cell proliferation during the first few hours (4h) of the 96 h culture time. Indomethacin-treatment allowed TNF-alpha to increase T cell proliferation stimulated by TBH M phi. A PGE2-specific enzyme-linked immunosorbent assay showed that TBH M phi T cell cultures contained significantly more PGE2 than those containing NH M phi, and that exogenous TNF-alpha increased PGE2 production in TBH M phi cultures more than in NH M phi cultures. Short-term (4h) pretreatment of M phi with TNF-alpha increased T cell proliferation stimulated by NH, but not TBH, M phi. However, long-term (16 h) TNF-alpha pretreatment reversed TBH M phi-mediated suppression, suggesting that early suppressor molecular production inhibits synthesis or activity of TNF-alpha-induced stimulatory monokines. Although TNF-alpha is known to increase T cell proliferation, these results show that the tumor-induced increase in M phi TNF-alpha synthesis suppress autoreactive T cell proliferation, which is mediated by PGE2 production.


Assuntos
Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Autoimunidade , Dinoprostona/biossíntese , Tolerância Imunológica , Técnicas In Vitro , Ativação Linfocitária , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monocinas/biossíntese
14.
J Leukoc Biol ; 54(2): 152-60, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8360594

RESUMO

Tumors down-regulate T cell responses partly by increasing macrophage (m phi) production of the suppressive molecule prostaglandin E2 (PGE2). Because tumor growth increases m phi tumor necrosis factor alpha (TNF-alpha) production and TNF-alpha stimulates m phi PGE2 synthesis, we examined the contribution of TNF-alpha to fibrosarcoma-induced m phi-mediated suppression of alloreactive CD4+ T cell proliferation. We showed that tumor-bearing host (TBH) m phi s express high levels of TNF-alpha mRNA, which leads to increased lipopolysaccharide-induced TNF-alpha production. Tumor cells were directly involved in m phi TNF-alpha synthesis because fibrosarcoma cells induced normal host (NH) m phi s to produce TNF-alpha. Addition of TBH m phi s to allogeneic mixed lymphocyte reaction (MLR) cultures suppressed CD4+ T cell proliferation more than NH m phi s. The neutralization of endogenous TNF-alpha activity with anti-TNF-alpha antibody (Ab) treatment reversed TBH, but not NH, m phi-mediated suppression. Conversely, exogenous TNF-alpha increased NH or TBH m phi-mediated suppression but stimulated T cell proliferation without m phi s. Kinetic treatment of MLR cultures with anti-TNF-alpha Ab or TNF-alpha showed that TNF-alpha production and activity occurred at the beginning of T cell proliferation. When arachidonic acid metabolite synthesis was inhibited, TNF-alpha-induced suppression was blocked in NH m phi-containing cultures and completely reversed in TBH m phi-containing cultures. A PGE2-specific enzyme-linked immunosorbent assay showed that TNF-alpha addition increased PGE2 production in NH m phi-containing cultures to that of TBH m phi-containing cultures. Exogenous PGE2 did not affect the TNF-alpha enhancement of T cell proliferation without m phi s. Therefore, suppression induced by TNF-alpha was caused by increased m phi PGE2 production and not by TNF-alpha in concert with PGE2. Even though TNF-alpha is known to enhance lymphocyte proliferation, we show that in the presence of m phi s, the main TNF-alpha producers, TNF-alpha suppresses T cell proliferation. Perhaps increased TNF-alpha production during pathological states, such as cancer, triggers the initial stages of suppression.


Assuntos
Fibrossarcoma/imunologia , Tolerância Imunológica/fisiologia , Macrófagos/fisiologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Dinoprostona/biossíntese , Fibrossarcoma/patologia , Ativação Linfocitária/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Fator de Necrose Tumoral alfa/fisiologia
15.
Mol Immunol ; 30(10): 911-20, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8341283

RESUMO

Class II MHC protein expression in macrophages (M phi) is reduced during tumor growth. Because regulation of class II MHC proteins occurs during transcription, tumor growth may suppress class II MHC protein expression by suppressing mRNA. The decrease in class II mRNA may result from (i) a decrease in M phi responsiveness to an inducing agent, such as interferon-gamma (IFN-gamma), or (ii) an increase in M phi sensitivity to suppressing agents, such as prostaglandin E2 (PGE2). To determine how tumors induce suppression of class II mRNA, M phi were cultured in the presence of IFN-gamma with or without other factors, and Northern blot analyses were performed. Unstimulated normal host (NH) or tumor-bearing host (TBH) M phi do not express detectable class II mRNA. The addition of IFN-gamma induces class II mRNA expression in NH and TBH M phi, but class II mRNA expression is significantly lower in TBH M phi. Kinetic studies suggested that NH M phi class II mRNA is induced faster and in greater amounts than TBH M phi class II mRNA. There is a decrease in M phi class II mRNA stability during tumor growth that may account for the decreased induction by IFN-gamma. Lipopolysaccharide (LPS) suppresses class II mRNA induction in both NH and TBH IFN-gamma-treated M phi, but TBH M phi are more sensitive to its suppression. PGE2 and tumor-necrosis factor-alpha (TNF-alpha), two factors produced by LPS-stimulated M phi, were tested for their ability to modulate class II mRNA expression in NH and TBH IFN-gamma-treated M phi. PGE2 suppressed class II mRNA expression in both NH and TBH M phi. The addition of TNF-alpha to IFN-gamma-treated M phi suppressed class II mRNA in NH M phi but, surprisingly, had an additive effect on IFN-gamma-induced class II mRNA expression. TNF-alpha did not induce class II mRNA expression in TBH M phi in the absence of IFN-gamma. The cause of the reduced class II mRNA expression during tumor growth is a decreased response to IFN-gamma and an increased sensitivity to PGE2. This change may cause the observed suppression mediated by TBH M phi.


Assuntos
Fibrossarcoma/imunologia , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/biossíntese , Macrófagos/imunologia , RNA Mensageiro/biossíntese , Animais , Northern Blotting , Células Cultivadas , Dinoprostona/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/genética , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Transcrição Gênica , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/farmacologia
16.
J Leukoc Biol ; 53(5): 550-8, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8388910

RESUMO

Although tumor growth enhances macrophage (m phi) cytotoxic activity by increasing their tumor necrosis factor-alpha (TNF-alpha) production, increased prostaglandin E2 (PGE2) synthesis reduces most immune responses during tumor growth. Macrophages that do not express major histocompatibility complex class II molecules (Ia- m phi) are the predominant suppressor and cytotoxic population and are more abundant in tumor-bearing hosts (TBHs). This study determined if TBH Ia- m phi s are the major population producing TNF-alpha and PGE2 and if these molecules affect Ia- m phi-mediated suppression of alloantigen-stimulated T cell proliferation. Normal host (NH) and TBH splenic Ia(+)-depleted (Ia-) m phi s synthesized more TNF-alpha than their respective whole populations (WPs) when cultured with lipopolysaccharide and interferon-gamma. TBH Ia- m phi s produced the most TNF-alpha. Northern blot analyses showed that Ia- m phi s had higher amounts of TNF-alpha mRNA expression than their respective WP, and TBH Ia- m phi s expressed the highest amounts of TNF-alpha mRNA. When WP and Ia- NH and TBH m phi s were added to alloantigen-stimulated T cells, suppression of T cell proliferation mediated by Ia- m phi s was greater than by their respective WP. TBH Ia- m phi s were most suppressive. The blockage of PGE2 production reduced suppression mediated by TBH Ia- m phi s more than by all other m phi populations. A PGE2-specific enzyme-linked immunosorbent assay showed that PGE2 production was greater in Ia- m phi- than in WP m phi-containing cultures and greatest in cultures containing TBH Ia- m phi s. Because TNF-alpha enhances T cell responses, its effects on Ia- m phi PGE2-mediated suppression was determined. When TNF-alpha was added to m phi-containing T cell cultures, TNF-alpha directly stimulated NH, but not TBH, Ia- m phi s, which enhanced T cell proliferation. However, inhibiting PGE2 production allowed TNF-alpha to stimulate T cell proliferation in TBH Ia- m phi-containing cultures. Collectively, these data show that Ia- m phi s are the major TNF-alpha- and PGE2-producing cells and that these molecules are partly responsible for the tumor-induced increase in m phi-mediated cytotoxicity and suppression, respectively. TNF-alpha not only mediates cytotoxicity but also counteracts Ia- m phi PGE2-mediated suppression. Although tumor growth increases Ia- m phi TNF-alpha production, enhanced PGE2 production blocks TNF-alpha's stimulatory action on Ia- m phi s, which favors their suppressor function during tumor growth.


Assuntos
Dinoprostona/metabolismo , Fibrossarcoma/patologia , Antígenos de Histocompatibilidade Classe II/análise , Tolerância Imunológica , Macrófagos/imunologia , Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Northern Blotting , Divisão Celular/efeitos dos fármacos , Dinoprostona/fisiologia , Fibrossarcoma/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologia , Fator de Necrose Tumoral alfa/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
17.
Immunopharmacology ; 25(3): 215-27, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8354638

RESUMO

Tumor growth enhances macrophage (M phi) suppressor activity by causing M phi to increase synthesis of inhibitory molecules such as prostaglandin E2 (PGE2) or decreasing their expression of up-regulatory molecules such as the class II MHC protein Ia. Although these tumor-induced changes are correlated, it is unknown whether tumor-bearing host (TBH) Ia- M phi become more suppressive by increasing their PGE2 synthesis. To assess the role of PGE2 in tumor-induced Ia- M phi-mediated suppression of CD4+ T-cell alloreactivity, unseparated (Ia(+)-enriched) or Ia(+)-depleted (Ia-) populations of murine normal host (NH) or TBH splenic M phi were added to mixed lymphocyte reaction (MLR) cultures. NH or TBH Ia- M phi were significantly more suppressive than their respective unseparated populations, and TBH Ia- M phi were more suppressive than their NH counterparts. When PGE2 production was blocked with indomethacin, TBH Ia- M phi-mediated suppression was reduced more than suppression mediated by all other M phi populations. A PGE2-specific ELISA showed more PGE2 in Ia- M phi-containing cultures than in those with whole M phi and more in cultures containing TBH Ia- M phi than in their NH counterparts. Because interferon-gamma (IFN-gamma) is a potent M phi activation molecule that regulates both Ia expression and PGE2 production, the effects of IFN-gamma on tumor-induced Ia- M phi-mediated suppression were investigated. Exogenous IFN-gamma reduced suppression mediated by all M phi populations except NH unseparated M phi. IFN-gamma suppressed alloreactivity without M phi or with NH unseparated M phi. Suppression mediated by NH or TBH Ia-, and TBH unseparated M phi was also reduced when M phi were pre-incubated with IFN-gamma before their addition to MLR cultures. IFN-gamma addition did not block Ia- M phi-mediated suppression by decreasing M phi PGE2 production. In fact, IFN-gamma addition increased PGE2 production two-fold in MLR cultures. However, IFN-gamma partly reduced suppression mediated by exogenous PGE2 added to M phi-depleted cultures. Cytofluorometric analysis showed that IFN-gamma increased the percentage of Ia+ M phi in NH and TBH Ia- M phi populations. Blocking TNF-alpha activity with anti-TNF-alpha antibodies caused IFN-gamma to suppress alloreactivity in all M phi-added cultures. Collectively, these data show that tumor-induced suppression mediated by Ia- M phi is caused by increased PGE2 synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)


Assuntos
Dinoprostona/fisiologia , Antígenos de Histocompatibilidade Classe II/fisiologia , Tolerância Imunológica/fisiologia , Interferon gama/fisiologia , Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Dinoprostona/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/fisiologia
18.
Immunol Invest ; 22(3): 169-87, 1993 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8099569

RESUMO

Tumor growth changes the functions and phenotypes of macrophages (M phi) and T cells. Suppression of CD4+ T cell autoresponses during tumor growth was contributed primarily by M phi. Tumor-induced alterations in the abilities of these cells to mediate autorecognition were assessed through syngeneic mixed lymphocyte reaction (SMLR) assays. Tumor-bearing host (TBH) M phi were significantly more suppressive (60-90%) than normal host (NH) M phi, and this suppression was caused partly by reduced Ia expression. TBH Ia- M phi were significantly more suppressive (50-80%) than their NH counterparts. The suppression mechanism was controlled partly by prostaglandin E2 (PGE2), because treating cultures with indomethacin and titrated NH and TBH Ia- M phi led to increased T-cell responsiveness, although responsiveness never reached levels of assays containing unseparated M phi. Blocking studies using anti-interferon-gamma (anti-IFN-gamma) monoclonal antibodies (mAb), anti-interleukin 4 (anti-IL-4) mAb, and indomethacin suggested that IFN-gamma, IL-4, and PGE2 contributed to tumor-induced M phi-mediated suppression. Our results suggested that a quantitative shift in M phi phenotype and a qualitative shift in M phi function in addition to differences in cytokine-directed accessory activities are partly responsible for tumor-induced suppression CD4+ T cell autoresponses.


Assuntos
Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Dinoprostona/fisiologia , Fibrossarcoma/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Síndromes de Imunodeficiência/etiologia , Interferon gama/fisiologia , Interleucina-4/fisiologia , Macrófagos/fisiologia , Animais , Células Apresentadoras de Antígenos/imunologia , Fibrossarcoma/complicações , Fibrossarcoma/patologia , Síndromes de Imunodeficiência/patologia , Teste de Cultura Mista de Linfócitos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Fenótipo
19.
Cancer Lett ; 69(1): 67-74, 1993 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-8481895

RESUMO

The galactose-specific animal lectin, Mac-2, has been identified in macrophage (M phi) membrane, cytoplasmic, and nuclear fractions. Flow cytometric analyses showed that there is a decrease in membrane Mac-2 during tumor growth. After 24-h adherence there was an increase in the number of normal host (NH) and tumor-bearing host (TBH) Mac-2+ M phi. Immunoblot analyses of NH and TBH M phi identified changes in the subcellular localization of Mac-2. The increase in nuclear Mac-2 during tumor growth, and after prolonged adherence of NH and TBH M phi, correlates with an increase in M phi entering the late G1 phases of the cell cycle. Northern blot analyses showed an increase in Mac-2 mRNA during tumor growth, and an increase in NH and TBH M phi after 24-h adherence. Tumor growth is able to manipulate the immune system through M phi by causing a down-regulation in membrane Mac-2 and an up-regulation in intracellular Mac-2. NH and TBH M phi respond to adherence by expressing increased membrane and nuclear Mac-2, but TBH M phi response is lower.


Assuntos
Antígenos de Diferenciação/análise , Fibrossarcoma/patologia , Macrófagos/química , Animais , Adesão Celular , Divisão Celular , Galectina 3 , Macrófagos/patologia , Masculino , Metilcolantreno , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , RNA Mensageiro/análise
20.
J Leukoc Biol ; 52(6): 661-9, 1992 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-1464737

RESUMO

Quantitative and qualitative tumor-associated changes in T cell phenotype and function were identified in CD8+ T cells. Tumor growth changed splenic CD4+/CD8+ T cell ratios and induced the appearance of more cells with the CD8+ phenotype. In comparison to equal concentrations of normal host (NH) counterparts, tumor-bearing host (TBH) CD8+ T cells were highly suppressive to allorecognition and autorecognition. Suppression was not due to quantitative reductions in CD4+ T cells, although minor qualitative differences were observed. Suppression appeared to be mediated partly by prostaglandin E2 (PGE2). Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) contributed to TBH CD8+ T cell-mediated suppression. Blocking studies using monoclonal antibodies (mAb) in conjunction with indomethacin suggested that cytokine networks involving IFN-gamma, IL-4, and PGE2 were disrupted during tumor growth and promoted TBH CD8+ T cell suppression. Alloresponses and autoresponses were significantly suppressed when TBH CD8+ T cells mediated these reactions simultaneously with TBH Ia- macrophages. Inhibition of PGE2 production was unable to reverse the additive suppression caused by these two cell types. These results collectively suggest that tumor-induced changes in CD8+ T cells lead to suppressed allo-recognition and autorecognition through both soluble mediator molecules and cellular interactions.


Assuntos
Antígenos CD8/imunologia , Fibrossarcoma/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Macrófagos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD4/imunologia , Células Cultivadas , Dinoprostona/fisiologia , Fibrossarcoma/induzido quimicamente , Fibrossarcoma/patologia , Citometria de Fluxo , Indometacina/farmacologia , Interferon gama/fisiologia , Interleucina-4/imunologia , Interleucina-4/fisiologia , Masculino , Metilcolantreno , Camundongos , Camundongos Endogâmicos BALB C , Valores de Referência , Linfócitos T/efeitos dos fármacos
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