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2.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36650020

RESUMO

BACKGROUND: Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment. METHODS: We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models. RESULTS: Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo. CONCLUSION: Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.


Assuntos
Reabsorção Óssea , Mieloma Múltiplo , Quinolonas , Animais , Camundongos , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Proliferação de Células , Imunossupressores/farmacologia , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Quinolonas/metabolismo , Microambiente Tumoral , Humanos
4.
Nat Commun ; 13(1): 7951, 2022 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-36572684

RESUMO

Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.


Assuntos
Diabetes Mellitus Tipo 1 , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Ratos , Animais , Masculino , Diabetes Mellitus Tipo 1/terapia , Terapia de Imunossupressão , Tolerância Imunológica , Imunossupressores/farmacologia , Sobrevivência de Enxerto
5.
J Immunother Cancer ; 10(12)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36543374

RESUMO

BACKGROUND: B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood. METHODS: We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing. RESULTS: Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell-cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy. CONCLUSIONS: We have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.


Assuntos
Linfócitos B , Linfócitos T , Imunossupressores/farmacologia , Sirolimo , Imunoterapia
6.
Molecules ; 27(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36364101

RESUMO

Tripterygium wilfordii Hook. f. is a well-known traditional Chinese medicine used to treat autoimmune diseases. Sesquiterpene pyridine alkaloids (SPAs) are a major class of components found in this herb that have piqued the interest of researchers due to their complex and diverse structures as well as significant biological activities. In this study, ten new SPAs, wilfordatine A-J (1-10), were isolated from the roots of T. wilfordii, along with ten known analogues (11-20). Their structures were primarily elucidated by extensive 1D and 2D NMR spectroscopic analysis. To search for more immunosuppressive ingredients related to the clinical efficacy of T. wilfordii, the total alkaloids (TA) and compounds 4, 5, and 9-16 were tested for their inhibitory effects on nuclear factor-kappa B (NF-κB) pathway in Lipopolysaccharide (LPS) induced HEK293/NF-κB-Luc cells. Among them, TA, compounds 5, 11, and 16 showed potent immunosuppressive activity, with IC50 values of 7.25 µg/mL, 8.75 µM, 0.74 µM, and 15.66 µM, respectively, and no influence on the cell viability at a concentration of 100 µg/mL (TA) or 100 µM (5, 11, and 16). Accordingly, TA, 5, 11, and 16, especially 11, were identified as promising candidates for further investigation into their potential use as immunosuppressive agents.


Assuntos
Alcaloides , Medicamentos de Ervas Chinesas , Sesquiterpenos , Humanos , Tripterygium/química , NF-kappa B , Células HEK293 , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Alcaloides/farmacologia , Alcaloides/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Piridinas/farmacologia , Piridinas/química , Imunossupressores/farmacologia
7.
Ann Plast Surg ; 89(6): 684-693, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36416704

RESUMO

BACKGROUND: This study evaluated the potential of Wharton's jelly mesenchymal stem cells with high tolerogenic properties in reducing immunosuppressive dosage and related adverse effects. METHODS: A 4- to 6-week-old, 30-40 g weight, male inbred CD57BL/6 mice were used as skin allograft donors, whereas Balb/c mice with similar characteristics were used as recipients. Wharton's jelly stem cells were obtained from a commercial kit sourced from human umbilical cord. Skin allografts were performed from CD57Bl6 to Balb/c mice (day 0). Group 1 (control) received no treatment. Group 2 received 15 mg/kg cyclosporin A on days 0 to 30. Group 3 received 5.7 × 10 6 and 10.3 × 10 6 cell/kg Wharton's jelly stem cells on days 0 and 3, respectively. Groups 4, 5, and 6 received a combination of 15, 10, and 5 mg/kg per day cyclosporine A (days 0 to 30) with the same stem cell dose with group 3, respectively. Graft rejection was evaluated with digital photography and thermal imaging, histopathology (Banff grading, epithelialization scores, dermoepidermal dissociation), immunochemistry (Ki-67 and Bcl-2), and biochemical methods (interleukin 10, interleukin 2, interferon γ, tumor necrosis factor α) (day 10). Cumulative adverse effects of cyclosporin A occurring in the groups were revealed by histopathological evaluation of kidney and liver (a modified semiquantitative method of infiltration of inflammatory cells around the portal area and lobular region in liver; modification of the Banff rating of proximal tubules and hypertrophia of juxtaglomerular apparatus cells in kidney) (day 30). RESULTS: There was no rejection in groups 2, 4, and 5 until the end of study. These were statistically different versus groups 1 (day 10 ± 0.71), 3 (day 11 ± 0.82), and 6 (day 11 ± 0.58) (all P 's < 0.05). Groups 4 and 5 have exhibited statistically similar findings in histopathological (4 epithelization score: 3.7 ± 1.3; 5 epithelization score: 3.5 ± 0.5; 4 Banff grading score: 0.8 ± 0.6; 5 Banff grading score: 1.0 ± 0.5; both P 's = 1.00), immunohistochemical (4 Bcl-2 score: 3.5 ± 0.5, P = 0.618; 5 Bcl-2 score: 3.4 ± 0.5, P = 1.00; 4 Ki-67 score: 3.7 ± 0.4, P = 1.00; 5 Ki-67 score: 3.5 ± 0.5, both P 's = 1.00), and levels of cytokines (both P 's = 1.00) versus group 2. Adverse effects on kidneys and liver were lowest and statistically similar in groups 3, 5, and 6 (all P 's = 00) versus group 1. CONCLUSIONS: Wharton's jelly mesenchymal stem cells alter bioavailability of cyclosporine, albeit at much lower doses and with fewer systemic adverse effects.


Assuntos
Ciclosporina , Células-Tronco Mesenquimais , Masculino , Humanos , Camundongos , Animais , Ciclosporina/farmacologia , Antígeno Ki-67 , Cordão Umbilical , Mesoderma , Imunossupressores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2
8.
Arch Immunol Ther Exp (Warsz) ; 70(1): 27, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318344

RESUMO

In particular conditions, inhibition of an immune response is required to prevent tissue damage. Among these conditions are diseases caused by an over-reactive immune response, such as autoimmune or allergic disorders, or imminent organ rejection after transplantation. To avoid tissue damage, drug-mediated systemic immune suppression is an option, but it comes with high costs in the form of susceptibility to viral and bacterial infections. Thus, the induction of antigen-specific tolerance is preferable. Extracellular vesicles (EVs) are capable of delivering antigen together with immunosuppressive signals and may be used to specifically induce antigen-specific tolerance. However, naturally occurring EVs are heterogeneous and not all of them show immunosuppressive character. In our trials to engineer cell culture derived EVs to increase their tolerogenic potential, we equipped them with immunosuppressive miRNA mimics. Small EVs (sEVs) were isolated and purified from the human monocytic THP-1 cell line or from healthy donor peripheral blood mononuclear cells, and electroporated with miR-494 and miR-146a mimics. The acquired immunosuppressive potential of the modified sEVs was demonstrated by their ability to alter the major histocompatibility complex molecules and co-stimulatory receptors present on dendritic cells (DCs). To avoid allogeneic responses, the same cells that produced the sEVs served also as recipient cells. In contrast to the treatment with unmodified sEVs, the tolerogenic sEVs impeded lipopolysaccharide-induced maturation and kept DCs in a more immature developmental stage. Our experiments show that simple manipulations of sEVs using immunosuppressive cargo can lead to the inhibition of DC maturation.


Assuntos
Vesículas Extracelulares , MicroRNAs , Humanos , MicroRNAs/metabolismo , Células Dendríticas , Leucócitos Mononucleares , Vesículas Extracelulares/metabolismo , Diferenciação Celular , Imunossupressores/farmacologia , Antígenos/metabolismo
9.
Sci Rep ; 12(1): 20656, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36450761

RESUMO

To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressants on the expression levels of multidrug resistance genes in patients with ulcerative colitis (UC), with the aim of providing a theoretical and therapeutic basis for the diagnosis, treatment, and prevention of UC. Fresh colonic mucosal tissues or postoperative pathological biopsies from 148 UC patients were collected, and the distribution sites and morphology of P-glycoprotein (P-gp) were detected using immunohistochemical staining. RT-PCR was used to quantify the expression levels of multidrug resistance gene (MDR1) mRNA before and after the corresponding treatment, and the effects of aminosalicylic acid, glucocorticoids and immunosuppressive drugs on P-gp were compared. In addition, the effects of the three drugs on MDR1 mRNA were analyzed. Administration of 5-aminosalicylic acid (5-ASA) drugs did not correlate with MDR1 expression in UC, whereas administration of glucocorticoids and immunosuppressive drugs was positively correlated with MDR1 expression profile. The expression levels of MDR1 mRNA and its product P-gp were significantly upregulated in patients who did not respond to glucocorticoids and immunosuppressive drugs. 5-ASA had no effect on the expression levels of MDR1 and its product P-gp in patients with a confirmed diagnosis of UC. However, the use of glucocorticoids and immunosuppressants can increase the expression level of MDR1.


Assuntos
Ácido Aminossalicílico , Colite Ulcerativa , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Mesalamina/farmacologia , Mesalamina/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , RNA Mensageiro/genética
10.
Int J Mol Sci ; 23(22)2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36430909

RESUMO

Azathioprine (AZA) is a pharmacologic immunosuppressive agent administrated in various conditions such as autoimmune disease or to prevent the rejection of organ transplantation. The mechanism of action is based on its biologically active metabolite 6-mercaptopurine (6-MP), which is converted, among others, into thioguanine nucleotides capable of incorporating into replicating DNA, which may act as a strong UV chromophore and trigger DNA oxidation. The interaction between azathioprine and DNA, before and after exposure to solar simulator radiation, was investigated using UV-vis spectrometry and differential pulse voltammetry at a glassy carbon electrode. The results indicated that the interaction of AZA with UV radiation was pH-dependent and occurred with the formation of several metabolites, which induced oxidative damage in DNA, and the formation of DNA-metabolite adducts. Moreover, the viability assays obtained for the L929 cell culture showed that both azathioprine and degraded azathioprine induced a decrease in cell proliferation.


Assuntos
Azatioprina , Mercaptopurina , Azatioprina/farmacologia , Fotólise , Mercaptopurina/farmacologia , DNA , Imunossupressores/farmacologia , Adutos de DNA
11.
J Med Chem ; 65(21): 14305-14325, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36263926

RESUMO

New drugs that precisely target the immune mechanisms critical for cytotoxic T lymphocyte (CTL) and natural killer (NK) cell driven pathologies are desperately needed. In this perspective, we explore the cytolytic protein perforin as a target for therapeutic intervention. Perforin plays an indispensable role in CTL/NK killing and controls a range of immune pathologies, while being encoded by a single copy gene with no redundancy of function. An immunosuppressant targeting this protein would provide the first-ever therapy focused specifically on one of the principal cell death pathways contributing to allotransplant rejection and underpinning multiple autoimmune and postinfectious diseases. No drugs that selectively block perforin-dependent cell death are currently in clinical use, so this perspective will review published novel small molecule inhibitors, concluding with in vivo proof-of-concept experiments performed in mouse models of perforin-mediated immune pathologies that provide a potential pathway toward a clinically useful therapeutic agent.


Assuntos
Autoimunidade , Citotoxicidade Imunológica , Camundongos , Animais , Perforina , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Imunossupressores/metabolismo , Proteínas Citotóxicas Formadoras de Poros , Glicoproteínas de Membrana/metabolismo , Linfócitos T Citotóxicos
12.
Front Cell Infect Microbiol ; 12: 958634, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211973

RESUMO

Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.


Assuntos
Coronavirus Humano 229E , Infecções por Coronavirus , Coronavirus , Coronavirus/genética , Coronavirus Humano 229E/genética , Infecções por Coronavirus/genética , Ciclofilinas , Ciclosporina/química , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Células HEK293 , Humanos , Imunossupressores/farmacologia , Luciferases de Renilla , Preparações Farmacêuticas , RNA , Tacrolimo/química , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Proteínas de Ligação a Tacrolimo/farmacologia , Proteínas de Ligação a Tacrolimo/uso terapêutico
13.
Biomolecules ; 12(10)2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-36291734

RESUMO

Cyclosporine A (CsA) is a selective and reversible immunosuppressant agent that is widely used as a medication for a wide spectrum of diseases in humans such as graft versus host disease, non-infectious uveitis, rheumatoid arthritis, psoriasis, and atopic dermatitis. Furthermore, the CsA is used to treat keratoconjunctivitis sicca, chronic superficial keratitis, immune-mediated keratitis and equine recurrent uveitis in animals. The selective activity of Cyclosporine A (CsA) was demonstrated to be an immunomodulation characteristic of T-lymphocyte proliferation and inhibits cytokine gene expression. Moreover, the lipophilic characteristics with poor bioavailability and low solubility in water, besides the side effects, force the need to develop new formulations and devices that will provide adequate penetration into the anterior and posterior segments of the eye. This review aims to summarize the effectiveness and safety of cyclosporine A delivery platforms in veterinary ophthalmology.


Assuntos
Ceratite , Oftalmologia , Uveíte , Humanos , Cavalos , Animais , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Uveíte/tratamento farmacológico , Ceratite/tratamento farmacológico , Citocinas , Água
14.
Cells ; 11(19)2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36230898

RESUMO

The cytoprotective effects of a novel hydroalcoholic extract (0.01-5 mg/mL) from Lens culinaria (Terre di Altamura Srl) were investigated within murine native skeletal muscle fibers, bone marrow cells, and osteoblasts, and in cell lines treated with the apoptotic agent staurosporine (2.14 × 10-6 M), the alkylating drug cisplatin (10-4 M), the topoisomerase I inhibitor irinotecan (10-4 M), the antimitotic pro-oxidant doxorubicin (10-6 M), and the immunosuppressant dexamethasone (2 × 10-6 M). An amount of 10g of plant material was used to obtain a 70% ethanol/water product, following two-step extraction, evaporation, lyophilization, and storage at -20 °C. For the murine osteoblasts, doxorubicin reduced survival by -65%, dexamethasone by -32% and -60% after 24 and 48 h of incubation time, respectively. The extract was effective in preventing the osteoblast count-reduction induced by dexamethasone; it was also effective at preventing the inhibition of mineralization induced by dexamethasone. Doxorubicin and cisplatin caused a significant reduction in cell growth by -77% for bone marrow cells, -43% for irinotecan, and -60% for dexamethasone, but there was no evidence for the cytoprotective effects of the extract in these cells. Staurosporine and doxorubicin caused a fiber death rate of >-40% after 18 and 24 h of incubation, yet the extract was not effective at preventing these effects. The extract was effective in preventing the staurosporine-induced reduction of HEK293 proliferation and colony formation in the crystal violet DNA staining and the clonogenic assays. It was also effective for the cisplatin-induced reduction in HEK293 cell proliferation. The extract, however, failed to protect the SHSY5Y neurons against cisplatin and irinotecan-induced cytotoxicity. A UV/VIS spectroscopy analysis showed three peaks at the wavelengths of 350, 260, and 190 nm, which correspond to flavonoids, proanthocyanins, salicylates, and AA, constituting the extract. These data suggest the possible development of this extract for use against dexamethasone-induced bone loss and renal chemotherapy-induced damage.


Assuntos
Antimitóticos , Dexametasona , Animais , Antimitóticos/metabolismo , Antimitóticos/farmacologia , Cisplatino/metabolismo , Cisplatino/farmacologia , Dexametasona/farmacologia , Doxorrubicina/farmacologia , Etanol/farmacologia , Flavonoides/farmacologia , Violeta Genciana/metabolismo , Violeta Genciana/farmacologia , Células HEK293 , Humanos , Imunossupressores/farmacologia , Irinotecano/farmacologia , Camundongos , Osteoblastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Salicilatos/metabolismo , Salicilatos/farmacologia , Estaurosporina/farmacologia , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Água/metabolismo
15.
Iran J Immunol ; 19(3): 219-231, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36190377

RESUMO

BACKGROUND: Impaired renal function is considered as a significant risk factor for cardiovascular events in chronic kidney disease patients. Several immunosuppressive drugs are used in these patients, which necessitates to minimize the drug-related side effects by employing alternative strategies. OBJECTIVE: This study aimed to evaluate prospectively the influence of low dose ATG induction therapy with two different protocols (Sirolimus versus Mycophenolate mofetil) on the expression of functional markers (LAG-3, CD39, and intracellular CTLA-4) on conventional Tregs in renal recipients. METHODS: Thirty-eight renal transplant recipients were enrolled in this study. The patients were randomly assigned into two groups, including TMP: Tacrolimus (Tac), Mycophenolate mofetil (MMF), and Prednisolone (n=23); and TSP: Tac, Sirolimus (SRL), and Prednisolone (n=15). The frequency of LAG-3, CD39, and intracellular CTLA-4 on circulating Tregs was analyzed by flow cytometry before and after transplantation. RESULTS: Analysis of the flow cytometry data showed that the frequency of CD4+CD25+FOXP3+ Tregs increased 4 months post-transplantation compared to pre-transplantation in both groups, although this increase was only significant in TMP group. In TMP treated patients, the frequency of LAG-3+ Tregs and CD39+ Tregs increased, whereas the frequency of intracellular CTLA-4+ Tregs decreased 4 months post-transplantation. In TSP group, while the frequency of CD39+ Tregs increased, the frequency of CTLA-4+ Tregs decreased in post-transplantation compared to pre-transplantation. CONCLUSIONS: it seems that both treatment regimen protocols with a low dose ATG induction therapy may be clinically applicable in kidney transplant recipients.


Assuntos
Transplante de Rim , Ácido Micofenólico , Sirolimo , Linfócitos T Reguladores , Aloenxertos , Antígeno CTLA-4 , Protocolos Clínicos , Fatores de Transcrição Forkhead , Humanos , Imunossupressores/farmacologia , Rim/fisiologia , Ácido Micofenólico/farmacologia , Prednisolona/farmacologia , Sirolimo/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Tacrolimo/farmacologia
16.
Front Immunol ; 13: 964263, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059457

RESUMO

Objectives: The analysis of gene module expression in SLE is emerging as a tool to identify active biological pathways, with the aim of developing targeted therapies for subsets of patients. Detailed information on the effect of immunosuppressants on gene module expression is lacking. We aimed to examine the impact of medication exposure on gene module expression. Methods: A set of commercially available disease-relevant gene modules were measured in 730 whole blood samples from a dedicated lupus clinic on whom prospectively collected, contemporaneous clinical data including medication exposure were available. Results: Compared to heathy controls, SLE patients showed over-expression of IFN and under-expression of B cell, T cell and pDC modules. Neutrophil module over-expression and under-expression of B and T cell modules were observed in patients with active lupus nephritis or highly active disease (SLEDAI-2K > 8), while Lupus Low Disease Activity State (LLDAS) had inverse associations. Disease activity in other organ domains was not associated with specific gene modules. In contrast, medications were associated with multiple effects. Glucocorticoid use was associated with under-expression of T cell, B cell and plasmablast modules, and over-expression of neutrophil modules. Mycophenolate and azathioprine exposure were associated with plasmablast module and B cell module under-expression respectively. Disease activity associations with neutrophil over-expression and lymphocyte module under-expression were attenuated by multivariable adjustment for medication exposure. Conclusion: Medications have significant effect on gene module expression in SLE patients. These findings emphasize the need to control for medications in studies of gene expression in SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/genética
17.
Int J Mol Sci ; 23(18)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36142329

RESUMO

Silibinin, a natural polyphenolic flavonoid, is known to possess anti-inflammatory, anticancer, antioxidant, and immunomodulatory properties. However, the effects of Silibinin on the maturation and immunostimulatory functions of human dendritic cells (DC) remain to be elucidated. In this study, we have attempted to ascertain whether Silibinin influences the maturation, cytokine production, and antigen-presenting capacity of human monocyte-derived DC. We show that Silibinin significantly suppresses the upregulation of costimulatory and MHC molecules in LPS-stimulated mature DC and inhibits lipopolysaccharide (LPS)-induced interleukin (IL)-12, IL-23, and TNF-α production. Furthermore, Silibinin impairs the proliferation response of the allogenic memory CD4 T lymphocytes elicited by LPS-matured DC and their Th1/Th17 profile. These findings demonstrate that Silibinin displays immunosuppressive activity by inhibiting the maturation and activation of human DC and support its potential application of adjuvant therapy in the treatment of autoimmune diseases.


Assuntos
Lipopolissacarídeos , Monócitos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Diferenciação Celular , Células Cultivadas , Citocinas/farmacologia , Células Dendríticas , Flavonoides/farmacologia , Humanos , Imunossupressores/farmacologia , Interleucina-12 , Interleucina-23 , Lipopolissacarídeos/farmacologia , Silibina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
18.
Transpl Immunol ; 75: 101704, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36057381

RESUMO

Non-human primate (NHP) renal transplantation models are widely used vivo models for researching new immunosuppressive therapies including allograft tolerance strategies. To enroll animals into a tolerance study, an immunosuppressive regimen that efficiently establishes stable renal function in NHPs is needed. Here, we assessed the effect of triple therapy comprising 2.0 mg/kg tacrolimus, mycophenolate mofetil and a steroid and its success rate for achieving stable renal function. In addition, to predict the pathophysiological consequences of withdrawing immunosuppressants, an indispensable process after induction of tolerance, we also assessed changes in the stable renal state maintained by triple therapy after drug withdrawal. Six cynomolgus monkeys were used. The median survival time was >176 days over the dosing period and 45 days after drug withdrawal. The triple therapy successfully induced stable graft function without calcineurin inhibitor nephrotoxicity in three of six recipients, although adopting trough-dependent tacrolimus dose adjustment rather than a preset dose regimen could improve on the present strategy. Further, drug withdrawal led to deterioration of renal function, de novo donor specific antibody production and increased the memory/naïve T cell ratio within two weeks post drug withdrawal. We expect that these findings contribute to establish one of the choices for animal model for evaluating future tolerance therapy for renal transplantation.


Assuntos
Transplante de Rim , Animais , Tacrolimo/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Ácido Micofenólico/uso terapêutico , Imunossupressores/uso terapêutico , Imunossupressores/farmacologia , Primatas , Inibidores de Calcineurina/uso terapêutico , Sobrevivência de Enxerto , Quimioterapia Combinada
19.
Transplant Proc ; 54(7): 1998-2007, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36041932

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. METHODS: Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. RESULTS: Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. CONCLUSIONS: Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.


Assuntos
Transplante de Pulmão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Ratos , Animais , Transplante de Células-Tronco Mesenquimais/métodos , Tacrolimo/farmacologia , Tecido Adiposo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células-Tronco Mesenquimais/metabolismo , Imunossupressores/farmacologia
20.
Front Biosci (Landmark Ed) ; 27(8): 230, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-36042174

RESUMO

BACKGROUND: This report aims to detail the use of the phosphorescence oxygen analyzer for in vitro investigation of thymic responses to pharmaceutical agents, in particular immunosuppressants and immunomodulators. Sirolimus (a highly specific inhibitor of the 'molecular target of rapamycin', mTOR) and ozanimod (an agonist of the sphingosine 1-phosphate receptor, recently approved for treatment of multiple sclerosis and ulcerative colitis) are used for this purpose. METHODS: Thymic fragments from mice were placed in glass vials containing phosphate-buffered saline, bovine albumin, and Pd(II) meso-tetra (sulfophenyl) tetrabenzoporphyrin. The vials were sealed from air, and the cellular oxygen consumption was monitored as function of time. RESULTS: The decline of dissolved oxygen concentration with time (d[O2]/dt) was linear; thus, its rate (thymocyte respiration) was expressed as µM O2 min-1. Cyanide inhibited respiration, confirming the oxygen consumption was in cytochrome oxidase. In age-matched mice, the rate of thymocyte respiration (mean ± SD, in µM O2 min-1 mg-1) was 0.046 ± 0.011 (median = 0.043, range = 0.028 to 0.062, n = 10). In thymic fragments from littermates, this rate was inhibited in the presence of sirolimus (16% lower) or ozanimod (29% lower). CONCLUSIONS: Thymocyte respiration can serve as a surrogate biomarker for studying the mode-of-action and the cytotoxicity of immunotoxins and immunosuppressants.


Assuntos
Consumo de Oxigênio , Sirolimo , Animais , Bovinos , Respiração Celular , Imunossupressores/farmacologia , Camundongos , Oxigênio , Consumo de Oxigênio/fisiologia , Sirolimo/farmacologia
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