Assuntos
Transportadores de Ânions Orgânicos , Osteoartropatia Hipertrófica Primária , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Povo Asiático/genética , População do Leste Asiático , Japão , Transportadores de Ânions Orgânicos/genética , Osteoartropatia Hipertrófica Primária/genética , Osteoartropatia Hipertrófica Primária/diagnósticoRESUMO
A 73-year-old man had sigmoidectomy for sigmoid colon cancer in December 2001. Although he was followed regularly with chemotherapy, his serum carcinoembryonic antigen (CEA) increased on August 2002. Abdominal computed tomography and magnetic resonance imaging showed a right adrenal mass and no other abnormality. The preoperative diagnosis was a solitary adrenal metastasis from sigmoid colon cancer; the lesion was removed in September 2002. On pathology, adrenal metastasis was confirmed. Although the patient's serum CEA normalized soon thereafter, 12 months after adrenalectomy, the CEA again increased; the patient had local recurrence of the resected adrenal lesion and liver metastasis. Therefore, the patient was given systemic chemotherapy, but his condition deteriorated, and he died 38 months after adrenalectomy. Adrenal metastasis from colorectal cancer is not unusual; however, a solitary metastasis is rarely found and resected surgically. As surgical treatment of the metastatic lesion could improve patients' prognosis to some extent if it is detected early, the possibility of adrenal metastasis should be kept in mind when colorectal cancer patients are followed.
Assuntos
Adenocarcinoma/secundário , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias do Colo Sigmoide/patologia , Adenocarcinoma/cirurgia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia , Idoso , Antígeno Carcinoembrionário/sangue , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Neoplasias do Colo Sigmoide/cirurgiaAssuntos
Artrite Reumatoide/complicações , Histiocitose/complicações , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Artrite Reumatoide/patologia , Biomarcadores/análise , Histiocitose/patologia , Humanos , Imuno-Histoquímica , Vasos Linfáticos/patologia , Masculino , Pessoa de Meia-IdadeAssuntos
Transportadores de Cassetes de Ligação de ATP/genética , Povo Asiático/genética , Predisposição Genética para Doença , Pênfigo/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , HumanosRESUMO
We analysed a polymorphism of the interleukin (IL)-1 receptor antagonist (IL1RN) gene in 93 Japanese patients with palmoplantar pustulosis (PPP). None of the IL1RN alleles was significantly increased in the patients compared with controls. Because PPP has been reported to be associated with the tumour necrosis factor (TNF) region, we examined the association between the TNF and IL1RN genes. There was a difference in IL1RN*2 positivity between patients with and without the AA genotype of the TNF gene. In contrast, such a difference was not found in controls. These data indicate a possible epistatic effect between TNF and IL1RN linked genes for susceptibility to the pathogenesis of PPP.
Assuntos
Psoríase/genética , Receptores de Interleucina-1/antagonistas & inibidores , Sialoglicoproteínas/genética , Adulto , Idoso , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Japão , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Psoríase/metabolismo , Sialoglicoproteínas/metabolismoRESUMO
The incidence of distant metastases is higher in the tumours with low oxygen pressure than in those with high oxygen pressure. It is well known that hypoxia induces the transcription of various genes involved in angiogenesis and anaerobic metabolism necessary for the growth of tumour cells in vivo, suggesting that hypoxia may also induce the transcription of metastasis-associated genes. We sought to identify the metastasis-associated genes differentially expressed in tumour cells under hypoxic conditions with the use of a DNA microarray system. We found that hypoxia enhanced the expression of autocrine motility factor mRNA in various cancer cells and also enhanced the random motility of pancreatic cancer cells. Autocrine motility factor inhibitors abrogated the increase of motility under hypoxic conditions. In order to explore the roles of hypoxia-inducible factor-1alpha, we established hypoxia-inducible factor-1alpha-transfectants and dominant negative hypoxia-inducible factor-1alpha-transfectants. Transfection with hypoxia-inducible factor-1alpha and dominant-negative hypoxia-inducible factor-1alpha enhanced and suppressed the expression of autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA and the random motility, respectively. These results suggest that hypoxia may promote the metastatic potential of cancer cells through the enhanced autocrine motility factor/phosphohexase isomerase/neuroleukin mRNA expression and that the disruption of the hypoxia-inducible factor-1 pathway may be an effective treatment for metastasis.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Glucose-6-Fosfato Isomerase/genética , Hipóxia/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição , Northern Blotting , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Dominantes , Glucose-6-Fosfato Isomerase/biossíntese , Sequências Hélice-Alça-Hélice , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Pancreáticas/genética , RNA Mensageiro/metabolismo , Receptores do Fator Autócrino de Motilidade , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Transfecção , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases , Regulação para CimaRESUMO
BACKGROUND: There have been only limited reports on major histocompatibility complex class I antigens in pemphigus. OBJECTIVES: To characterize HLA-A, B and C class I alleles by genotyping in Japanese patients with pemphigus, and to analyse the possible association of class I alleles with disease susceptibility within a relatively homogeneous ethnic population. METHODS: Alleles of HLA-A, B and C, and DRB1 and DQB1 loci were fully determined in 51 Japanese patients with pemphigus. RESULTS: Asian alleles of the HLA-B15 family, including the allele B*1507, which was significantly increased in comparison with normal controls, were prevalent in patients with pemphigus vulgaris (PV). The prevalence of B*15 alleles in patients with PV was not due to linkage disequilibrium with HLA-DR4 or DR14 alleles, which have been shown to confer strong susceptibility to PV across racial barriers. In contrast to the unique distribution of the HLA-B alleles, HLA-A and C alleles were unremarkable in patients with PV when compared with normal control subjects. CONCLUSIONS: These results suggest that there may be differences in the ethnic concentrations of different HLA-B alleles in patients with PV.
Assuntos
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Pênfigo/genética , Alelos , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Genótipo , Humanos , Desequilíbrio de LigaçãoRESUMO
Skin metastasis of internal carcinoma is a rare situation and its risk is reported as 0.7-9%. The site of skin metastasis is more popular at upper part of the body such as neck and face. We report a case of perineal and penile skin metastases of gastric carcinoma associated with prostatic carcinoma. A 72-year-old man, who underwent total gastrectomy for gastric carcinoma 4 years ago, was found to have sclerotic change at perineal and penile skin. As his serum PSA level was 10.6 ng/ml, transrectal prostate biopsy and penile skin biopsy were performed. The prostate tissue pathologically demonstrated moderately differentiated adenocarcinoma and it was positive for both anti-PSA and anti-CEA antibody by immunohistochemical staining. The skin tissue was found to be infiltrative adenocarcinoma, negative for PSA and positive for CEA, which was compatible with the primary gastric carcinoma specimen. The patient had been treated for 7 months with administration of Doxifluridine and injection of LH-RH agonist, but died for progression of gastric carcinoma. A risk of skin metastasis of gastric carcinoma is reported as 6%, however, its metastasis to perineal and penile skin is the first case reported in the literature.
Assuntos
Adenocarcinoma/secundário , Neoplasias Primárias Múltiplas , Neoplasias da Próstata/complicações , Neoplasias Cutâneas/secundário , Neoplasias Gástricas/patologia , Idoso , Humanos , Masculino , Pênis , Neoplasias Gástricas/cirurgiaRESUMO
Hypovasculature is an outstanding characteristic of pancreatic cancers in imaging diagnosis, suggesting that blood supply is poor in pancreatic cancer tissues. Despite poor blood supply, pancreatic cancer cells survive and proliferate in severe hypoxia and nutrient deprivation. To demonstrate how pancreatic cancer cells adapt themselves to hypoxia and nutrient deprivation, we investigated the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) protein and HIF-1-inducible genes in human pancreatic cancer cell lines in comparison with other cancer cell lines. We found that HIF-1alpha protein was constitutively expressed in 15 of 20 pancreatic cancer cell lines (75%) but in none of other cancer cell lines tested in this study. The cells with constitutive expression of HIF-1alpha were more resistant to apoptosis induced by hypoxia and glucose deprivation than those without constitutive expression of HIF-1alpha. Transfection with HIF-1alpha transformed the latter cells resistant to apoptosis and increased in vivo tumorigenicity. Furthermore, anaerobic metabolism-associated genes, Glut1 and aldolase A, were more highly expressed in the cells with constitutive expression of HIF-1alpha than in the cells without it. These results suggest that constitutive expression of HIF-1alpha contributes to the survival and proliferation of pancreatic cancer cells in hypoxia and glucose deprivation through the activation of anaerobic metabolism.
Assuntos
Apoptose/fisiologia , Carcinoma Ductal Pancreático/patologia , Proteínas de Ligação a DNA/biossíntese , Glucose/deficiência , Proteínas Nucleares/biossíntese , Neoplasias Pancreáticas/patologia , Fatores de Transcrição , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Divisão Celular/fisiologia , Hipóxia Celular/fisiologia , Sobrevivência Celular/fisiologia , Proteínas de Ligação a DNA/genética , Frutose-Bifosfato Aldolase/biossíntese , Frutose-Bifosfato Aldolase/genética , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1 , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Camundongos , Camundongos Nus , Proteínas de Transporte de Monossacarídeos/biossíntese , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Nucleares/genética , Oxigênio/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Transfecção , Células Tumorais CultivadasRESUMO
The deleterious effects of ultraviolet B radiation (UVR) on cutaneous immunity are mediated in part by cytokines released from cutaneous cells following radiation exposure. On the one hand, TNF-alpha has been advocated as the primary mediator of failed contact hypersensitivity induction, and, on the other hand, IL-10 has been held responsible for tolerance. While keratinocytes exposed to UVR have been found to produce both TNF-alpha and IL-10, there is reason to question whether these major cellular constituents of the epidermis are the relevant source of immunomodulatory cytokines after UVR. Dermal mast cells also produce TNF-alpha and IL-10, and we have recently reported that mast cell-derived TNF-alpha is required for UVR-induced impairment of CH induction. In this study, we have examined whether mast cells are also a relevant source of IL-10 in UVR-dependent tolerance. We found that (a) UVR fails to induce tolerance in mast cell-deficient mice, and (b) that tolerance occurs if mast cells are triggered to degranulate after ligation of the IgE receptor. Both types of tolerance were neutralized with anti-IL-10 antibodies, are hapten specific, and are associated with regulatory lymphoid cells. We conclude that mast cells are required in UVR-induced tolerance and may be one of the major sources of IL-10 that mediates the tolerance induced by acute, low-dose UVR.
Assuntos
Degranulação Celular , Tolerância Imunológica/imunologia , Mastócitos/imunologia , Cloreto de Picrila/imunologia , Pele/efeitos da radiação , Raios Ultravioleta , Adjuvantes Imunológicos , Animais , Degranulação Celular/imunologia , Degranulação Celular/efeitos da radiação , Dermatite de Contato/imunologia , Liberação de Histamina/imunologia , Imunoglobulina E/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Mastócitos/efeitos da radiação , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Oxazolona/administração & dosagem , Oxazolona/imunologia , Cloreto de Picrila/administração & dosagem , Doses de Radiação , Pele/citologia , Pele/imunologiaRESUMO
We investigated the allelic distributions of single nucleotide polymorphisms (SNPs) of the TNFA, TNFB and IKBL genes, 3 microsatellites within the tumor necrosis factor (TNF) region of HLA locus, and the HLA phenotypes as well as the TLR4 gene in Chromosome 9 in 26 healthy Caucasian volunteers. These individuals were also assessed as ultraviolet B (UVB)-susceptible (S) or UVB-resistant (R). Our results identified 12 UVB-S and 14 UVB-R individuals. Attempts to correlate particular HLA-A, -B, -C, and -DR antigens with the UVB phenotypes failed. Similarly, attempts to correlate SNP at the NcoI-RFLP within intron 1 of the TNFB, IKBL and TLR4 gene with UVB phenotypes also failed. However, microsatellite analyses of TNFa, TNFc, and TNFd markers revealed a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of 5 SNPs of the TNFA promoter region revealed a significant increase in the frequency of the allele B of the TNFA gene (TNFApB) representing the nucleotide A at position -863 and C at position -1031 (P=0.015). Since it is known that TNFa2 and TNFApB is a high TNF-alpha responder, whereas TNFd3 is a TNF-alpha low responder, we propose that the TNF region of HLA contains polymorphic genes that confer susceptibility and resistance to the deleterious effects of UVB radiation on the induction of contact hypersensitivity. This proposal is consistent with previous reports that a unique microsatellite region of the Tnfa gene in mice contains alleles that dictate the UVB-dependent phenotypes in mice, and implicate TNF-alpha as the primary mediator of the immune-damaging effects of UVB radiation.
Assuntos
Dermatite de Contato/genética , Dermatite de Contato/imunologia , Proteínas de Drosophila , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Proteínas Adaptadoras de Transdução de Sinal , Frequência do Gene , Antígenos de Histocompatibilidade Classe II/genética , Teste de Histocompatibilidade , Humanos , Sistema Imunitário/efeitos da radiação , Glicoproteínas de Membrana/genética , Repetições de Microssatélites , Fenótipo , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas/genética , Receptores de Superfície Celular/genética , Receptor 4 Toll-Like , Receptores Toll-Like , Raios UltravioletaRESUMO
Polymorphisms of the 5'-flanking promoter/enhancer region of the TNAFA gene were determined in 80 Japanese patients with pulmoplantar pustulosis (PPP). The 5'-flanking region of the TNFA gene from -1107 to 66 was amplified by polymerase chain reaction (PCR) method. Nucleotide sequencing data from the PCR products revealed that 5 single nucleotide polymorphisms at position 1031, -863, -857, -307 and -237. None of the nucleotide substitutions were significantly increased in PPP patients when compared with those in controls. To clarify the linkage among the neighboring genetic marker, we analyzed the association between the polymorphisms in the TNFA promoter region and the NcoI polymorphism in the first intron of the TNFB gene as well as HLA-DR9. The genotype at 1031C is strongly associated with TNFB1 and negatively associated with TNFB2 which is reported to be associated with PPP. These data indicate that TNFA gene centromeric to TNFB is not associated with PPP and the susceptible gene of PPP is located between TNFB and HLA-B.
Assuntos
Polimorfismo de Nucleotídeo Único/imunologia , Regiões Promotoras Genéticas/genética , Psoríase/genética , Psoríase/imunologia , Fator de Necrose Tumoral alfa/genética , Genótipo , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Subtipos Sorológicos de HLA-DR , Humanos , Linfotoxina-alfa/genética , Linfotoxina-alfa/imunologia , Regiões Promotoras Genéticas/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Malignant histiocytosis was diagnosed in 4 cows. In all cases the tumor tissues were composed of cytologically atypical histiocytes with evidence of erythrophagocytosis. The tumor in case 1 appeared highly anaplastic with marked nuclear pleomorphism, and had areas of spindle cell differentiation, but had no relation to malignant fibrous histiocytoma. The neoplastic tissue in case 2, characterized by cohesive growth of tumor cells, was distinguishable from anaplastic carcinoma cells by cytokeratin immunostaining. There were many hemosiderin-laden neoplastic cells suggestive of high phagocytic activity in a lymph node of case 3. The neoplastic cells in case 4, frequently multinucleated, were less atypical than in the other cases. All cases expressed histiocyte-associated markers (lysozyme and HAM56), and were negative for cytokeratin, S100, and T- and B-cell lineage-specific markers (CD3 and CD79a). The most frequent HAM56 immunoreactivity was detected in case 4, and the giant, multinucleated forms, reminiscent of epithelioid cell differentiation. seemed not to indicate cytological pleomorphism as a result of neoplastic transformation.
Assuntos
Doenças dos Bovinos/patologia , Sarcoma Histiocítico/veterinária , Linfonodos/patologia , Animais , Anticorpos Monoclonais , Bovinos , Evolução Fatal , Feminino , Sarcoma Histiocítico/patologia , Imuno-Histoquímica/veterináriaRESUMO
Our laboratory has previously demonstrated that ultraviolet B radiation impairs contact hypersensitivity induction in ultraviolet B susceptible mice through a tumor necrosis factor-alpha-dependent mechanism, involving calcitonin gene related peptide and cutaneous mast cells. This study was designed to test directly whether mast cells are the source of tumor necrosis factor-alpha, to account for the ultra-violet B-susceptible phenotype. As dermal mast cells seem to release tumor necrosis factor-alpha following exposure to ultraviolet B, we investigated whether tumor necrosis factor-alpha released by mast cells could mediate impairment of contact hypersensitivity in a manner similar to that found with ultraviolet B radiation treatment. First, we loaded Fcepsilon receptors of mast cells of ultraviolet B-susceptible (C3H/HeN), ultraviolet B-resistant (C3H/HeJ), and mast-cell deficient (Sl/Sld) mice by intradermal injections of anti-dinitrophenyl immunoglobulin E antibodies. Twenty-four hours later, dinitrophenyl was injected intravenously, and within 30 min oxazolone was painted on injected skin sites. Contact hypersensitivity induction was impaired in ultraviolet B-susceptible mice, but not in ultraviolet B-resistant or Sl/Sld mice, and treatment with anti-tumor necrosis factor-alpha antibodies was able to reverse this impairment of contact hypersensitivity. Second, we have found that ultraviolet B radiation did not impair contact hypersensitivity induction when haptens were painted on irradiated skin of mast cell deficient mice. As ultraviolet B radiation impairs contact hypersensitivity induction through a tumor necrosis factor-alpha-dependent mechanism, we conclude that ultraviolet B radiation triggers the prompt release of tumor necrosis factor-alpha from dermal mast cells, and that mast cell-derived tumor necrosis factor-alpha interferes with generation of the hapten-specific signal required for contact hypersensitivity induction. In addition, we are providing data that indicate that tumor necrosis factor-alpha levels released from mast cells as well as sensitivity of Langerhans cells to tumor necrosis factor-alpha contribute in defining the phenotypes of resistance versus sensitivity to ultra-violet B radiation.
Assuntos
Dermatite de Contato/prevenção & controle , Células de Langerhans/fisiologia , Mastócitos/efeitos da radiação , Tolerância a Radiação , Fator de Necrose Tumoral alfa/metabolismo , Raios Ultravioleta , Animais , Degranulação Celular , Imunoglobulina E/imunologia , Mastócitos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/genéticaRESUMO
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are caused by autoantibodies against keratinocyte adhesion molecules desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1), respectively. To determine possible major histocompatibility complex (MHC) class II associations with autoantibody responses to desmogleins, haplotype and allele distributions, along with molecular polymorphisms of HLA-DR and -DQ genes were analyzed based on the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) results in 85 Japanese patients with pemphigus. Each of 55 PV patients carried at least one allele of HLA-DRB1*04 and DRB1*14 subtypes, with significant increases of HLA-DRB1*0406/DQA1*0301/DQB1*0302, DRB1*14/DQA1*0104/DQB1*05 and DRB1*1406/DQA1*0503/ DQB1*0301 haplotypes compared to normal controls. The HLA-DRB1*04 and DRB*14 alleles carried by PV patients shared hydrophobic amino acid residues Phe26, Leu67 and Val86, as well as hydrophilic amino acid residues at positions 70 and 71 on the DRB1 beta chain. HLA-DR/DQ distributions did not differ among PV patients according to the presence or absence of anti-Dsg1 co-existing with anti-Dsg3. Thirty PF patients, all producing autoantibodies only to Dsg1, showed more diverse HLA-DR/DQ distributions, sharing hydrophobic amino acid residues at positions 26 and 67, as well as hydrophilic amino acid residues at positions 70 and 71, of the DRB1 chain. These findings suggest that autoantibody responses to desmogleins might be regulated by amino acid residues at positions 26, 67, 70, 71 and 86 at peptide binding sites of HLA-DRB1 molecules, and that autoimmune responses to Dsg3 might be more strictly regulated by specific amino acid residues at these positions on the HLA-DRB1 chain than responses to Dsg1.
Assuntos
Doenças Autoimunes/genética , Proteínas do Citoesqueleto/genética , Antígenos HLA-DR/genética , Pênfigo/genética , Pênfigo/imunologia , Polimorfismo Genético , Alelos , Sequência de Aminoácidos , Especificidade de Anticorpos , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Proteínas do Citoesqueleto/imunologia , Desmogleína 1 , Desmogleína 3 , Desmogleínas , Desmoplaquinas , Genótipo , Cadeias HLA-DRB1 , Haplótipos , Humanos , JapãoRESUMO
We investigated the allele and genotype distribution of a polymorphism of the tumor necrosis factor (TNF) B gene and the frequency of HLA-DR9 in 49 patients with Palmoplantar pustulosis (PPP) and 51 healthy controls. We found that the frequency of TNFB2 in the PPP patients was significantly higher than that in the controls. Furthermore, the DR9-TNFB2 haplotype was significantly more frequent in the PPP patients (P=0.0045). These results suggest that TNFB2 may confer susceptibility to PPP.
Assuntos
Linfotoxina-alfa/genética , Polimorfismo Genético/genética , Psoríase/genética , Alelos , Genótipo , HumanosRESUMO
The role of antigen-presenting cells (APC) in the induction of antigen-specific unresponsiveness was examined, using two functionally distinct murine macrophage hybridomas, #59 and #63 cells. Derivatized with the hapten (dinitrofluorobenzene; DNFB), #59 cells induced contact hypersensitivity (CH) in mice. Hapten-derivatized #63 cells failed to induce CH. Instead, they prevented recipients from acquiring CH when exposed subsequently to a sensitizing dose of the hapten. Similarly, hapten-derivatized #59 cells, pretreated in vitro with transforming growth factor-beta2 (TGF-beta2) lost their capacity to evoke CH, and induced tolerance. Hapten-derivatized #63 cells and TGF-beta2-treated #59 cells eliminated CH in mice sensitized to hapten. Reverse transcription-polymerase chain reaction analysis of mRNAs for various accessory molecules important in T-cell activation revealed that #63 and TGF-beta2-treated #59 cells differed only in their expression of tumour necrosis factor-alpha (TNF-alpha) mRNA. The latter expressed higher levels of TNF-alpha mRNA than did untreated #59 cells. As a consequence, #63 and TGF-beta2-treated #59 cells, both of which induce tolerance, secrete TNF-alpha protein unlike untreated #59 cells, which do not induce tolerance to hapten. Since neutralizing anti-TNF-alpha antibodies abrogated the tolerogenic potential of #63 cells in vivo, we conclude that TGF-beta2 equips hapten-bearing APC with the capacity to evoke systemic immune deviation in which CH is selectively silenced. We speculate that one effect of TGF-beta2 is to cause APC to up-regulate TNF-alpha production. In turn, this cytokine biases the functional property of responding hapten-specific T cells in a direction that not only interferes with acquisition, but suppresses induction of CH.