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1.
Biomed Res Int ; 2021: 9318725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692845

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic poses a special risk for both immunosuppressed patients, especially transplant recipients. Although the knowledge about this infection is growing, many uncertainties remain, particularly regarding the kidney. Kidney transplant recipients (KDRs) should be considered immunocompromised hosts since a potential risk for infection, comorbidity, and immunosuppression exposure exists. Additionally, the management of immunosuppressive agents in KDRs remains challenging. Potential drug interactions with immunosuppressive treatment escalated the risk of unwanted side effects. In this review, we aimed to attain an augmented awareness and improved management immunosuppressant for COVID-19 KDRs.


Assuntos
COVID-19/imunologia , Imunossupressores/uso terapêutico , Transplante de Rim , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/imunologia , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , SARS-CoV-2/efeitos dos fármacos
2.
Expert Rev Clin Pharmacol ; 14(11): 1321-1323, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34402354

RESUMO

Pregnancy is still a challenge in women with autoimmune diseases or kidney transplantation. In this context, management of the immunosuppressive therapy is critical, but, in spite of more than 60 years of experience, many issues remain open, also because of the difficulty in disentangling, in complex patients, the effect of the disease and of the frequent multiple treatments. For this purpose, we have tried to synthesize the existing knowledge and the unresolved issues, to support counseling and promote patient empowerment.


Assuntos
Imunossupressores/administração & dosagem , Complicações na Gravidez/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Feminino , Humanos , Imunossupressores/imunologia , Nefropatias/tratamento farmacológico , Nefropatias/imunologia , Transplante de Rim/métodos , Gravidez , Complicações na Gravidez/imunologia
3.
J Vet Sci ; 22(5): e63, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34423601

RESUMO

BACKGROUND: Recently, mesenchymal stem cells therapy has been performed in dogs, although the outcome is not always favorable. OBJECTIVES: To investigate the therapeutic efficacy of mesenchymal stem cells (MSCs) using dog leukocyte antigen (DLA) matching between the donor and recipient in vitro. METHODS: Canine adipose-derived MSCs (cA-MSCs) isolated from the subcutaneous tissue of Dog 1 underwent characterization. For major DLA genotyping (DQA1, DQB1, and DRB1), peripheral blood mononuclear cells (PBMCs) from two dogs (Dogs 1 and 2) were analyzed by direct sequencing of polymerase chain reaction (PCR) products. The cA-MSCs were co-cultured at a 1:10 ratio with activated PBMCs (DLA matching or mismatching) for 3 days and analyzed for immunosuppressive (IDO, PTGS2, and PTGES), inflammatory (IL6 and IL10), and apoptotic genes (CASP8, BAX, TP53, and BCL2) by quantitative real-time reverse transcriptase-PCR. RESULTS: cA-MSCs were expressed cell surface markers such as CD90+/44+/29+/45- and differentiated into osteocytes, chondrocytes, and adipocytes in vitro. According to the Immuno Polymorphism Database, DLA genotyping comparisons of Dogs 1 and 2 revealed complete differences in genes DQA1, DQB1, and DRB1. In the co-culturing of cA-MSCs and PBMCs, DLA mismatch between the two cell types induced a significant increase in the expression of immunosuppressive (IDO/PTGS2) and apoptotic (CASP8/BAX) genes. CONCLUSIONS: The administration of cA-MSCs matching the recipient DLA type can alleviate the need to regulate excessive immunosuppressive responses associated with genes, such as IDO and PTGES. Furthermore, easy and reliable DLA genotyping technology is required because of the high degree of genetic polymorphisms of DQA1, DQB1, and DRB1 and the low readability of DLA 88.


Assuntos
Tecido Adiposo/metabolismo , Imunossupressores/imunologia , Transplante de Células-Tronco Mesenquimais/veterinária , Células-Tronco Mesenquimais/imunologia , Animais , Cães , Masculino
4.
Ann Rheum Dis ; 80(10): 1322-1329, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34362747

RESUMO

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.


Assuntos
Doenças Autoimunes/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Hospedeiro Imunocomprometido/imunologia , Imunogenicidade da Vacina/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Doenças Autoimunes/tratamento farmacológico , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Linfócitos T/imunologia
5.
Sci Rep ; 11(1): 13559, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193890

RESUMO

Prostaglandin E2 (PGE2), an active lipid compound derived from arachidonic acid, regulates different stages of the immune response of the host during several pathologies such as chronic infections or cancer. In fact, manipulation of PGE2 levels was proposed as an approach for countering the Type I IFN signature of tuberculosis (TB). However, very limited information regarding the PGE2 pathway in patients with active TB is currently available. In the present work, we demonstrated that PGE2 exerts a potent immunosuppressive action during the immune response of the human host against Mycobacterium tuberculosis (Mtb) infection. Actually, we showed that PGE2 significantly reduced the surface expression of several immunological receptors, the lymphoproliferation and the production of proinflammatory cytokines. In addition, PGE2 promoted autophagy in monocytes and neutrophils cultured with Mtb antigens. These results suggest that PGE2 might be attenuating the excessive inflammatory immune response caused by Mtb, emerging as an attractive therapeutic target. Taken together, our findings contribute to the knowledge of the role of PGE2 in the human host resistance to Mtb and highlight the potential of this lipid mediator as a tool to improve anti-TB treatment.


Assuntos
Dinoprostona/farmacologia , Imunossupressores/farmacologia , Monócitos/imunologia , Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Tuberculose/imunologia , Adulto , Dinoprostona/imunologia , Feminino , Humanos , Imunossupressores/imunologia , Masculino
6.
Front Immunol ; 12: 676558, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135902

RESUMO

Allergen-specific-immunotherapy (ASIT) can cause long-term resolution of allergic diseases, reduces drug use and chances of new allergen sensitization. Nevertheless, therapeutic vaccine and data on ASIT efficacy for cockroach (CR) allergy are relatively scarce. In this study, efficacy and mechanism of a novel intranasal vaccine consisting of liposome (L)-entrapped mixture of American CR (Periplaneta americana) major allergen (Per a 9) and immunosuppressive protein of Brugia malayi nematode named transforming growth factor-beta homologue (TGH) in treatment of CR allergy were investigated along with two other vaccines (L-Per a 9 alone and L-TGH alone). All three vaccines could reduce pathogenic type 2 response and lung immunopathology in the vaccines-treated CR-allergic mice, but by different mechanisms. L-Per a 9 caused a deviation of the pathogenic type 2 to type 1 response (IFN-γ-upregulation), whereas the L-(TGH + Per a 9) and L-TGH generated regulatory immune responses including up-expression of immunosuppressive cytokine genes and increment of serum adenosine and lung indoleamine-2,3-dioxygenase-1 which are signatures of regulatory T cells (Tregs) and tolerogenic dendritic cells, respectively. The L-(TGH + Per a 9) should be further evaluated towards clinical application, as this vaccine has a propensity to induce broadly effective therapeutic effects for inhalant allergies.


Assuntos
Alérgenos/imunologia , Arginina Quinase/imunologia , Brugia Malayi/imunologia , Dessensibilização Imunológica/métodos , Hipersensibilidade/imunologia , Hipersensibilidade/prevenção & controle , Imunossupressores/imunologia , Proteínas de Insetos/imunologia , Periplaneta/imunologia , Fator de Crescimento Transformador beta/imunologia , Vacinas/imunologia , Administração Intranasal , Alérgenos/sangue , Animais , Arginina Quinase/sangue , Células Dendríticas/imunologia , Modelos Animais de Doenças , Hipersensibilidade/sangue , Hipersensibilidade/parasitologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/sangue , Resultado do Tratamento , Vacinas/administração & dosagem
7.
Curr Opin Endocrinol Diabetes Obes ; 28(4): 404-410, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34101653

RESUMO

PURPOSE OF REVIEW: Current therapies for autoimmune disorders often employ broad suppression of the immune system. Antigen-specific immunotherapy (ASI) seeks to overcome the side-effects of immunosuppressive therapy by specifically targeting only disease-related autoreactive T and B cells. Although it has been in development for several decades, ASI still is not in use clinically to treat autoimmunity. Novel ways to deliver antigen may be effective in inducing ASI. Here we review recent innovations in antigen delivery. RECENT FINDINGS: New ways to deliver antigen include particle and nonparticle approaches. One main focus has been the targeting of antigen-presenting cells in a tolerogenic context. This technique often results in the induction and/or expansion of regulatory T cells, which has the potential to be effective against a complex, polyclonal immune response. SUMMARY: Whether novel delivery approaches can help bring ASI into general clinical use for therapy of autoimmune diseases remains to be seen. However, preclinical work and early results from clinical trials using these new techniques show promising signs.


Assuntos
Doenças Autoimunes , Tolerância Imunológica , Imunoterapia/métodos , Antígenos/administração & dosagem , Antígenos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
8.
Front Immunol ; 12: 639942, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959124

RESUMO

Kidney transplantation is currently the first choice of treatment for various types of end-stage renal failure, but there are major limitations in the application of immunosuppressive protocols after kidney transplantation. When the dose of immunosuppressant is too low, graft rejection occurs easily, while a dose that is too high can lead to graft loss. Therefore, it is very important to explore the immune status of patients receiving immunosuppressive agents after kidney transplantation. To compare the immune status of the recipient's whole peripheral blood before and after receipt of immunosuppressive agents, we used single-cell cytometry by time-of-flight (CyTOF) to detect the peripheral blood immune cells in five kidney transplant recipients (KTRs) from the Department of Organ Transplantation of Zhujiang Hospital of Southern Medical University before and after receiving immunosuppressive agents. Based on CyTOF analysis, we detected 363,342 live single immune cells. We found that the immune cell types of the KTRs before and after receipt of immunosuppressive agents were mainly divided into CD4+ T cells, CD8+ T cells, B cells, NK cells/γδ T cells, monocytes/macrophages, granulocytes, and dendritic cells (DCs). After further reclustering of the above cell types, it was found that the immune cell subclusters in the peripheral blood of patients underwent major changes after receipt of immunosuppressants. After receiving immunosuppressive therapy, the peripheral blood of KTRs had significantly increased levels of CD57+NK cells and significantly decreased levels of central memory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, effector memory CD8+ T cells and naive CD8+ T cells. This study used CyTOF to classify immune cells in the peripheral blood of KTRs before and after immunosuppressive treatment, further compared differences in the proportions of the main immune cell types and immune cell subgroups before and after receipt of immunosuppressants, and provided relatively accurate information for assessment and treatment strategies for KTRs.


Assuntos
Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Imunossupressores/imunologia , Transplante de Rim/efeitos adversos , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Falência Renal Crônica/imunologia , Falência Renal Crônica/cirurgia , Células Matadoras Naturais/imunologia , Transplantados
9.
Eur J Immunol ; 51(7): 1580-1591, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961297

RESUMO

The field of tissue transplantation has revolutionized the treatment of patients with failing organs. Its success, thus far, has depended on combinations of immunosuppressive drugs that damp host immunity, while also imposing numerous unwanted side-effects. There is a longstanding recognition that better treatment outcomes, will come from replacing these drugs, fully or in part, by taking advantage of tractable physiological mechanisms of self-tolerance. The past 50 years have seen many advances in the field of self-tolerance, but perhaps, the most tractable of these has been the more recent discovery of a subset T-cells (Treg) whose role is to regulate or damp immunity. This article is intended to first provide the reader with some historical background to explain why we have been slow to identify these cells, despite numerous clues to their existence, and also to indicate how little we know about how they achieve their regulatory function in averting transplant rejection. However, as is often the case in immunology, the therapeutic needs often dictate that our advances move to translation even before detailed explanations of the science are available. The final part of the article will briefly summarize how Treg are being harnessed as agents to interface with or perhaps, replace current drug combinations.


Assuntos
Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante/imunologia , Animais , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/imunologia
10.
Gastroenterology ; 161(3): 827-836, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34048782

RESUMO

BACKGROUND & AIMS: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly expanded; however, clinical trials excluded patients taking immunosuppressive medications such as those with inflammatory bowel disease (IBD). Therefore, we explored real-world effectiveness of coronavirus disease 2019 (COVID-19) vaccination on subsequent infection in patients with IBD with diverse exposure to immunosuppressive medications. METHODS: This was a retrospective cohort study of patients in the Veterans Health Administration with IBD diagnosed before December 18, 2020, the start date of the Veterans Health Administration patient vaccination program. IBD medication exposures included mesalamine, thiopurines, anti-tumor necrosis factor biologic agents, vedolizumab, ustekinumab, tofacitinib, methotrexate, and corticosteroid use. We used inverse probability weighting and Cox's regression with vaccination status as a time-updating exposure and computed vaccine effectiveness from incidence rates. RESULTS: The cohort comprised 14,697 patients, 7321 of whom received at least 1 vaccine dose (45.2% Pfizer, 54.8% Moderna). The cohort had median age 68 years, 92.2% were men, 80.4% were White, and 61.8% had ulcerative colitis. In follow-up data through April 20, 2021, unvaccinated individuals had the highest raw proportion of SARS-CoV-2 infection (197 [1.34%] vs 7 [0.11%] fully vaccinated). Full vaccination status, but not partial vaccination status, was associated with a 69% reduced hazard of infection relative to an unvaccinated status (hazard ratio, 0.31, 95% confidence interval, 0.17-0.56; P < .001), corresponding to an 80.4% effectiveness. CONCLUSIONS: Full vaccination (> 7 days after the second dose) against SARS-CoV-2 infection has an ∼80.4% effectiveness in a broad IBD cohort with diverse exposure to immunosuppressive medications. These results may serve to increase patient and provider willingness to pursue vaccination in these settings.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunossupressores , Doenças Inflamatórias Intestinais , SARS-CoV-2 , Idoso , COVID-19/complicações , COVID-19/imunologia , COVID-19/terapia , Vacinas contra COVID-19/efeitos adversos , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Masculino , Estudos Retrospectivos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Resultado do Tratamento , Vacinação , Veteranos
11.
J Crohns Colitis ; 15(8): 1376-1386, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-33721882

RESUMO

Since the beginning of the pandemic, patients with inflammatory bowel diseases [IBD] have been considered at high risk for infection and complications of COVID-19. IBD patients and patients taking immunosuppressive therapy were excluded from clinical phase III vaccine trials, complicating the assessment of effectiveness of these new vaccines. From past experience we know that adapted vaccination strategies may be appropriate in some IBD patients to optimise immunogenicity. We review current evidence on SARS-CoV-2 vaccination relevant to IBD patients, including immune responses from humoral to cellular, emerging data on new variants, and off-label vaccination schemes. We also identify clinical and scientific knowledge gaps that can be translated into both large-scale population-based studies and targeted vaccine studies to describe the precise immune responses induced by SARS-CoV-2 vaccines in IBD patients. We strongly endorse the recommendation of vaccinating IBD patients to ensure maximal protection from COVID-19 both for the individual and the community.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunossupressores/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Vacinação , Humanos , Imunidade Celular , Imunidade Humoral , Imunossupressores/uso terapêutico , SARS-CoV-2 , Vacinação/métodos
12.
Curr Opin Rheumatol ; 33(3): 233-239, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33741809

RESUMO

PURPOSE OF REVIEW: This review examines recently published randomized placebo-controlled trials for the treatment of neuromyelitis optica spectrum disorders (NMOSD). RECENT FINDINGS: Until recently, treatments for NMOSD were used-off label and had not been subjected to randomized placebo-controlled trials. Increased understanding of the pathophysiology of NMOSD, particularly aquaporin-4-IgG seropositive NMOSD, lead to the investigation of eculizumab, inebilizumab, and satralizumab for maintenance therapy. Eculizumab inhibits the cleavage of the terminal complement protein C5, inebilizumab depletes immune cells of B-lymphocyte lineage, and satralizumab inhibits interleukin-6 receptors. International, phase 3, randomized, placebo-controlled trials have demonstrated that each of these therapies reduces the risk of NMOSD relapse. In some cases, the studied therapies were administered in conjunction with other immunosuppressants. Each therapy has important safety considerations, notably risk of meningococcal infection with eculizumab and risks of infection and hypogammaglobulinemia with inebilizumab. Reviewing trial design highlights future areas of inquiry for the treatment of NMOSD. SUMMARY: Eculizumab, inebilizumab, and satralizumab are effective maintenance therapies approved for the treatment of AQP-4 seropositive NMOSD.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/imunologia , Aquaporina 4/imunologia , Complemento C5/antagonistas & inibidores , Humanos , Imunoglobulina G/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Neuromielite Óptica/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Interleucina-6/antagonistas & inibidores
13.
Clin Exp Immunol ; 205(1): 28-43, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33788257

RESUMO

Cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency (CHAI) and lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency (LATAIE) are newly identified inborn errors of immunity with shared molecular pathomechanisms and clinical manifestations. In this review, we aimed to provide differential comparisons regarding demographic, clinical, immunological and molecular characteristics between these two similar conditions. A literature search was conducted in PubMed, Web of Science and Scopus databases and included studies were systematically evaluated. Overall, 434 (222 CHAI and 212 LATAIE) patients were found in 101 eligible studies. The CHAI patients were mainly reported from North America and western Europe, while LATAIE patients were predominantly from Asian countries. In CHAI, positive familial history (P < 0·001) and in LATAIE, consanguineous parents (P < 0·001) were more common. In CHAI patients the rates of granulomas (P < 0·001), malignancies (P = 0·001), atopy (P = 0·001), cutaneous disorders (P < 0·001) and neurological (P = 0·002) disorders were higher, while LATAIE patients were more commonly complicated with life-threatening infections (P = 0·002), pneumonia (P = 0·006), ear, nose and throat disorders (P < 0·001), organomegaly (P = 0·023), autoimmune enteropathy (P = 0·038) and growth failure (P < 0·001). Normal lymphocyte subsets and immunoglobulins except low serum levels of CD9+ B cells (14·0 versus 38·4%, P < 0·001), natural killer (NK) cells (21 versus 41·1%, P < 0·001), immunoglobulin (Ig)G (46·9 versus 41·1%, P = 0·291) and IgA (54·5 versus 44·7%, P = 0·076) were found in the majority of CHAI and LATAIE patients, respectively. The most frequent biological immunosuppressive agents prescribed for CHAI and LATAIE patients were rituximab and abatacept, respectively. Further investigations into the best conditioning and treatment regimens pre- and post-transplantation are required to improve the survival rate of transplanted CHAI and LATAIE patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Haploinsuficiência/genética , Haploinsuficiência/imunologia , Humanos , Imunoglobulinas/imunologia , Imunossupressores/imunologia , Linfócitos/imunologia
14.
Curr Opin Pulm Med ; 27(3): 176-183, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33779588

RESUMO

PURPOSE OF REVIEW: Patients on chronic immunosuppressive treatments at baseline are at increased risk of opportunistic infections. These patients are at especially increased risk of morbidity and mortality during the coronavirus-19 (COVID-19) pandemic. This review will focus on patients with diseases in which immunosuppression is a vital part of the treatment regimen, including those with solid organ transplants, rheumatologic disorders, sarcoidosis, and inflammatory bowel disease (IBD). We will summarize the current knowledge of immunosuppression in these diseases and the risk of contracting COVID-19. Furthermore, we will discuss if immunosuppression increases severity of COVID-19 presentation. RECENT FINDINGS: Since the start of the COVID-19 pandemic, a large number patients receiving chronic immunosuppression have been infected with SARS-CoV-2. Moreover, our understanding of the immunology of SARS-CoV-2 is advancing at a rapid pace. Currently, a number of clinical trials are underway to investigate the role of immunosuppressive treatments in the management of this disease. SUMMARY: Currently, there is no conclusive evidence to suggest that solid organ transplant recipients on chronic immunosuppression are at increased risk of contracting COVID-19. Solid organ transplant recipients may be at increased risk for worse COVID-19 outcomes but the data are not consistent. There is evidence to suggest that patients with rheumatologic disorders or IBDs are not at increased risk of contracting COVID-19 and do not necessarily experience worse clinical outcomes. Patients with sarcoidosis are not necessarily at increased risk of COVID-19, although there is limited data available to determine if immunosuppression worsens outcomes in this population.


Assuntos
COVID-19 , Imunossupressores , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/terapia , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Medição de Risco , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Transplantados
16.
Med Sci Monit ; 27: e926820, 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421049

RESUMO

BACKGROUND Immunosuppression is regarded as the main cause of death induced by sepsis. Anti-programmed death-ligand 1 (PD-L1) therapy is promising in reversing sepsis-induced immunosuppression but no evidence is available on use of commercially available anti-PD-L1 medications for this indication. The present preclinical study was performed to investigate the therapeutic effect of an anti-PD-L1 nanobody (KN035) in sepsis. MATERIAL AND METHODS The level of expression of PD-L1 in PD-L1 humanized mice was confirmed with flow cytometry. Plasma concentrations of KN035 at different dosages at different time points were detected using an enzyme-linked immunosorbent assay. PD-L1 humanized mice were allocated into 4 groups: sham, cecal ligation and puncture (CLP), isotype (isotype+CLP), and PD-L1 (KN035+CLP). The 7-day survival rate was observed to investigate outcomes in CLP mice. Disease severity was assessed with histopathological scoring of mice lungs and livers. Immune status was assessed based on cell apoptosis in the spleen and bacterial clearance. RESULTS PD-L1 levels were significantly elevated in peripheral lymphocytes, monocytes, and neutrophils after CLP surgery. Blood concentrations of KN035 showed that 2.5 mg/kg had potential to be an ideal dosage for KN035 therapy. Survival analysis demonstrated that KN035 was associated with significantly reduced mortality on Day 7 after surgery (P=0.0083). The histopathological tests showed that KN035 alleviated sepsis-induced injury in the lungs and liver. KN035 reduced the number of apoptotic cells in the spleen and almost eliminated bacterial colonies in the peritoneal lavage fluid from the CLP mice. CONCLUSIONS KN035, an anti-PD-L1 antibody, can improve the rate of survival in CLP mice and alleviate sepsis-induced apoptosis in the spleen.


Assuntos
Antígeno B7-H1/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunossupressores/uso terapêutico , Sepse/tratamento farmacológico , Anticorpos de Cadeia Única/uso terapêutico , Animais , Antígeno B7-H1/antagonistas & inibidores , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Imunossupressores/imunologia , Masculino , Camundongos , Anticorpos de Cadeia Única/imunologia
17.
Cancer Immunol Immunother ; 70(8): 2197-2207, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33471137

RESUMO

BACKGROUND: Limited data are available on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with preexisting autoimmune diseases (PAD). METHODS: Retrospective study of patients with PAD referred for rheumatologic evaluation prior to starting or during immunotherapy between January 2013 and July 2019 from 10 academic sites across Canada. Data were extracted by chart review using a standardized form. RESULTS: Twenty-seven patients with PAD on ICI therapy were identified. The most common PADs were rheumatoid arthritis (30%), psoriasis/psoriatic arthritis (30%), inflammatory bowel disease (IBD, 15%) and axial spondyloarthritis (11%), and the most frequently observed cancers were lung cancer and melanoma. All patients received anti-PD-1 therapies, and 2 received additional sequential anti-CTLA-4 therapy. PAD exacerbations occurred in 52% over a median (IQR) follow-up of 11.0 (6.0-17.5) months, with 14% being severe, 57% requiring corticosteroids, 50% requiring immunosuppression and 14% requiring ICI discontinuation. Flares were generally more frequent and severe in patients who previously required more intensive immunosuppression (i.e., biologics). Flares occurred despite background immunosuppression at the time of ICI initiation. In patients with preexisting psoriasis, IBD and axial spondyloarthritis, rheumatic immune-related adverse events (irAEs), mostly polyarthritis and tenosynovitis, were frequently observed. Tumor progression was not associated with exposure to immunosuppressive drugs before or after ICI initiation and was numerically less frequent in patients with irAEs. CONCLUSION: PAD exacerbations in the context of ICI treatment are common, although generally mild, and occur despite background immunosuppression. Exacerbations are more frequent and severe in patients on more intensive immunosuppressive therapies pre-immunotherapy.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Doenças Autoimunes/imunologia , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/imunologia , Melanoma/imunologia , Receptor de Morte Celular Programada 1/imunologia , Canadá , Feminino , Humanos , Imunossupressores/imunologia , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Reumatologia/métodos
18.
J Med Virol ; 93(3): 1314-1319, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33044760

RESUMO

Recent evidence suggested that neurological manifestations occur in patients with a severe form of coronavirus disease (COVID-19). On the basis of this issue, neurologists are very concerned about patients with neurological disorders, especially multiple sclerosis (MS), as consumers of immunosuppressive or immune-modulating drugs. Therefore, the administration of proper disease-modifying therapies (DMTs) in MS patients is critical during the pandemic status. On the one hand, both the autoimmune diseases and immunosuppressive drugs increase the risk of infection due to impairment in the immune system, and on the other hand, postponing of MS treatment has serious consequences on the central nervous system. In the present study, we discussed recent literature about the effect of DMTs administration on the severity of COVID-19 in the MS patients. Overall, it seems that DMTs do not provoke the COVID-19 infection in the MS patients by declining immune responses and cytokine storm. However, as a precaution, the supervision of a neurologist is highly recommended.


Assuntos
COVID-19/patologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Animais , COVID-19/imunologia , Humanos , Fatores Imunológicos/imunologia , Imunossupressores/imunologia , Esclerose Múltipla/imunologia , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
19.
Curr Opin Nephrol Hypertens ; 30(1): 63-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33186221

RESUMO

PURPOSE OF REVIEW: Immunological factors are a major cause of kidney allograft loss. Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival; however, they in turn contribute to long-term kidney allograft loss from chronic CNI nephrotoxicity. Tolerance induction in transplantation can avoid the long-term adverse effects of immunosuppressive medications. This review aims to critically discuss recent efforts in inducing transplantation tolerance. RECENT FINDINGS: Tolerance induction mediated by chimerism has shown some promise in minimizing or even complete withdrawal of immunosuppressive treatments in kidney allograft recipients. There has been a number of approaches as varied as the number of centres conducting these trials. However, they can be grouped into those mediated by transient microchimerism and those facilitated by more stable macro or full donor chimerism. The success rates in terms of long-term drug-free graft survival has been limited in microchimerism-mediated tolerance induction approaches. Mixed macrochimerism of less than 50% donor may be unstable with mostly the recipient's native immune system overpowering the donor chimeric status.Tolerance induction leading to chimerism has been limited to living donor kidney transplantation and additional long-term outcomes are required. Furthermore, immune monitoring after tolerance induction has faced a limitation in studying due to a lack of sufficient study participants and appropriate study controls. SUMMARY: Tolerance induction is one of several strategies used to prolong kidney allograft survival, but it has not been routinely utilized in clinical practice. However, future applications from the trials to clinical practice remain limited to living donor kidney transplantation. Once further data regarding tolerance inductions exist and practicality becomes widely accepted, tolerance induction may shift the paradigm in the field of kidney transplantation to achieve the best possible outcome of 'One Organ for Life'.


Assuntos
Quimerismo , Sobrevivência de Enxerto , Tolerância Imunológica , Transplante de Rim , Insuficiência Renal Crônica/cirurgia , Aloenxertos/imunologia , Ensaios Clínicos como Assunto , Previsões , Facilitação Imunológica de Enxerto/métodos , Facilitação Imunológica de Enxerto/tendências , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Rim/imunologia , Rim/cirurgia , Transplante de Rim/efeitos adversos , Doadores Vivos , Condicionamento Pré-Transplante , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia
20.
Clin Exp Immunol ; 203(3): 409-423, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33205401

RESUMO

Biological treatments such as enzyme-replacement therapies (ERT) can generate anti-drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low-dose methotrexate (TLD-MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long-lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD-MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high-risk, cross-reactive immunological material (CRIM)-negative infantile-onset Pompe disease (IOPD) patients. More recently, evaluation of TLD-MTX demonstrated benefit in CRIM-positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD-MTX, non-targeted transcriptional and proteomic screens were conducted and revealed up-regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter-119+ CD71+ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD-MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Eritroblastos/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Metotrexato/administração & dosagem , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Relação Dose-Resposta a Droga , Eritroblastos/citologia , Eritroblastos/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/imunologia , Eritrócitos/metabolismo , Eritropoese/efeitos dos fármacos , Eritropoese/genética , Eritropoese/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Metotrexato/imunologia , Camundongos Endogâmicos C57BL , Proteômica/métodos , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , alfa-Glucosidases/administração & dosagem
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