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1.
J Allergy Clin Immunol ; 153(3): 572-575, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38253261

RESUMO

Systemic immunotherapeutics have been a clinical staple in the treatment of cancer, infectious diseases, organ and cell transplantation, autoimmunity, and allergies. Although their utility remains unquestioned, systemic administration of these drugs is associated with limited efficacy, significant adverse off-target effects, transient activity, and the requirement for frequent repeated dosing. To this end, recent technological advancements have provided novel means for sustained drug delivery to specific tissues and targeted localized approaches for immunotherapeutics. In this article, we present various cutting-edge platform technologies, including implants, multireservoir systems, and scaffolds encapsulating immunomodulatory agents for local administration. Examples of their application in cancer, cell transplantation, allergy, and infectious diseases are discussed, highlighting the potential of such systems for innovative immunomodulatory intervention.


Assuntos
Doenças Transmissíveis , Neoplasias , Humanos , Imunomodulação , Sistemas de Liberação de Medicamentos , Administração Cutânea
2.
J Allergy Clin Immunol ; 151(2): 324-344, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36424209

RESUMO

The family of cytokines that comprises IL-3, IL-5, and GM-CSF was discovered over 30 years ago, and their biological activities and resulting impact in clinical medicine has continued to expand ever since. Originally identified as bone marrow growth factors capable of acting on hemopoietic progenitor cells to induce their proliferation and differentiation into mature blood cells, these cytokines are also recognized as key mediators of inflammation and the pathobiology of diverse immunologic diseases. This increased understanding of the functional repertoire of IL-3, IL-5, and GM-CSF has led to an explosion of interest in modulating their functions for clinical management. Key to the successful clinical translation of this knowledge is the recognition that these cytokines act by engaging distinct dimeric receptors and that they share a common signaling subunit called ß-common or ßc. The structural determination of how IL-3, IL-5, and GM-CSF interact with their receptors and linking this to their differential biological functions on effector cells has unveiled new paradigms of cell signaling. This knowledge has paved the way for novel mAbs and other molecules as selective or pan inhibitors for use in different clinical settings.


Assuntos
Medicina Clínica , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Citocinas/metabolismo , Interleucina-3/metabolismo , Interleucina-5/metabolismo , Eosinófilos , Biologia
3.
N Engl J Med ; 389(23): 2189-2195, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38055256
5.
Curr Allergy Asthma Rep ; 14(1): 408, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24346805

RESUMO

Basophils have emerged in recent years as a small but potent subpopulation of leukocytes capable of bridging innate and adaptive immunity. They can be activated through IgE-dependent and IgE-independent mechanisms to release preformed mediators and to produce Th2 cytokines. In addition to their role in protective immunity to helminths, basophils are major participants in allergic reactions as diverse as anaphylaxis and immediate hypersensitivity reactions, late-phase hypersensitivity reactions, and delayed hypersensitivity reactions. Additionally, basophils have been implicated in the pathophysiology of autoimmune diseases such as lupus nephritis and rheumatoid arthritis, and the modulation of immune responses to bacterial infections, as well as being a feature of myelogenous leukemias. Distinct signals for activation, degranulation, transendothelial migration, and immune regulation are being defined, and demonstrate the important role of basophils in promoting a Th2 microenvironment. These mechanistic insights are driving innovative approaches for diagnostic testing and therapeutic targeting of basophils.


Assuntos
Doenças Autoimunes/imunologia , Basófilos/imunologia , Hipersensibilidade/imunologia , Infecções/imunologia , Neoplasias/imunologia , Imunidade Adaptativa , Anafilaxia/imunologia , Animais , Citocinas/imunologia , Humanos , Leucócitos/imunologia
6.
J Med Educ Curric Dev ; 11: 23821205241227328, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38304279

RESUMO

Physicians must adapt their learning and expertise to the rapid evolution of healthcare. To train for the innovation-efficient demands of adaptive expertise, medical students need to acquire the skill of adaptive self-regulated learning, which includes accessing, interpreting, and synthesizing emerging basic and translational research to support patient care. In response, we developed the course Medical Student Grand Rounds (MSGR). It engages all pre-clerkship students at our institution with self-regulated learning from translational basic research literature. In this report, we describe MSGR's methodology and important outcomes. Students found, interpreted, critically assessed, and presented basic research literature about self-selected clinically relevant topics. In less than one semester and mentored by basic science researchers, they completed eight milestones: (a) search research literature databases; (b) choose a clinical topic using searching skills; (c) outline the topic's background; (d) outline a presentation based on the topic's mechanistic research literature; (e) attend translational research-oriented grand rounds by faculty; (f) learn to prepare oral presentations; (g) write an abstract; and (h) present at Grand Rounds Day, emphasizing their topic's research literature. Graded milestones and end-of-course self-assessments indicated students became proficient in interpreting research articles, preparing and delivering presentations, understanding links among basic and translational research and clinical applications, and pursuing self-regulated learning. Qualitative analysis of self-assessment surveys found most students thought they progressed toward the learning objectives: find scientific information about a research topic (56% positive responses), interpret and critically assess scientific information (64%), and prepare and deliver a scientific presentation (50%). Milestones improve time management and provide a scaffolded method for presenting focused research topics. MSGR equips students with critical thinking skills for lifelong, adaptive, self-regulated learning-a foundation for adaptive expertise. The master adaptive learner cycle of planning, learning, assessing, and adjusting is a conceptual framework for understanding students' MSGR learning experiences.

7.
J Exp Med ; 204(8): 1837-47, 2007 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-17635955

RESUMO

Interleukin (IL) 25 (IL-17E), a distinct member of the IL-17 cytokine family, plays important roles in evoking T helper type 2 (Th2) cell-mediated inflammation that features the infiltrations of eosinophils and Th2 memory cells. However, the cellular sources, target cells, and underlying mechanisms remain elusive in humans. We demonstrate that human Th2 memory cells expressing distinctive levels of IL-25 receptor (R) are one of the responding cell types. IL-25 promotes cell expansion and Th2 cytokine production when Th2 central memory cells are stimulated with thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs), homeostatic cytokines, or T cell receptor for antigen triggering. The enhanced functions of Th2 memory cells induced by IL-25 are associated with sustained expression of GATA-3, c-MAF, and JunB in an IL-4-independent manner. Although keratinocytes, mast cells, eosinophils, and basophils express IL-25 transcripts, activated eosinophils and basophils from normal and atopic subjects were found to secrete bioactive IL-25 protein, which augments the functions of Th2 memory cells. Elevated expression of IL-25 and IL-25R transcripts was observed in asthmatic lung tissues and atopic dermatitis skin lesions, linking their possible roles with exacerbated allergic disorders. Our results provide a plausible explanation that IL-25 produced by innate effector eosinophils and basophils may augment the allergic inflammation by enhancing the maintenance and functions of adaptive Th2 memory cells.


Assuntos
Citocinas/metabolismo , Sistema Imunitário , Interleucina-17/fisiologia , Células Th2/imunologia , Proliferação de Células , Células Dendríticas/metabolismo , Eosinófilos/metabolismo , Fator de Transcrição GATA3/metabolismo , Humanos , Hipersensibilidade/metabolismo , Memória Imunológica , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo , Células Th2/metabolismo , Linfopoietina do Estroma do Timo
8.
Front Cardiovasc Med ; 10: 1213428, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38264262

RESUMO

Background: Traf2 and Nck-interacting kinase (TNIK) is known for its regulatory role in various processes within cancer cells. However, its role within endothelial cells (ECs) has remained relatively unexplored. Methods: Leveraging RNA-seq data and Ingenuity Pathway Analysis (IPA), we probed the potential impact of TNIK depletion on ECs. Results: Examination of RNA-seq data uncovered more than 450 Differentially Expressed Genes (DEGs) in TNIK-depleted ECs, displaying a fold change exceeding 2 with a false discovery rate (FDR) below 0.05. IPA analysis unveiled that TNIK depletion leads to the inhibition of the interferon (IFN) pathway [-log (p-value) >11], downregulation of IFN-related genes, and inhibition of Hypercytokinemia/Hyperchemokinemia [-log (p-value) >8]. The validation process encompassed qRT-PCR to evaluate mRNA expression of crucial IFN-related genes, immunoblotting to gauge STAT1 and STAT2 protein levels, and ELISA for the quantification of IFN and cytokine secretion in siTNIK-depleted ECs. These assessments consistently revealed substantial reductions upon TNIK depletion. When transducing HUVECs with replication incompetent E1-E4 deleted adenovirus expressing green fluorescent protein (Ad-GFP), it was demonstrated that TNIK depletion did not affect the uptake of Ad-GFP. Nonetheless, TNIK depletion induced cytopathic effects (CPE) in ECs transduced with wild-type human adenovirus serotype 5 (Ad-WT). Summary: Our findings suggest that TNIK plays a crucial role in regulating the EC response to virus infections through modulation of the IFN pathway.

9.
Curr Allergy Asthma Rep ; 12(5): 402-12, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22875242

RESUMO

The eosinophil is a multifunctional granulocyte best known for providing host defense against parasites. Paradoxically, eosinophils are also implicated in the pathogenesis of allergic inflammation, asthma, and hypereosinophilic syndromes. Emerging evidence also supports the potential for harnessing the cytotoxic power of eosinophils and redirecting it to kill solid tumors. Central to eosinophil physiology is interleukin-5 (IL-5) and its receptor (IL-5R) which is composed of a ligand-specific alpha chain (IL-5Rα) and the common beta chain (ßc). Eosinophil activation can lead to their degranulation, resulting in rapid release of an arsenal of tissue-destructive proinflammatory mediators and cytotoxic proteins that can be both beneficial and detrimental to the host. This review discusses eosinophil immunobiology and therapeutic strategies for targeting of IL-5 and IL-5R, as well as the potential for harnessing eosinophil cytotoxicity as a tumoricide.


Assuntos
Citotoxicidade Imunológica , Eosinófilos/imunologia , Síndrome Hipereosinofílica/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Interleucina-5/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptores de Interleucina-5/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/tratamento farmacológico , Síndrome de Churg-Strauss/tratamento farmacológico , Ensaios Clínicos como Assunto , Dermatite Atópica/tratamento farmacológico , Humanos , Síndrome Hipereosinofílica/imunologia , Hipersensibilidade/imunologia , Inflamação/tratamento farmacológico , Pólipos Nasais/tratamento farmacológico , Neoplasias/imunologia , Oligonucleotídeos Fosforotioatos/uso terapêutico
10.
Biomaterials ; 280: 121297, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34902729

RESUMO

Landmark successes in oncoimmunology have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor reduction in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunologically cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells. Biomaterial-based cancer vaccines enhance the cancer-immunity cycle by harnessing cellular recruitment and activation against tumor-specific antigens. In this review, we discuss biomaterial-based vaccine strategies to induce lymphocytic responses necessary to mediate anti-tumor immunity. We focus on strategies that selectively attract dendritic cells via immunostimulatory gradients, activate them against presented tumor-specific antigens, and induce effective cross-presentation to T cells in secondary lymphoid organs, thereby generating immunity. We posit that personalized cancer vaccines are promising targets to generate long-term systemic immunity against patient- and tumor-specific antigens to ensure long-term cancer remission.


Assuntos
Vacinas Anticâncer , Neoplasias , Antígenos de Neoplasias/uso terapêutico , Materiais Biocompatíveis/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Humanos , Imunoterapia , Neoplasias/tratamento farmacológico
11.
Acad Med ; 97(5): 684-688, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34789666

RESUMO

PROBLEM: Understanding and communicating medical advances driven by basic research, and acquiring foundational skills in critically appraising and communicating translational basic research literature that affects patient care, are challenging for medical students to develop. APPROACH: The authors developed a mandatory course from 2012 to 2018 at Texas A&M University College of Medicine to address this problem. Medical Student Grand Rounds (MSGR) trains first-year students to find, critically assess, and present primary research literature about self-selected medically relevant topics. With basic science faculty mentoring, students completed milestones culminating in oral presentations. Students learned to search literature databases and then choose a clinical subject using these skills. They outlined the clinical subject area background and a mechanistic research topic into a clinical problem based on deeper evaluation of primary research literature. "Mechanistic" was defined in this context as providing experimental evidence that explained the "how" and "why" underlying clinical manifestations of a disease. Students received evaluations and feedback from mentors about discerning the quality of information and synthesizing information on their topics. Finally, students prepared and gave oral presentations, emphasizing the primary literature on their topics. OUTCOMES: In the early stages of the course development, students had difficulty critically assessing and evaluating research literature. Mentored training by research-oriented faculty, however, dramatically improved student perceptions of the MSGR experience. Mentoring helped students develop skills to synthesize ideas from basic research literature. According to grades and self-evaluations, students increased proficiency in finding and interpreting research articles, preparing and delivering presentations, and understanding links among basic and translational research and clinical applications. NEXT STEPS: The authors plan to survey fourth-year students who have completed MSGR about their perceptions of the course in the context of clinical experiences in medical school to guide future refinements.


Assuntos
Educação de Graduação em Medicina , Estudantes de Medicina , Humanos , Mentores , Faculdades de Medicina , Pesquisa Translacional Biomédica
12.
Front Pharmacol ; 13: 833380, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105216

RESUMO

Allergic asthma is a chronic inflammatory respiratory disease associated with eosinophilic infiltration, increased mucus production, airway hyperresponsiveness, and airway remodeling. Epidemiologic data reveal that the prevalence of allergic sensitization and associated diseases has increased in the twentieth century. This has been hypothesized to be partly due to reduced contact with microbial organisms (the hygiene hypothesis) in industrialized society. Airway epithelial cells, once considered a static physical barrier between the body and the external world, are now widely recognized as immunologically active cells that can initiate, maintain, and restrain inflammatory responses, such as those that mediate allergic disease. Airway epithelial cells can sense allergens via expression of myriad Toll-like receptors (TLRs) and other pattern-recognition receptors. We sought to determine whether the innate immune response stimulated by a combination of Pam2CSK4 ("Pam2", TLR2/6 ligand) and a class C oligodeoxynucleotide ODN362 ("ODN", TLR9 ligand), when delivered together by aerosol ("Pam2ODN"), can modulate the allergic immune response to allergens. Treatment with Pam2ODN 7 days before sensitization to House Dust Mite (HDM) extract resulted in a strong reduction in eosinophilic and lymphocytic inflammation. This Pam2ODN immunomodulatory effect was also seen using Ovalbumin (OVA) and A. oryzae (Ao) mouse models. The immunomodulatory effect was observed as much as 30 days before sensitization to HDM, but ineffective just 2 days after sensitization, suggesting that Pam2ODN immunomodulation lowers the allergic responsiveness of the lung, and reduces the likelihood of inappropriate sensitization to aeroallergens. Furthermore, Pam2 and ODN cooperated synergistically suggesting that this treatment is superior to any single agonist in the setting of allergen immunotherapy.

13.
Curr Allergy Asthma Rep ; 10(5): 320-5, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20623372

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare disease of the lung characterized by the accumulation of surfactant-derived lipoproteins within pulmonary alveolar macrophages and alveoli, resulting in respiratory insufficiency and increased infections. The disease is caused by a disruption in surfactant catabolism by alveolar macrophages due to loss of functional granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. The underlying molecular mechanisms causing deficiencies in GM-CSF signaling are as follows: 1) high levels of neutralizing GM-CSF autoantibodies observed in autoimmune PAP; 2) mutations in CSF2RA, the gene encoding the alpha chain of the GM-CSF receptor, observed in hereditary PAP; and 3) reduced numbers and function of alveolar macrophages as a result of other clinical diseases seen in secondary PAP. Recent studies investigating the biology of GM-CSF have revealed that not only does this cytokine have an indispensable role in lung physiology, but it is also a critical regulator of innate immunity and lung host defense.


Assuntos
Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/fisiopatologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos , Autoimunidade/imunologia , Contagem de Células , Humanos , Lipoproteínas/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/patologia , Mutação , Proteinose Alveolar Pulmonar/terapia , Alvéolos Pulmonares/fisiopatologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Transdução de Sinais
14.
J Leukoc Biol ; 81(4): 1137-48, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17227823

RESUMO

IL-5, IL-3, and GM-CSF are related hematopoietic cytokines, which regulate the function of myeloid cells and are mediators of the allergic inflammatory response. These cytokines signal through heteromeric receptors containing a specific alpha chain and a shared signaling chain, betac. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the betac-sharing receptors. In this study, the upstream molecular events leading to proteasome degradation of the IL-5 receptor (IL-5R) were examined. By using biochemical and flow cytometric methods, we show that JAK kinase activity is required for betac ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the betac cytoplasmic domain and identify lysine residues 566 and 603 as sites of betac ubiquitination. Lastly, we show that ubiquitination of the betac cytoplasmic domain begins at the plasma membrane, increases after receptor internalization, and is degraded by the proteasome after IL-5R internalization. We propose an updated working model of IL-5R down-regulation, whereby IL-5 ligation of its receptor activates JAK2/1 kinases, resulting in betac tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the betac cytoplasmic domain, and the truncated receptor complex is terminally degraded in the lysosomes. These data establish a critical role for JAK kinases and the Ub/proteasome degradation pathway in IL-5R down-regulation.


Assuntos
Regulação para Baixo , Janus Quinases/metabolismo , Receptores de Interleucina-5/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo , Quinases da Família src/metabolismo , Linhagem Celular , Células Cultivadas , Citoplasma/metabolismo , Endocitose , Inibidores Enzimáticos/farmacologia , Eosinófilos/enzimologia , Eosinófilos/metabolismo , Eosinófilos/fisiologia , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Lisina/química , Modelos Biológicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/fisiologia , Tirfostinas/farmacologia
17.
Pharmacol Ther ; 94(3): 253-64, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12113801

RESUMO

For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (T(H)2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key T(H)2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the T(H)2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.


Assuntos
Interleucina-13/uso terapêutico , Interleucina-5/uso terapêutico , Humanos , Hipersensibilidade/imunologia , Interleucina-13/fisiologia , Interleucina-4/fisiologia , Interleucina-4/uso terapêutico , Interleucina-5/fisiologia , Receptores de Interleucina/fisiologia , Células Th2/metabolismo
19.
Clin Rev Allergy Immunol ; 23(2): 201-16, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12221865

RESUMO

Urticarial vasculitis is a clinico-pathologic entity typified by recurrent episodes of urticaria that have the histopathologic features of leukocytoclastic vasculitis. The cutaneous features may include painful, burning or pruritic skin lesions, the persistence of individual lesions greater than 24 hours, palpable purpura, pronounced central clearing of lesions, and residual hyperpigmentation following resolution. However, because clinical characteristics of urticarial vasculitis may overlap with those of allergic urticaria, confirmation of the diagnosis requires a lesional skin biopsy. This condition is idiopathic in many patients but can also occur in the context of autoimmune disorders, infections, drug reactions, or as a paraneoplastic syndrome. In idiopathic urticarial vasculitis common laboratory findings are an elevation of erythrocyte sedimentation rate and reduction of serum complement. An association between urticarial vasculitis and systemic lupus erythematosus has been hypothesized as some clinical manifestations of disease overlap and C1q autoantibodies may be present in both diseases. Normo-complementemic patients usually have minimal or no systemic involvement and often have a better prognosis. On-the-other-hand, hypocomplementemic patients have the propensity to have more severe multi-organ involvement. Response to treatment is variable and a wide variety of therapeutic agents may be efficacious. Initial recommendations for treatment of urticarial vasculitis manifest only as non-necrotizing skin lesions include antihistamines, dapsone, colchicine, hydroxychloroquine or indomethacin, but corticosteroids are often required. With necrotizing skin lesions or visceral involvement, corticosteroids are regularly indicated. Cases of severe corticosteroid resistant urticarial vasculitis or where corticosteroid morbidity is evident [table: see text] may require treatment with other immunosuppressive agents such as azathioprine, cyclophosphamide, or cyclosporine.


Assuntos
Urticária/fisiopatologia , Vasculite Leucocitoclástica Cutânea/fisiopatologia , Humanos , Urticária/diagnóstico , Urticária/epidemiologia , Urticária/terapia , Vasculite Leucocitoclástica Cutânea/diagnóstico , Vasculite Leucocitoclástica Cutânea/terapia
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