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‣ Terapia celular em doenças pulmonares: existem perspectivas?; Cell therapy in pulmonary diseases: are there perspectives?

RIBEIRO-PAES, João T.; BILAQUI, Aldemir; GRECO, Oswaldo T.; RUIZ, Milton A.; ALVES-DE-MORAES, Luis B. C.; FARIA, Carolina A.; STESSUK, Talita
Fonte: Associação Brasileira de Hematologia e Hemoterapia e daSociedade Brasileira de Transplante de Medula Óssea Publicador: Associação Brasileira de Hematologia e Hemoterapia e daSociedade Brasileira de Transplante de Medula Óssea
Tipo: Artigo de Revista Científica
Português
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A terapia celular poderia ser conceituada de forma ampla e genérica como o emprego de células para tratamento de doenças. Apesar de um número não tão expressivo de relatos tendo o pulmão como objeto de estudo na terapia celular em pacientes humanos, há dados consistentes da literatura, tanto em humanos, quanto em modelos animais,que evidenciam a migração de células-tronco da medula óssea para o pulmão,em diferentes situações experimentais. Esses resultados forneceram o embasamento experimental para o emprego de células-tronco na regeneração do tecido pulmonar em modelos animais. Em nosso laboratório, vários projetos de pesquisa têm sido conduzidos com a finalidade de avaliar a resposta pulmonar (morfológica e funcional) ao tratamento com células-tronco adultas em camundongos com doença pulmonar obstrutiva crônica (DPOC) induzida experimentalmente. Os resultados obtidos, aliados àqueles de outros grupos de pesquisa, permitem aventar a possibilidade de aplicação, a curto prazo, da terapia celular em pacientes com DPOC. Em outra patologia pulmonar, fibrose cística (FC), cuja abordagem terapêutica com células-tronco apresenta aspectos particulares em relação às patologias pulmonares crônico-degenerativas...

‣ Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema

Ribeiro-Paes, Joao Tadeu; Bilaqui, Aldemir; Greco, Oswaldo T.; Ruiz, Milton Artur; Marcelino, Monica Y.; Stessuk, Talita; de Faria, Carolina A.; Lago, Mario R.
Fonte: Dove Medical Press Ltd Publicador: Dove Medical Press Ltd
Tipo: Artigo de Revista Científica Formato: 63-71
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Within the chronic obstructive pulmonary disease (COPD) spectrum, lung emphysema presents, as a primarily histopathologic feature, the destruction of pulmonary parenchyma and, accordingly, an increase in the airflow obstruction distal to the terminal bronchiole. Notwithstanding the significant advances in prevention and treatment of symptoms, no effective or curative therapy has been accomplished. In this context, cellular therapy with stem cells (SCs) arises as a new therapeutic approach, with a wide application potential. The -purpose of this study is to evaluate the safety of SCs infusion procedure in patients with advanced COPD (stage IV dyspnea). After selection, patients underwent clinical examination and received granulocyte colony-stimulating factor, immediately prior to the bone marrow harvest. The bone marrow mononuclear cells (BMMC) were isolated and infused into a peripheral vein. The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed...

‣ An inducible caspase 9 safety switch for T-cell therapy

Straathof, Karin C.; Pulè, Martin A.; Yotnda, Patricia; Dotti, Gianpietro; Vanin, Elio F.; Brenner, Malcolm K.; Heslop, Helen E.; Spencer, David M.; Rooney, Cliona M.
Fonte: © 2005 by The American Society of Hematology Publicador: © 2005 by The American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 01/06/2005 Português
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The efficacy of adoptive T-cell therapy as treatment for malignancies may be enhanced by genetic modification of infused cells. However, oncogenic events due to vector/transgene integration, and toxicities due to the infused cells themselves, have tempered enthusiasm. A safe and efficient means of removing aberrant cells in vivo would ameliorate these concerns. We describe a “safety switch” that can be stably and efficiently expressed in human T cells without impairing phenotype, function, or antigen specificity. This reagent is based on a modified human caspase 9 fused to a human FK506 binding protein (FKBP) to allow conditional dimerization using a small molecule pharmaceutical. A single 10-nM dose of synthetic dimerizer drug induces apoptosis in 99% of transduced cells selected for high transgene expression in vitro and in vivo. This system has several advantages over currently available suicide genes. First, it consists of human gene products with low potential immunogenicity. Second, administration of dimerizer drug has no effects other than the selective elimination of transduced T cells. Third, inducible caspase 9 maintains function in T cells overexpressing antiapoptotic molecules. These characteristics favor incorporation of inducible caspase 9 as a safety feature in human T-cell therapies.

‣ Adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer

Li, Qiao; Iuchi, Takekazu; Jure-Kunkel, Maria N.; Chang, Alfred E.
Fonte: Ivyspring International Publisher Publicador: Ivyspring International Publisher
Tipo: Artigo de Revista Científica
Publicado em 20/11/2007 Português
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Administration of anti-4-1BB mAb has been found to be a potent adjuvant when combined with other therapeutic approaches, e.g. chemotherapy, cytokine therapies, anti-OX40 therapy, and peptide or DC vaccines. However, the adjuvant effect of anti-4-1BB mAb administration in adoptive T cell therapy of cancer has not been fully evaluated. In this report, effector T cells were generated in vitro by anti-CD3/anti-CD28 activation of tumor-draining lymph node (TDLN) cells and used in an adoptive immunotherapy model. While T cells or anti-4-1BB alone showed no therapeutic efficacy in mice bearing macroscopic 10-day pulmonary metastases, T cells plus anti-4-1BB mediated significant tumor regression in an anti-4-1BB dose dependent manner. Mice bearing microscopic 3-day lung metastases treated with T cells alone demonstrated tumor regression which was significantly enhanced by anti-4-1BB administration. NK cell depletion abrogated the augmented therapeutic efficacy rendered by anti-4-1BB. Cell transfer between congenic hosts demonstrated that anti-4-1BB administration increased the survival of adoptively transferred TDLN cells. Using STAT4-/- mice, we found that modulated IFNγ secretion in wt TDLN cells after anti-CD3/CD28/4-1BB activation in vitro was lost in similarly stimulated STAT4-/- TDLN cells. Additionally...

‣ Use of Biological Therapy to Enhance Both Virotherapy and Adoptive T-Cell Therapy for Cancer

Kottke, Timothy; Diaz, Rosa M; Kaluza, Karen; Pulido, Jose; Galivo, Feorillo; Wongthida, Phonphimon; Thompson, Jill; Willmon, Candice; Barber, Glen N; Chester, John; Selby, Peter; Strome, Scott; Harrington, Kevin; Melcher, Alan; Vile, Richard G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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To protect viral particles from neutralization, sequestration, nonspecific adhesion, and mislocalization following systemic delivery, we have previously exploited the natural tumor-homing properties of antigen-specific CD8+ T cells. Thus, OT-I T cells, preloaded in vitro with the oncolytic vesicular stomatitis virus (VSV), can deliver virus to established B16ova tumors to generate significantly better therapy than that achievable with OT-I T cells, or systemically delivered VSV, alone. Here, we demonstrate that preconditioning immune-competent mice with Treg depletion and interleukin-2 (IL-2), before adoptive T-cell therapy with OT-I T cells loaded with VSV, leads to further highly significant increases in antitumor therapy. Therapy was associated with antitumor immune memory, but with no detectable toxicities associated with IL-2, Treg depletion, or systemic dissemination of the oncolytic virus. Efficacy was contributed by multiple factors, including improved persistence of T cells; enhanced delivery of VSV to tumors; increased persistence of OT-I cells in vivo resulting from tumor oncolysis; and activation of NK cells, which acquire potent antitumor and proviral activities. By controlling the levels of virus loaded onto the OT-I cells...

‣ Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice

James, Scott E.; Orgun, Nural N.; Tedder, Thomas F.; Shlomchik, Mark J.; Jensen, Michael C.; Lin, Yukang; Greenberg, Philip D.; Press, Oliver W.
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 24/12/2009 Português
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We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR+ T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR+ T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR+ T cells from the lungs, enhanced T-cell survival, and promoted cTCR+ T cell–dependent elimination of established mouse CD20+ leukemia. Furthermore, CD20-specific cTCR+ T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR+ T cells to survive and control tumors.

‣ Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors

Qiao, J; Wang, H; Kottke, T; Diaz, RM; Willmon, C; Hudacek, A; Thompson, J; Parato, K; Bell, J; Naik, J; Chester, J; Selby, P; Harrington, K; Melcher, A; Vile, RG
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Although adoptive T-cell therapy has shown clinical success, efficacy is limited by low levels of T-cell trafficking to, and survival in, the immunosuppressive environment of an established tumor. Oncolytic virotherapy has recently emerged as a promising approach to induce both direct tumor cell killing and local proinflammatory environments within tumors. However, inefficient systemic delivery of oncolytic viruses remains a barrier to use of these agents against metastatic disease that is not directly accessible to the end of a needle. Here we show that the ability of antigen-specific T cells to circulate freely, and to localize to tumors, can be exploited to achieve the systemic delivery of replication-competent, oncolytic vesicular stomatitis virus (VSV). Thus, VSV loaded onto OT-I T cells, specific for the SIINFEKL epitope of the ovalbumin antigen, was efficiently delivered to established B16ova tumors in the lungs of fully immune-competent C57Bl/6 mice leading to significant increases in therapy compared to the use of virus, or T cells, alone. Although OT-I T-cell-mediated delivery of VSV led to viral replication within tumors and direct viral oncolysis, therapy was also dependent upon an intact host immune system. Moreover, VSV loading onto the T cells increased both T-cell activation in vitro and T-cell trafficking in vivo. The combination of adoptive T-cell transfer of antigen-specific T cells...

‣ IL-21 augments the efficacy of T cell therapy by eliciting concurrent cellular and humoral responses1

Iuchi, Takekazu; Teitz-Tennenbaum, Seagal; Huang, Jianhua; Redman, Bruce G.; Hughes, Steven D.; Li, Mu; Jiang, Guihua; Chang, Alfred E.; Li, Qiao
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/06/2008 Português
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Interleukin (IL)-21 modulates T cell, B cell, and NK cell-associated immunity. However, the potential of IL-21 to simultaneously stimulate cellular and humoral antitumor responses and the mechanisms involved have not yet been adequately explored. In this report, we examined the immune modulating effect of IL-21 when used in vitro and its adjuvant effects when administrated concomitantly with T cell transfer for cancer therapy. Use of IL-21 in concert with IL-2 in culture up-regulated both type 1 and type 2 cytokine production of activated tumor-draining lymph node (TDLN) cells and enhanced their therapeutic efficacy. Administration of IL-21 and IL-2 as an adjuvant to T cell transfer resulted in simultaneously elicited cellular and humoral responses. This concurrent response has led to effective regression of established pulmonary metastatic tumors and subcutaneous tumors. T cell transfer plus IL-21/IL-2 administration conferred systemic immunity to the treated hosts. This was evident by the induction of protective immunity against tumor re-challenge; expansion of memory T cells, and significantly elevated serum levels of IFNγ and IL-10. Furthermore, we observed significantly enhanced tumor-associated antibody response after T cell+IL-2+IL-21 therapy. Cytotoxic antibody subclass IgG2b increased strikingly in the sera of treated animals; they bound specifically to MCA205 tumor cells...

‣ Adoptive T-cell Therapy Using Autologous Tumor-infiltrating Lymphocytes for Metastatic Melanoma: Current Status and Future Outlook

Wu, Richard; Forget, Marie-Andree; Chacon, Jessica; Bernatchez, Chantale; Haymaker, Cara; Chen, Jie Qing; Hwu, Patrick; Radvanyi, Laszlo
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2012 Português
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Immunotherapy using autologous T-cells has emerged to be a powerful treatment option for patients with metastatic melanoma. These include the adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL), T-cells transduced with high-affinity T-cell receptors (TCR) against major melanosomal tumor antigens, and T cells transduced with chimeric antigen receptors (CAR) composed of hybrid immunoglobulin light chains with endo-domains of T-cell signaling molecules. Among these and other options for T-cell therapy, TIL together with high-dose IL-2 has had the longest clinical history with multiple clinical trials in centers across the world consistently demonstrating durable clinical response rates near 50% or more. A distinct advantage of TIL therapy making it still the T-cell therapy of choice is the broad nature of the T-cell recognition against both defined as well as un-defined tumors antigens against all possible MHC, rather than the single specificity and limited MHC coverage of the newer TCR and CAR transduction technologies. In the past decade, significant inroads have been made in defining the phenotypes of T cells in TIL mediating tumor regression. CD8+ T cells are emerging to be critical, although the exact subset of CD8+ T cells exhibiting the highest clinical activity in terms of memory and effector markers is still controversial. We present a model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long-term tumor control in responding patients. Although TIL therapy has shown great potential to treat metastatic melanoma...

‣ Effects of tumor irradiation on host T regulatory cells and systemic immunity in the context of adoptive T cell therapy in mice

Wei, Shuang; Egenti, Martin U.; Teitz-Tennenbaum, Seagal; Zou, Weiping; Chang, Alfred E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/2013 Português
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In this study, we employed a murine D5 melanoma model to study the effects of local tumor irradiation on the therapeutic efficacy of adoptive T cell therapy. Tumor irradiation was delivered in 5 daily fractions (8.5 Gy) to s.c. tumors on days 7-11 after tumor inoculation. After the last radiation dose, activated tumor-draining lymph node cells were transferred i.v. followed by i.p. IL-2 administration. Tumor irradiation alone had no significant effect on tumor growth; however it synergistically enhanced the therapeutic efficacy of T cell therapy. For 2 days following tumor irradiation there was a significant reduction in T, B cells and CD11c+ dendritic cells in both the tumor microenvironment and the systemic lymphoid compartments. By days 4-6 after irradiation, the relative reduction in the number of Treg cells within the tumor and the systemic compartments was greater than the reduction in conventional T cells. Furthermore, the suppressive function of the Tregs was significantly impaired in irradiated versus untreated mice. Using effector T cells derived from congenic mice, we found that local tumor irradiation resulted in increased proliferation of donor T cells within the tumor and the systemic lymphoid compartments. Radiation was associated with increased expression of the effector cytokines IFN-γ and TNF-α by donor and host CD4+ and CD8+ T cells. Altogether...

‣ Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants

Kaluza, Karen M.; Thompson, Jill M.; Kottke, Timothy J.; Flynn Gilmer, Heather C.; Knutson, Darlene L.; Vile, Richard G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Adoptive T cell therapy has proven effective against melanoma in mice and humans. However, because most responses are incomplete or transient, cures remain rare. To maximize the efficacy of this therapy, it will be essential to gain a better understanding of the processes which result in tumor relapse. We studied these processes using B16ova murine melanoma and adoptive transfer of OT-I T cells. Transfer of T cells as a single therapy provided a significant survival benefit for mice with established subcutaneous tumors. However, tumors which initially regressed often recurred. By analyzing tumors which emerged in the presence of a potent OT-I response, we identified a novel tumor escape mechanism in which tumor cells evaded T cell pressure by undergoing major genomic changes involving loss of the gene encoding the target tumor antigen. Furthermore, we show that these in vivo processes can be recapitulated in vitro using T cell/tumor cell co-cultures. A single round of in vitro co-culture led to significant loss of the ova gene and a tumor cell population with rapidly induced and diverse karyotypic changes. Although these current studies focus on the model OVA antigen, the finding that T cells can directly promote genomic instability has important implications for the development of adoptive T cell therapies.

‣ Reassessing target antigens for adoptive T cell therapy

Hinrichs, Christian S.; Restifo, Nicholas P.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Adoptive T cell therapy can target and kill widespread malignant cells thereby inducing durable clinical responses in melanoma and selected other malignances. However, many commonly targeted tumor antigens are also expressed by healthy tissues, and T cells do not distinguish between benign and malignant tissues if both express the target antigen. As such, autoimmune toxicity from T-cell-mediated destruction of normal tissue has limited the development and adoption of this otherwise promising type of cancer therapy. A review of the unique biology of T-cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities. In selecting target antigens for adoptive T-cell therapy, expression by tumors and not by essential healthy tissues is of paramount importance. The risk of autoimmune adverse events can be further mitigated by generating antigen receptors using strategies that reduce the chance of cross-reactivity against epitopes in unintended targets. In general, a circumspect approach to target selection and thoughtful preclinical and clinical studies are pivotal to the ongoing advancement of these promising treatments.

‣ Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

Adusumilli, Prasad S.; Cherkassky, Leonid; Villena-Vargas, Jonathan; Colovos, Christos; Servais, Elliot; Plotkin, Jason; Jones, David R.; Sadelain, Michel
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 05/11/2014 Português
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Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. Following intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced anti-tumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intra-tumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor...

‣ Longitudinal confocal microscopy imaging of solid tumor destruction following adoptive T cell transfer

Schietinger, Andrea; Arina, Ainhoa; Liu, Rebecca B; Wells, Sam; Huang, Jianhua; Engels, Boris; Bindokas, Vytas; Bartkowiak, Todd; Lee, David; Herrmann, Andreas; Piston, David W; Pittet, Mikael J; Lin, P Charles; Zal, Tomasz; Schreiber, Hans
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
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A fluorescence-based, high-resolution imaging approach was used to visualize longitudinally the cellular events unfolding during T cell-mediated tumor destruction. The dynamic interplay of T cells, cancer cells, cancer antigen loss variants, and stromal cells—all color-coded in vivo—was analyzed in established, solid tumors that had developed behind windows implanted on the backs of mice. Events could be followed repeatedly within precisely the same tumor region—before, during and after adoptive T cell therapy—thereby enabling for the first time a longitudinal in vivo evaluation of protracted events, an analysis not possible with terminal imaging of surgically exposed tumors. T cell infiltration, stromal interactions, and vessel destruction, as well as the functional consequences thereof, including the elimination of cancer cells and cancer cell variants were studied. Minimal perivascular T cell infiltrates initiated vascular destruction inside the tumor mass eventually leading to macroscopic central tumor necrosis. Prolonged engagement of T cells with tumor antigen-crosspresenting stromal cells correlated with high IFNγ cytokine release and bystander elimination of antigen-negative cancer cells. The high-resolution, longitudinal...

‣ Target discovery for T cell therapy: next steps to advance Immunotherapies

Bot, Adrian; Brewer, Joanna E; Eshhar, Zelig; Frankel, Stanley R; Hickman, Emma; Jungbluth, Achim A; Morgan, Richard; Peretz, Yoav; Radvanyi, Laszlo; Ramos, Carlos A; Robbins, Paul F; Wucherpfennig, Kai W
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
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Investigators from academia and industry gathered on August 14, 2014, in Boston at the Inaugural ImVacS conference entitled “Target Discovery for T Cell Therapy: Next Step to Advance Immunotherapies”. Novel targets, discovery strategies and enabling technologies were presented and discussed.

‣ Uso da terapia celular em lesões digitais induzidas em bovinos manejados intensivamente; Use of cell therapy in induced digital lesions in intensively managed cattle

Noronha Filho, Antônio Dionísio Feitosa
Fonte: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Ciência Animal (EVZ); Escola de Veterinária e Zootecnia - EVZ (RG) Publicador: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Ciência Animal (EVZ); Escola de Veterinária e Zootecnia - EVZ (RG)
Tipo: Dissertação Formato: application/pdf
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Digital diseases worries livestock industry and arouse interest in extensionists because of the economic losses and difficult control. Losses come from decrease in productive and reproductive performance and, in some cases, the premature culling of high value breeding animals. Besides these, lameness causes negative impact on animal welfare. Digital diseases assume different characteristics in distinct production systems, requiring specific solutions that fits each farms condition. Innovative treatments have been discussed, but are not always economically viable, however, in last years in Veterinary Medicine has increased the interest on the possibility of applying cell therapy in the treatment of diseases related to the locomotor systems, including digital diseases. In the equine, it has been studied its use in the repair of tendineous, articular and osseous lesions, and the perspective of application in other important diseases like laminitis. Considering the importance of digital diseases, especially laminitis, for cattle, cell therapy can represent an additional option for treatment. This study evaluated the development of digital lesions in cattle intensively managed and its response to the treatment with bone marrow mononuclear cells. Were used 15 animals...

‣ T Cell Proliferation and Apoptosis in HIV-1-Infected Lymphoid Tissue: Impact of Highly Active Antiretroviral Therapy

Dyrhol-Riise, Anne Ma; Ohlsson Teague, Maria; Skarstein, Kathrine; Nygaard, Svein J. T.; Olofsson, Jan; Jonsson, Roland; Asjo, Birgitt
Fonte: Academic Press Publicador: Academic Press
Tipo: Artigo de Revista Científica
Publicado em //2001 Português
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T cell turnover was studied in situ in tonsillar lymphoid tissue (LT) from HIV-1-infected individuals during 48 weeks of highly active antiretroviral therapy (HAART) and compared to that of HIV-1-negative controls. Prior to therapy, CD4 cell proliferation (%CD4+ Ki67+) and apoptosis (%CD4+ TUNEL+) were increased in HIV-1-infected LT and both parameters correlated with tonsillar viral load. CD8 cell proliferation (%CD8+ Ki67+) was increased 4- to 10-fold, mainly in the germinal centers. Apoptotic CD8+ T cell levels (%CD8+ TUNEL+) were raised preferentially in the tonsillar T cell zone. The frequency of CD8+ Ki67+ and CD8+ TUNEL+ T cells correlated with tonsillar viral load and with the fraction of CD8+ T cells expressing activation markers. During HAART, CD4 cell turnover normalized while CD8 cell turnover was dramatically reduced. However, low level viral replication concomitant with slightly elevated levels of CD8 cell turnover indicated a persistent cellular immune response in LT. In conclusion, enhanced T cell turnover may reflect effector cells related to HIV-1 infection.; http://www.elsevier.com/wps/find/journaldescription.cws_home/622806/description#description; Anne Ma Dyrhol-Riise, Maria Ohlsson, Kathrine Skarstein, Svein J. T. Nygaard...

‣ Adoptive T-cell therapy: adverse events and safety switches

Tey, Siok-Keen
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 20/06/2014 Português
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The potential of adoptive T-cell therapy in effecting complete and durable responses has been demonstrated in a number of malignant and infectious diseases. Ongoing progress in T-cell engineering has given cause for optimism in the broader clinical applicability of this approach. However, the development of more potent T cells is checked by safety concerns, highlighted by the occurrence of on-target and off-target toxicities that, although uncommon, have been fatal on occasions. Timely pharmacological intervention is effective in the management of a majority of adverse events but adoptively transferred T cells can persist long term, along with any unwanted effects. A recently validated cellular safety switch, inducible caspase 9 (iCasp9), has the potential to mitigate the risks of T-cell therapy by enabling the elimination of transferred T cells if required. In haematopoietic stem cell transplantation, iCasp9-modified donor T cells can be rapidly eliminated in the event of graft-versus-host disease. This review presents an overview of the risks associated with modern T-cell therapy and the development, clinical results and potential future application of the iCasp9 safety switch.

‣ Mechanisms of CD8+ T Cell Mediated Virus Inhibition in HIV-1 Virus Controllers

Payne, Tamika Leola
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2014 Português
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CD8+ T cells are associated with long term control of virus replication to low or undetectable levels in a population of HIV+ therapy-naïve individuals known as virus controllers (VCs; <5000 RNA copies/ml and CD4+ lymphocyte counts >400 cells/µl). These subjects' ability to control viremia in the absence of therapy makes them the gold standard for the type of CD8+ T-cell response that should be induced with a vaccine. Studying the regulation of CD8+ T cells responses in these VCs provides the opportunity to discover mechanisms of durable control of HIV-1. Previous research has shown that the CD8+ T cell population in VCs is heterogeneous in its ability to inhibit virus replication and distinct T cells are responsible for virus inhibition. Further defining both the functional properties and regulation of the specific features of the select CD8+ T cells responsible for potent control of viremia the in VCs would enable better evaluation of T cell-directed vaccine strategies and may inform the design of new therapies.

Here we discuss the progress made in elucidating the features and regulation of CD8+ T cell response in virus controllers. We first detail the development of assays to quantify CD8+ T cells' ability to inhibit virus replication. This includes the use of a multi-clade HIV-1 panel which can subsequently be used as a tool for evaluation of T cell directed vaccines. We used these assays to evaluate the CD8+ response among cohorts of HIV-1 seronegative...

‣ Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation

Sivanathan, K.N.; Gronthos, S.; Rojas-Canales, D.; Thierry, B.; Coates, P.T.
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Bone marrow-derived mesenchymal stem cells (MSC) have unique immunomodulatory and reparative properties beneficial for allotransplantation cellular therapy. The clinical administration of autologous or allogeneic MSC with immunosuppressive drugs is able to prevent and treat allograft rejection in kidney transplant recipients, thus supporting the immunomodulatory role of MSC. Interferon-gamma (IFN-γ) is known to enhance the immunosuppressive properties of MSC. IFN-γ preactivated MSC (MSC-γ) directly or indirectly modulates T cell responses by enhancing or inducing MSC inhibitory factors. These factors are known to downregulate T cell activation, enhance T cell negative signalling, alter T cells from a proinflammatory to an anti-inflammatory phenotype, interact with antigen-presenting cells and increase or induce regulatory cells. Highly immunosuppressive MSC-γ with increased migratory and reparative capacities may aid tissue repair, prolong allograft survival and induce allotransplant tolerance in experimental models. Nevertheless, there are contradictory in vivo observations related to allogeneic MSC-γ therapy. Many studies report that allogeneic MSC are immunogenic due to their inherent expression of major histocompatibility (MHC) molecules. Enhanced expression of MHC in allogeneic MSC-γ may increase their immunogenicity and this can negatively impact allograft survival. Therefore...