RESUMO
BACKGROUND: Human T cell lymphotropic virus type 1 (HTLV-1) infection has been associated with recurrent and disseminated strongyloidiasis and adult T cell leukemia/lymphoma (ATLL). METHODS: We compared immunological aspects and markers for ATLL in HTLV-1 patients with or without strongyloidiasis, and evaluated the influence of Strongyloides stercoralis treatment on the immune response and clinical outcomes of HTLV-1 infection. RESULTS: Levels of TNFα and IFNγ were lower in patients coinfected with HTLV-1 and S. stercoralis than in patients with HTLV-1 only (p < 0.05), and there was an increase in TNFα levels after anthelmintic treatment. Levels of sIL-2R were higher in patients with HTLV-1 coinfected with S. stercoralis and anthelmintic treatment decreased sIL-2R levels (p < 0.05). The one patient who developed ATLL was coinfected with S. stercoralis. CONCLUSION: These data show that helminthic infection has a modulatory role in HTLV-1 infection and that S. stercoralis may be a cofactor in the development of ATLL.
Assuntos
Anti-Helmínticos/uso terapêutico , Infecções por HTLV-I/tratamento farmacológico , Receptores de Interleucina-2/sangue , Estrongiloidíase/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue , Adulto , Animais , Coinfecção , Progressão da Doença , Feminino , Infecções por HTLV-I/sangue , Infecções por HTLV-I/complicações , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/imunologia , Strongyloides stercoralis/imunologia , Estrongiloidíase/sangue , Estrongiloidíase/complicações , Estrongiloidíase/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Tumor cells are known to modify their surroundings in order to escape immunologic detection, and IL-2, a killer cell activator, is one of the factors known to overcome this escape mechanism. In this regard, when we cocultured cells from the human cervical cancer cell line INBL with mice blood leukocytes, no inhibition of tumor cell growth was observed, but when a similar coculture was done in the presence of cationic liposomes bearing IL-2 on their external surface (CL-IL-2), all the INBL cells were killed. In order to evaluate whether this in vitro property of CL-IL-2 to overcome tumor cell detection by lymphocytes could also be reproduced in vivo, INBL cells were intraperitoneally (i.p.) inoculated into immunodepressed mice to produce solid tumors. We observed that the subsequent i.p. delivery of CL-IL-2 rendered the tumor masses significantly smaller. The presence of a large number of infiltrating lymphocytes on those tumors, and the fact that many had a cytotoxic CD8(+) phenotype suggests that these lymphocytes were responsible for the observed antitumor effect. Finally, the possible formation of a bridge between the IL-2R receptors on both, the lymphocytes and the INBL cells, mediated by the IL-2-bearing liposomes, and its possible effect on the activation of antitumor cytotoxic lymphocytes is discussed.
Assuntos
Antineoplásicos/administração & dosagem , Interleucina-2/administração & dosagem , Leucócitos/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/imunologia , Cátions , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Hospedeiro Imunocomprometido , Interleucina-2/imunologia , Lipossomos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos CBA , Receptores de Interleucina-2/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologiaRESUMO
We present evidence that cervical cancer cells express a functional IL-2 receptor (IL-2R). In fact, by RT-PCR we obtained that the IL-2R is present in CALO, and INBL cells, and that it consisted of the alphaIL-2R, betaIL-2R, and gammaIL-2R chains. We also found that IL-2 is a growth factor for these cell lines, and unexpectedly that CALO and INBL themselves being cancer cells produce, and secrete IL-2. Antibodies against the alpha and beta subunits of the IL-2R inhibited cell proliferation thus hinting to a cell growth dependency on this factor. Our results thus provide evidence that the IL-2R on cervical cancer cells is part of an autocrine mechanism for its growth to the extent that, like lymphocytes, they produce and become partially dependent on this growth factor. We think that in view of our results caution should be taken when IL-2 is being considered for cancer therapy; in particular when the patient's cancer cells present the IL-2R, because as indicated by our results, the use of this factor could promote tumor growth. Finally, the possible implications of the expression of both IL-2, and IL-2R on cervical cancer cells on the immune escape mechanism of tumor cells are discussed.
Assuntos
Comunicação Autócrina , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-2/metabolismo , Neoplasias do Colo do Útero/metabolismo , Anticorpos Antineoplásicos/imunologia , Comunicação Autócrina/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-2/genética , Interleucina-2/farmacologia , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Receptores de Interleucina-2/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologiaRESUMO
UNLABELLED: The optimal immunosuppressive regimen for simultaneous kidney pancreas transplantation (SKPT) is still not established. We conducted a study to compare the safety and efficacy of no induction versus anti-IL-2 receptor induction protocols in SKPT recipients receiving the same maintenance regimen. METHODS: Sixty-three SKPT recipients were divided into two groups: no induction group (n = 42) and anti-IL-2 receptor induction group (n = 21). All patients were maintained on tacrolimus, mycophenolate mofetil, and prednisone. Primary endpoints were 1-year acute rejection incidence and patient and graft survivals. RESULTS: Demographic characteristics were similar between the groups. Acute rejection incidence at 1 year was equal in both groups (28.6%). Kidney and pancreas allograft survival in the no induction group were 78.6% and 76.2%, and in the anti-IL-2R induction group, 81% and 71.4%, respectively (P = NS). Patient survival was also similar: 83.3% in the no induction versus 85.7% in the anti-IL-2R induction group. Deaths due to sepsis were higher in the anti-IL-2R induction group, albeit not significantly. CONCLUSION: The use of a no-induction protocol in SKPT is safe and effective immunosuppression that also reduces transplantation costs.
Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Transplante de Pâncreas/imunologia , Receptores de Interleucina-2/imunologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biópsia , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/prevenção & controle , Daclizumabe , Quimioterapia Combinada , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Imunoglobulina G/uso terapêutico , Terapia de Imunossupressão/métodos , Transplante de Rim/mortalidade , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Transplante de Pâncreas/mortalidade , Seleção de Pacientes , Prednisona/uso terapêutico , Análise de SobrevidaRESUMO
Active tuberculosis (TB) is associated with prolonged suppression of Mycobacterium tuberculosis (MTB)-specific immune responses, but mechanisms involved are understood incompletely. We investigated a potential role for CD4+CD25+ regulatory T cells in depressed anti-MTB immunity by evaluating serially CD4 cell phenotype and interferon (IFN)-gamma production by mononuclear cells from patients with TB. At diagnosis, frequencies of CD4+CD25+ T cells were increased in blood from TB patients compared to healthy purified protein derivative (PPD)-positive controls (with a history of prior TB exposure), and remained elevated at completion of therapy (6 months). By contrast, expression of another activation marker, CD69, by CD4 T cells was increased at diagnosis, but declined rapidly to control levels with treatment. Among CD4+CD25+ T cells from TB patients at diagnosis those expressing high levels of CD25, probably representing regulatory T cells, were increased 2.9-fold when compared to control subjects, while MTB-stimulated IFN-gamma levels in whole blood supernatants were depressed. A role for CD4+CD25+ T cells in depressed IFN-gamma production during TB was substantiated in depletion experiments, where CD25+-depleted CD4 T cells produced increased amounts of IFN-gamma upon MTB stimulation compared to unseparated T cells. At follow-up, IFN-gamma production improved most significantly in blood from TB patients with high baseline frequencies of CD4+CD25+ T cells (more than threefold higher than controls for both total and CD25hi+ CD4 T cells), who also had a significant drop in frequencies of both total and 'regulatory' CD4+CD25+ T cells in response to treatment. Expansion of CD4+CD25+ regulatory T cells during active TB may play a role in depressed T cell IFN-gamma production.
Assuntos
Receptores de Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Antígenos de Bactérias/imunologia , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Lectinas Tipo C , Pulmão/imunologia , Masculino , Monócitos/imunologia , Mycobacterium tuberculosis/imunologia , Fenótipo , Fator de Crescimento Transformador beta/imunologia , Tuberculina/imunologia , Tuberculose Pulmonar/microbiologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Graft thrombosis is the most common cause of first year graft failure in pediatric renal transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database was analyzed for cases of graft failure due to thrombosis among patients transplanted from 1998 to 2004. The impact of interleukin-2 (IL-2) receptor antagonists as induction therapy was determined. There were a total of 51 graft failures due to thrombosis among the 2750 reported renal transplants (1.85%) (95% CI (1.39%, 2.41%)). This represents the most common cause of graft loss during the first year post-transplant accounting for 35% of first year losses and 18% of all graft losses. The incidence of thrombosis among patients who received IL-2 receptor antibodies was 1.07% (12/1126) compared to 2.40% (39/1624) among patients who did not (OR 0.44, 95% CI 0.23, 0.84, p = 0.014). Use of IL-2 receptor blockade was the only significant prognostic factor in a multivariate model with previously identified risk factors. Analysis of NAPRTCS data found that the use of IL-2 receptor antibodies as induction therapy is associated with a significantly decreased risk of graft failure due to thrombosis. This provocative finding requires further investigation to determine whether thrombotic failure can be decreased by this therapeutic strategy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Receptores de Interleucina-2/antagonistas & inibidores , Obstrução da Artéria Renal/prevenção & controle , Trombose/prevenção & controle , Adolescente , Canadá/epidemiologia , Criança , Pré-Escolar , Costa Rica/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , México/epidemiologia , Receptores de Interleucina-2/imunologia , Obstrução da Artéria Renal/epidemiologia , Obstrução da Artéria Renal/etiologia , Estudos Retrospectivos , Fatores de Risco , Trombose/epidemiologia , Trombose/etiologia , Transplante Homólogo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
We show in this study that long-term tolerance to allogeneic skin grafts can be established in the absence of immunosuppression by the combination of the following elements: 1) augmenting the frequency of regulatory CD4(+)CD25(+) T cells (Treg) and 2) presentation of the allogeneic stimuli through linked recognition of allo- and self-epitopes on semiallogeneic F(1) APCs. BALB/c spleen cells enriched for CD4(+)CD25(+) T lymphocytes were transferred either to BALB/c nu/nu mice or to BALB/c nu/nu previously injected with F(1)(BALB/c x B6.Ba) spleen cells, or else grafted with F(1)(BALB/c x B6.Ba) skin (chimeric BALB/c nu/nu-F(1)). Chimeric BALB/c nu/nu-F(1) reconstituted with syngeneic CD25(+)-enriched spleen cells were unable to reject the previously transferred F(1)(BALB/c x B6.Ba) spleen cells or F(1)(BALB/c x B6.Ba) skin grafts, and a specific tolerance to a secondary B6 graft was obtained, with rejection of third-party CBA grafts. BALB/c nu/nu mice reconstituted only with syngeneic CD25(+)-enriched spleen cells rejected both B6 and CBA skin grafts. In contrast, when chimeric BALB/c nu/nu-F(1) were reconstituted with spleen populations comprising normal frequencies of Treg cells, the linked recognition of allo and self resulted in breaking of self tolerance and rejection of syngeneic grafts, strongly suggesting that linked recognition works in both directions, either to establish tolerance to allo, or to break tolerance to self, the critical parameter being the relative number of Treg cells.
Assuntos
Autoantígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade/imunologia , Tolerância Imunológica/imunologia , Isoantígenos/imunologia , Receptores de Interleucina-2/imunologia , Animais , Sobrevivência de Enxerto/imunologia , Camundongos , Fenótipo , Transplante de Pele/imunologia , Baço/imunologia , Transplante Homólogo/imunologiaRESUMO
The history of immunosuppression is a long one. From the utilization of steroids and azathioptine in the 50's to the design of humanized molecules that specifically block cell surface receptors. Liver transplantation is one of the procedures that benefit the most with the development of new immunosuppressors and is also one of the reasons to create a new branch in research and clinical practice: transplant medicine. It also set the standards for research in the "immunologic tolerance" field. The cornerstone in the post-liver transplant stage is the utilization of calcineurin inhibitors combined with new anti-metabolites and monoclonal antibodies. All these settings conforms a promising field in the research of new and better immunosuppressing agents.
Assuntos
Terapia de Imunossupressão/tendências , Imunossupressores/uso terapêutico , Transplante de Fígado/imunologia , Anticorpos Monoclonais/uso terapêutico , Antimetabólitos/uso terapêutico , Azatioprina/uso terapêutico , Inibidores de Calcineurina , Ciclosporina/uso terapêutico , Previsões , Rejeição de Enxerto/prevenção & controle , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/classificação , Metilprednisolona/uso terapêutico , Receptores de Interleucina-2/antagonistas & inibidores , Receptores de Interleucina-2/imunologia , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate whether the CD25 + CD4 + regulatory T-cell population, which plays important roles not only in maintaining immunologic self-tolerance but also in controlling the magnitude and character of antimicrobial immune responses, is related to the pathophysiology of Kawasaki disease (KD). STUDY DESIGN: The patient group consisted of 54 patients (median age, 30 months; 27 female and 27 male patients) fulfilling the criteria for KD. Age-matched control subjects included 17 patients with active infections and 24 healthy children. We analyzed CD25 + CD4 + cells and the mRNA expression of Foxp3, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and transforming growth factor beta in peripheral blood mononuclear cells and purified CD4 + T cells. RESULTS: The proportions of CD25 + CD4 + cells in patients with acute-phase KD (median, 2.35% of total lymphocytes) were significantly lower than those in healthy control subjects (median, 3.14%) and control subjects with disease (median, 3.15%). The proportions returned to the normal level after intravenous gammaglobulin treatment (median, 3.86%). The mRNA expression of Foxp3, CTLA4, and GITR showed similar tendencies. CONCLUSIONS: The decrease of CD25 + CD4 + regulatory T cells in the acute phase might have a role in the development of KD.
Assuntos
Antígenos CD4/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Receptores de Interleucina-2/imunologia , Antígenos CD4/sangue , Antígenos CD4/genética , Estudos de Casos e Controles , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Receptores de Interleucina-2/sangue , Receptores de Interleucina-2/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Experimental Autoimmune Encephalomyelitis (EAE) can be induced in mice of the C57BL/6 strain by subcutaneous immunization with myelin/oligodendrocyte glycoprotein (MOG) peptide p35-55 in CFA, administered twice at an interval of one week and supplemented with Bordetella pertussis toxin given IV. Here, we studied the effect on the induction of EAE of depleting antibodies to CD4, CD8, or CD25 administered before either the first or the second dose of MOG p35-55. We found that anti-CD4 abolished EAE when given before the first immunization; anti-CD4 did not affect the disease when it was given before the second immunization. Anti-CD8 enhanced EAE induction when given before either of the two immunizations. Anti-CD25 enhanced EAE to the same degree as anti-CD8 when given before the first immunization, but anti-CD25 was even more effective in enhancing EAE when given before the second immunization. The anti-CD25 treatment led to significantly enhanced IFNgamma production by T cells responding to MOG p35-55 and persisting anti-MOG antibodies detectable 56 days after the first immunization. Administration of anti-CD8 or anti-CD25 abolished the need for pertussis toxin to induce EAE. These findings are compatible with the idea that CD4 T cells are required for the initial induction of EAE and that the disease is down-regulated by T cells expressing CD8 or CD25. These regulatory T cells exist prior to MOG immunization, but the CD25+ regulators appear to be further amplified by immunization.