RESUMO
Heroin addiction and withdrawal influence multiple physiological functions, including immune responses, but the mechanism remains largely elusive. The objective of this study was to investigate the molecular inflammatory interactome, particularly the cytokines and transcriptome regulatory network in heroin addicts undergoing withdrawal, compared to healthy controls (HCs). Twenty-seven cytokines were simultaneously assessed in 41 heroin addicts, including 20 at the acute withdrawal (AW) stage and 21 at the protracted withdrawal (PW) stage, and 38 age- and gender-matched HCs. Disturbed T-helper(Th)1/Th2, Th1/Th17, and Th2/Th17 balances, characterized by reduced interleukin (IL)-2, elevated IL-4, IL-10, and IL-17A, but normal TNF-α, were present in the AW subjects. These imbalances were mostly restored to the baseline at the PW stage. However, the cytokines TNF-α, IL-2, IL-7, IL-10, and IL-17A remained dysregulated. This study also profiled exosomal long non-coding RNA (lncRNA) and mRNA in the plasma of heroin addicts, constructed co-expression gene regulation networks, and identified lncRNA-mRNA-pathway pairs specifically associated with alterations in cytokine profiles and Th1/Th2/Th17 imbalances. Altogether, a large amount of cytokine and exosomal lncRNA/mRNA expression profiling data relating to heroin withdrawal was obtained, providing a useful experimental and theoretical basis for further understanding of the pathogenic mechanisms of withdrawal symptoms in heroin addicts.
Assuntos
Ácidos Nucleicos Livres/sangue , Citocinas/sangue , Usuários de Drogas , Vesículas Extracelulares/metabolismo , Dependência de Heroína/sangue , RNA Longo não Codificante/sangue , RNA Mensageiro/sangue , Síndrome de Abstinência a Substâncias/sangue , Subpopulações de Linfócitos T/metabolismo , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Ácidos Nucleicos Livres/genética , Vesículas Extracelulares/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Dependência de Heroína/genética , Dependência de Heroína/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/imunologia , Subpopulações de Linfócitos T/imunologia , Fatores de Tempo , Transcriptoma , Adulto JovemRESUMO
Exosomes play an important role in cell-to-cell communication as they can transfer functional molecules such as microRNAs (miRNAs) from one cell to another, exerting biological and immunological functions. Here, we investigated the impact of HIV infection and/or heroin use on the expression of the miRNAs in plasma exosomes. We found that HIV infection or heroin use upregulated the majority (98%) of a panel of plasma exosomal miRNAs associated with immune regulation and inflammation. We also observed the enhanced effect of HIV infection and heroin use on some of these upregulated miRNAs. Our further investigation showed that the levels of four of neuro-inflammation-related miRNAs (146a, 126, 21, and let-7a) were higher in HIV-infected heroin users as compared with the control subjects. These findings indicate that the dysregulations of the plasma exosomal miRNAs support further studies to determine the role of the miRNAs in HIV and/or heroin use-mediated immune modulation and neuro-inflammation. Graphical abstract.
Assuntos
Exossomos/metabolismo , Infecções por HIV/genética , Infecções por HIV/metabolismo , Dependência de Heroína/genética , Dependência de Heroína/metabolismo , MicroRNAs/sangue , Adulto , Comunicação Celular , Encefalite/genética , Encefalite/metabolismo , Feminino , Infecções por HIV/imunologia , Dependência de Heroína/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Regulação para Cima , Adulto JovemRESUMO
Drug addiction is a serious health problem prevalent worldwide. Currently available therapies including pharmacotherapy and psychotherapy are insufficient to meet the clinical needs for treating drug abuse. Recently, immunotherapy has emerged as a promising approach to treat such drug-use disorders. Pharmacokinetic antagonists are used in immunotherapy, functioning by sequestering the drugs in the periphery but without allowing the drug to cross the blood-brain barrier. This can reduce the toxic and rewarding effects of the drugs, while preventing addiction and facilitating reduced relapse rates. Herein, we update recent developments in the immunotherapeutic strategies to treat abuse of drugs like methamphetamine, heroin and cocaine. In addition, we summarize the drug design used so far and its optimization strategies. Further, we document the efficacy of anti-drug vaccines and monoclonal antibodies, with an aim to promote development of new anti-drug immunotherapies.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Dependência de Heroína/tratamento farmacológico , Transtornos Relacionados ao Uso de Anfetaminas/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Transtornos Relacionados ao Uso de Cocaína/imunologia , Desenho de Fármacos , Desenvolvimento de Medicamentos , Dependência de Heroína/imunologia , Humanos , Imunoterapia/métodos , Metanfetamina/efeitos adversos , Vacinas/administração & dosagem , Vacinas/imunologiaRESUMO
BACKGROUND: On a national level, heroin-related hospital admissions have reached an all-time high. With the foot being the fourth most common injection site, heroin-related lower-extremity infections have become more prevalent owing to many factors, including drug preparation, injection practices, and unknown additives. METHODS: We present a 16-month case series in which eight patients with lower-extremity infections secondary to heroin abuse presented to The Jewish Hospital in Cincinnati, Ohio. RESULTS: Three cases of osteomyelitis were seen. All of the infections were cultured and yielded a wide array of microbes, including Staphyloccoccus, Streptococcus, Bacillus, Serratia, Prevotella, and Eikenella. All of the patients were treated with intravenous antibiotic agents, with nearly all receiving combination therapy. Seven of the eight patients underwent surgery during their hospital stay, with two undergoing amputation. Only half of the patients followed up after discharge. CONCLUSIONS: This case series brings to light many considerations in the diagnosis and management of the heroin user, including multivariable attenuation of immunity, existing predisposition to infection backed by unsterile drug preparation and injection practices, innocuous presentation of deep infections, microbial spectrum, and recommendations on antimicrobial intervention, noncompliance, and poor follow-up. By having greater knowledge in unique considerations of diagnosis and treatment, more efficient care can be provided to this unique patient population.
Assuntos
Dependência de Heroína/complicações , Osteomielite/diagnóstico , Infecções dos Tecidos Moles/diagnóstico , Abuso de Substâncias por Via Intravenosa/complicações , Adulto , Antibacterianos/uso terapêutico , Feminino , Heroína/efeitos adversos , Dependência de Heroína/imunologia , Humanos , Hiperalgesia/induzido quimicamente , Extremidade Inferior , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteomielite/tratamento farmacológico , Osteomielite/etiologia , Manejo da Dor , Cooperação do Paciente , Radiografia , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologia , Infecções dos Tecidos Moles/cirurgiaRESUMO
The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection. Complement levels are significantly increased in the HIV-1-infected brain, thus HIV-induced complement synthesis may represent an important mechanism for the pathogenesis of AIDS in the brain, but remains underexplored. Anti-HIV-1 antibodies are able to initiate complement activation in HIV-1 infected CNS cells such as microglia and astrocytes during the course of disease progression; however, this complement activation fails to clear and eradicate HIV-1 from infected cells. In addition, the antiretroviral agents used for HIV therapy cause dysregulation of lipid metabolism, endothelial, and adipocyte cell function, and activation of pro-inflammatory cytokines. We speculate that both HIV-1 and opiates trigger a cytokine-mediated pro-inflammatory stimulus that modulates the complement cascade to exacerbate the virus-induced neurological damage. We examined the expression levels of C1q, SC5b-9, C5L2, C5aR, C3aR, and C9 key members of the complement cascade both in vivo in post mortem brain frontal cortex tissue from patients with HAND who used/did not use heroin, and in vitro using human microglial cultures treated with HIV tat and/or heroin. We observed significant expression of C1q and SC5b-9 by immunofluorescence staining in both the brain cortical and hippocampal region in HAND patients who abused heroin. Additionally, we observed increased gene expression of C5aR, C3aR, and C9 in the brain tissue of both HIV-1 infected patients with HAND who abused and did not abuse heroin, as compared to HIV negative controls. Our results show a significant increase in the expression of complement proteins C9, C5L2, C5aR, and C3aR in HIV transfected microglia and an additional increase in the levels of these complement proteins in heroin-treated HIV transfected microglia. This study highlights the a) potential roles of complement proteins in the pathogenesis of HIV-1-related neurodegenerative disorders; b) the combined effect of an opiate, like heroin, and HIV viral protein like HIV tat on complement proteins in normal human microglial cells and HIV transfected microglial cells. In the context of HAND, targeting selective steps in the complement cascade could help ameliorating the HIV burden in the CNS, thus investigations of complement-related therapeutic approaches for the treatment of HAND are warranted.
Assuntos
Nefropatia Associada a AIDS/imunologia , Proteínas do Sistema Complemento/metabolismo , Lobo Frontal/metabolismo , Infecções por HIV/imunologia , HIV-1/fisiologia , Dependência de Heroína/imunologia , Mediadores da Inflamação/metabolismo , Microglia/metabolismo , Nefropatia Associada a AIDS/epidemiologia , Cadáver , Células Cultivadas , Comorbidade , Ativação do Complemento , Citocinas/metabolismo , Infecções por HIV/epidemiologia , Dependência de Heroína/epidemiologia , Humanos , Imunomodulação , Microglia/patologia , Microglia/virologia , Regulação para Cima , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismoRESUMO
OBJECTIVE: The incidence of autoantibodies may be associated with the duration of drug use. In this study, we assessed the association between the duration of heroin dependence and various humoral immunologic indicators, including IgA, IgG, IgM, complement component 3, complement component 4, rheumatoid factor, anti-ß2-glycoprotein 1 (IgA, IgG, IgM), antinuclear antibody, circulating immune complexes, and cryoglobulins. METHODS: A total of 363 patients with heroin dependence were enrolled in this cross-sectional and prospective study over a 3.5-year period. Depending on the duration of heroin use, participants were divided into 3 groups: up to 3 years, 4 to 7 years, and more than 7 years of heroin dependence. All patients were analyzed for the indicators. RESULTS: There was a significant difference between the duration of heroin dependence and increased concentration of IgA (Pâ=â0.0000), IgG (Pâ=â0.0000), IgM (Pâ=â0.0001), complement component 3 (Pâ=â0.042), rheumatoid factor (Pâ=â0.0001), anti-ß2-glycoprotein 1 (IgA, Pâ=â0.0098; IgG, Pâ=â0.0000; IgM, Pâ=â0.0000), the presence of antinuclear antibody (Pâ=â0.01) and cryoglobulins (Pâ=â0.0000), and decreased concentration of complement component 4 (Pâ=â0.002). There was no significant difference in circulating immune complex concentration (Pâ=â0.097). CONCLUSIONS: A longer duration of heroin dependence was associated with increased concentrations of IgA, IgG, IgM, complement component 3, rheumatoid factor, anti-ß2-glycoprotein 1 (IgA, IgG, IgM), presence of antinuclear antibodies and cryoglobulins, and decreased concentrations of complement component 4, but there was no influence on circulating immune complex values.
Assuntos
Dependência de Heroína/imunologia , Adolescente , Adulto , Estudos Transversais , Feminino , Dependência de Heroína/sangue , Dependência de Heroína/urina , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Influenza vaccination is recommended for vulnerable individuals, including active drug users, to prevent influenza complications and decrease influenza spread. Recent studies suggest that opioids negatively regulate immune responses in experimental models, but the extent to which opioid use will affect the humoral responses to influenza vaccine in humans is unknown. This information is critical in maximizing vaccination efforts. OBJECTIVE: To determine whether there is a difference in antibody response after influenza vaccination in heroin or methadone users compared to control subjects. METHODS: We studied active heroin users, subjects on methadone maintenance treatment (MMT) and subjects that did not use any drugs before and 1 and 4 weeks after vaccination with trivalent influenza vaccine (TIV). We measured hemagglutination inhibition and microneutralization titers, and we compared geometric mean titers (GMT), and rates of seroprotection and seroconversion for each of the vaccine strains among the 3 groups of subjects. RESULTS: Heroin users, subjects on MMT and non-user controls mount a similarly robust serologic response to TIV. GMT and rates of seroprotection and seroconversion were not significantly different among groups. CONCLUSION: Our results suggest that opioid use do not significantly alter antibody responses to influenza vaccine supporting the vaccination effort in these populations.
Assuntos
Dependência de Heroína/imunologia , Imunidade Humoral/efeitos dos fármacos , Vacinas contra Influenza/imunologia , Metadona/imunologia , Adulto , Anticorpos Antivirais/sangue , Estudos de Casos e Controles , Feminino , Testes de Inibição da Hemaglutinação , Dependência de Heroína/tratamento farmacológico , Humanos , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza B , Vacinas contra Influenza/administração & dosagem , Masculino , Metadona/efeitos adversos , Metadona/uso terapêutico , Testes de Neutralização , Tratamento de Substituição de Opiáceos/efeitos adversos , Estudos Prospectivos , Soroconversão , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Adulto JovemRESUMO
INTRODUCTION: Cryoglobulins are single or mixed immunoglobulins that are subject to reversible precipitation at low temperatures. OBJECTIVE: The aims of this paper were: 1. Comparison of cryoglobulin positive (CP), cryoglobulin negative (CN) heroin addicts and the control group (CG) in terms of serum immunoglobulins IgG, IgA and IgM and complement components C3 and C4; 2. Comparison of CP and CN heroin addicts in terms of rheumatoid factor (RF) and circulating immune complexes (CIC); 3. Assessment of clinical manifestations in CP heroin addicts. METHODS: This is a comparative study of cases (outpatients) treated at the University Clinic of Toxicology in Skopje over 3.5 years, from January 2009 to June 2012. In this study 140 heroin addicts without HbsAg were examined, seronegative for HCV and HIV infections.They were divided into 2 groups: 70 CP and 70 CN heroin addicts. A previously designed self-administered questionnaire was used as a data source on participants. All heroin addicts underwent the following analyses: urea and creatinine in serum; creatinine in urine; proteinuria; 24-hour proteinuria; IgM, IgG, IgA, C3, C4; RF; CIC; creatinine clearance; ECG; toxicological analyses for opioids in a urine sample; cryoglobulins. In addition to these 2 groups, IgG, IgA, IgM, C3 and C4 were also examined in 70 healthy subjects (CG). RESULTS: The study showed that there was no statistically significant difference between CP, CN heroin addicts and CG regarding the concentration of IgA, IgG, IgM, C3 and C4, and between CP and CN regarding the concentration of CIC. There was significant difference between CP and CN regarding the concentration of RF. The following conditions were significantly more frequently manifested in CP than in CN heroin addicts: arthralgia, Raynaud's phenomenon, respiratory difficulties, neurological disorders, manifested skin changes, hematuria, 24-hour proteinuria levels, and decreased renal clearance. CONCLUSION: There were no differences in concentrations of IgG, IgA, IgM, C3, C4 and CIC, while there was a difference in concentration of RF between CP and CN heroin addicts. Clinical manifestations (arthralgias, Raynaud's phenomenon, respiratory, neurologic, renal disorders and skin changes) were more common in CP heroin addicts.
Assuntos
Autoanticorpos/análise , Autoanticorpos/imunologia , Crioglobulinas/análise , Dependência de Heroína/imunologia , Adulto , Autoanticorpos/sangue , Autoanticorpos/urina , Crioglobulinemia/sangue , Feminino , Vírus de Hepatite/imunologia , Dependência de Heroína/sangue , Dependência de Heroína/urina , Humanos , Imunidade Humoral , Testes Imunológicos , Masculino , Pessoa de Meia-IdadeRESUMO
Vaccines against drugs of abuse have induced antibodies in animals that blocked the biological effects of the drug by sequestering the drug in the blood and preventing it from crossing the blood-brain barrier. Drugs of abuse are too small to induce antibodies and, therefore, require conjugation of drug hapten analogs to a carrier protein. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant. Previously, we have shown that 1 (MorHap), a heroin/morphine hapten, conjugated to tetanus toxoid (TT) and mixed with liposomes containing monophosphoryl lipid A [L(MPLA)] as adjuvant, partially blocked the antinociceptive effects of heroin in mice. Herein, we extended those findings, demonstrating greatly improved vaccine induced antinociceptive effects up to 3% mean maximal potential effect (%MPE). This was obtained by evaluating the effects of vaccine efficacy of hapten 1 vaccine conjugates with varying hapten densities using two different commonly used carrier proteins, TT and cross-reactive material 197 (CRM197). Immunization of mice with these conjugates mixed with L(MPLA) induced very high anti-1 IgG peak levels of 400-1500 µg/mL that bound to both heroin and its metabolites, 6-acetylmorphine and morphine. Except for the lowest hapten density for each carrier, the antibody titers and affinity were independent of hapten density. The TT carrier based vaccines induced long-lived inhibition of heroin-induced antinociception that correlated with increasing hapten density. The best formulation contained TT with the highest hapten density of ≥30 haptens/TT molecule and induced %MPE of approximately 3% after heroin challenge. In contrast, the best formulation using CRM197 was with intermediate 1 densities (10-15 haptens/CRM197 molecule), but the %MPE was approximately 13%. In addition, the chemical synthesis of 1, the optimization of the conjugation method, and the methods for the accurate quantification of hapten density are described.
Assuntos
Analgésicos Opioides/imunologia , Proteínas de Bactérias/química , Portadores de Fármacos/química , Haptenos/administração & dosagem , Heroína/imunologia , Toxoide Tetânico/química , Vacinas Conjugadas/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Analgésicos Opioides/farmacologia , Animais , Afinidade de Anticorpos , Cristalografia por Raios X , Feminino , Haptenos/química , Haptenos/imunologia , Haptenos/farmacologia , Heroína/farmacologia , Dependência de Heroína/imunologia , Dependência de Heroína/prevenção & controle , Imunização , Imunoglobulina G/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Camundongos Endogâmicos BALB C , Modelos Moleculares , Vacinas Conjugadas/química , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/farmacologiaRESUMO
Opioid use may affect HIV infection through altered expression of HIV co-receptors. This was examined in Indonesia among antiretroviral therapy-naive HIV patients, many of whom use drugs. C-C chemokine receptor type 5 (CCR5) expression on CD4+ cells was higher in heroin (P = 0.007), methadone (P = 0.024) and former opioid users (P = 0.003) compared to nonusers, whereas production of RANTES and other CCR5 ligands was similar or lower. This suggests that opioids can affect HIV susceptibility through up-regulation of CCR5 or down-regulation of its ligands.
Assuntos
Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/efeitos dos fármacos , Quimiocina CCL5/análise , Dependência de Heroína/imunologia , Transtornos Relacionados ao Uso de Opioides/imunologia , Receptores CCR5/análise , Receptores de HIV/análise , Adulto , Feminino , Humanos , Indonésia , MasculinoRESUMO
BACKGROUND: Opioid use is associated with increased incidence of infectious diseases. Although experimental studies have shown that opioids affect various functions of immune cells, only limited data are available from human studies. Drug use is an important risk factor for HIV transmission; however no data are available whether heroin and/or methadone modulate immune response. Therefore, we examined the effect of heroin and methadone use among HIV-infected individuals on the production of cytokines after ex vivo stimulation with various pathogens. METHODS: Treatment naïve HIV-infected individuals from Indonesia were recruited. Several cohorts of individuals were recruited: 1) using heroin 2) receiving methadone opioid substitution 3) using heroin over 1 year ago and 4) controls (never used opioids). Whole blood was stimulated with Mycobacterium tuberculosis, Candida albicans and LPS for 24 to 48 hours. Cytokine production (IL-1 ß, IL-6, IL-10, IFN-α, IFN-γ and TNF-α) was determined using multiplex beads assay. RESULTS: Among 82 individuals, the cytokine levels in unstimulated samples did not differ between groups. Overall, heroin users had significantly lower cytokine response after exposure to LPS (p<0.05). After stimulation with either M. tuberculosis or C. albicans the cytokine production of all groups were comparable. CONCLUSION: The cytokine production after exposure to LPS is significantly down-regulated in HIV-infected heroin users. Interesting, methadone use did not suppress cytokine response, which could have implications guidelines of opioid substitution.
Assuntos
Citocinas/sangue , Infecções por HIV/imunologia , Dependência de Heroína/imunologia , Adulto , Feminino , Infecções por HIV/sangue , Dependência de Heroína/sangue , Humanos , Lipopolissacarídeos/farmacologia , Masculino , Adulto JovemRESUMO
Opioid addiction influences many physiological functions including reactions of the immune system. The objective of this study was to investigate the immune system function in heroin addicted patients undergoing methadone maintenance treatment (MMT) compared to healthy controls. We tested the cytokine production of IL-1ß, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α from a group of heroin addicts (n=34) and healthy controls (n=20). The results show that production of IL-1ß, IL-6 and IL-8 was significantly higher in the group of methadone-maintained patients than in the healthy control group. Plasma TNF-α and IL-6 levels were significantly correlated with the dairy methadone dosage administered, and the IL-1ß level was significantly correlated with the duration of methadone maintenance treatment. These findings suggest that methadone maintenance treatment influences the immune system functions of opioid-dependent patients and may also induce long-term systemic inflammation.
Assuntos
Dependência de Heroína/reabilitação , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metadona/administração & dosagem , Tratamento de Substituição de Opiáceos/métodos , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Heroína , Dependência de Heroína/imunologia , Humanos , Inflamação , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Masculino , Metadona/uso terapêutico , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The intent of the study was to evaluate immune system changes during 12 weeks of abstinence in heroin users. We recruited men (N = 65) aged 18-45 years and collected demographic and heroin use pattern data. Serum blood levels of total interleukin 2 (IL-2), interferon γ (IFN-γ), immunoglobulin (Ig) A, IgG, and IgM were assessed at five time points. The IL-2 level was increased on day 84 as compared to that in healthy controls. The IFN-γ level was higher in heroin users than in healthy controls between days 0 and 28, and was decreased on day 84. IgG and IgM levels in heroin users were higher than those in healthy controls in our 12-week study, and were in positive correlation with the way of using the drug, duration of heroin dependence, and daily heroin intake. Our data revealed that the immune system was not restored during the 12 weeks of heroin withdrawal.
Assuntos
Dependência de Heroína/imunologia , Síndrome de Abstinência a Substâncias/imunologia , Adulto , Estudos de Casos e Controles , Citocinas/sangue , Dependência de Heroína/sangue , Humanos , Masculino , Síndrome de Abstinência a Substâncias/sangueRESUMO
UNLABELLED: The antimicrobial peptide cathelicidin is critical in killing pathogens by innate immune cells, including Mycobacterium tuberculosis and Candida albicans. These pathogens often cause infections in opioid users, a risk that is greatly increased with concurrent human immunodeficiency virus (HIV) infection. Therefore, we examined the association between opioid use and cathelicidin in HIV-infected subjects from Bandung, Indonesia. The following three groups of HIV-infected individuals were included: (i) Active drug users: used heroin in the last 30 days; (ii) Methadone clients: received methadone maintenance therapy in the last 30 days; and (iii) CONTROLS: never used opioids or did not use opioids in the year preceding inclusion. In addition to interviews, blood samples were taken to examine the RNA expression of cathelicidin. We found that the RNA expression of cathelicidin was significantly decreased (p=0.007) in heroin users, compared with controls. Opioids are associated with immunosuppression, and cathelicidin could be an important factor in this association. However, more research is needed to examine the direct effects of decreased cathelicidin levels.
Assuntos
Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/sangue , Infecções por HIV/imunologia , Dependência de Heroína/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/sangue , Adulto , Células Sanguíneas/imunologia , Feminino , Infecções por HIV/complicações , Heroína/administração & dosagem , Heroína/farmacologia , Dependência de Heroína/complicações , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Indonésia , Entrevistas como Assunto , Masculino , Adulto Jovem , CatelicidinasRESUMO
Three haptens have been synthesized with linkers for attachment to carrier macromolecules at either the piperidino-nitrogen or via an introduced 3-amino group. Two of the haptens, with a 2-oxopropyl functionality at either C6, or at both the C3 and C6 positions on the 4,5-epoxymorphinan framework, as well as the third hapten (DiAmHap) with diamido moieties at both the C3 and C6 positions, should be much more stable in solution, or in vivo in a vaccine, than a hapten with an ester in one of those positions, as found in many heroin-based haptens. A "classical" opioid synthetic scheme enabled the formation of a 3-amino-4,5-epoxymorphinan which could not be obtained using palladium chemistry. Our vaccines are aimed at the reduction of the abuse of heroin and, as well, at the reduction of the effects of its predominant metabolites, 6-acetylmorphine and morphine. One of the haptens, DiAmHap, has given interesting results in a heroin vaccine and is clearly more suited for the purpose than the other two haptens.
Assuntos
Haptenos/imunologia , Heroína/imunologia , Vacinas/síntese química , Vacinas/imunologia , Animais , Feminino , Haptenos/química , Heroína/química , Dependência de Heroína/imunologia , Dependência de Heroína/prevenção & controle , Dependência de Heroína/terapia , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Substâncias Macromoleculares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Vacinas/químicaRESUMO
Immunotherapy against drugs of abuse is being studied as an alternative treatment option in addiction medicine and is based on antibodies sequestering the drug in the bloodstream and blocking its entry into the brain. Producing an efficient vaccine against heroin has been considered particularly challenging because of the rapid metabolism of heroin to multiple psychoactive molecules. We have previously reported that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the predominant mediator for heroin's acute behavioral effects and that heroin is metabolized to 6-MAM primarily prior to brain entry. On this basis, we hypothesized that antibody sequestration of 6-MAM is sufficient to impair heroin-induced effects and therefore examined the effects of a monoclonal antibody (mAb) specific for 6-MAM. In vitro experiments in human and rat blood revealed that the antibody was able to bind 6-MAM and block the metabolism to morphine almost completely, whereas the conversion of heroin to 6-MAM remained unaffected. Mice pretreated with the mAb toward 6-MAM displayed a reduction in heroin-induced locomotor activity that corresponded closely to the reduction in brain 6-MAM levels. Intraperitoneal and intravenous administration of the anti-6-MAM mAb gave equivalent protection against heroin effects, and the mAb was estimated to have a functional half-life of 8 to 9 days in mice. Our study implies that an antibody against 6-MAM is effective in counteracting heroin effects.
Assuntos
Anticorpos Monoclonais/imunologia , Encéfalo/metabolismo , Dependência de Heroína/tratamento farmacológico , Heroína/efeitos adversos , Heroína/sangue , Derivados da Morfina/imunologia , Adulto , Animais , Anticorpos Monoclonais/administração & dosagem , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Heroína/química , Heroína/farmacocinética , Dependência de Heroína/imunologia , Dependência de Heroína/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Derivados da Morfina/sangue , Derivados da Morfina/química , Derivados da Morfina/farmacocinética , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Distribuição TecidualAssuntos
Antraz/etiologia , Antraz/imunologia , Dependência de Heroína/microbiologia , Abuso de Substâncias por Via Intravenosa/microbiologia , Sequência de Aminoácidos , Antígenos de Bactérias/imunologia , Bacillus anthracis/imunologia , Epitopos/química , Epitopos/imunologia , Dependência de Heroína/imunologia , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Abuso de Substâncias por Via Intravenosa/imunologiaRESUMO
Active immunization is an effective means of blocking the pharmacodynamic effects of drugs and holds promise as a treatment for heroin addiction. Previously, we demonstrated the efficacy of our first-generation vaccine in blocking heroin self-administration in rats, however, many vaccine components can be modified to further improve performance. Herein we examine the effects of varying heroin vaccine injection route and adjuvant formulation. Mice immunized via subcutaneous (sc) injection exhibited inferior anti-heroin titers compared to intraperitoneal (ip) and sc/ip coadministration injection routes. Addition of TLR9 agonist cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) to the original alum adjuvant elicited superior antibody titers and opioid affinities compared to alum alone. To thoroughly assess vaccine efficacy, full dose-response curves were generated for heroin-induced analgesia in both hot plate and tail immersion tests. Mice treated with CpG ODN 1826 exhibited greatly shifted dose-response curves (10-13-fold vs unvaccinated controls) while non-CpG ODN vaccine groups did not exhibit the same robust effect (2-7-fold shift for ip and combo, 2-3-fold shift for sc). Our results suggest that CpG ODN 1826 is a highly potent adjuvant, and injection routes should be considered for development of small molecule-protein conjugate vaccines. Lastly, this study has established a new standard for assessing drugs of abuse vaccines, wherein a full dose-response curve should be performed in an appropriate behavioral task.
Assuntos
Vias de Administração de Medicamentos/veterinária , Dependência de Heroína/prevenção & controle , Heroína/administração & dosagem , Imunização/métodos , Oligodesoxirribonucleotídeos/farmacologia , Receptor Toll-Like 9/agonistas , Vacinas Conjugadas/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Analgésicos/administração & dosagem , Animais , Anticorpos/sangue , Anticorpos/imunologia , Ensaio de Imunoadsorção Enzimática , Heroína/imunologia , Dependência de Heroína/sangue , Dependência de Heroína/imunologia , Injeções Intraperitoneais , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Camundongos , Ratos , Vacinas Conjugadas/química , Vacinas Conjugadas/imunologiaRESUMO
UNLABELLED: Different autoantibodies and immunologic abnormalities have been described in heroin addicts. AIMS: dpending on the route of heroin application in heroin addicts to determine: 1) immunoglobulins: IgA, IgG, IgM; 2) complement (C3, C4); 3) some other autoantibodies RF, anti ß2GP1 fractions: IgA, IgG, IgM, ANA; 4) CIC; 5)monitoring the cryoglobulin presence; 6) clinical manifestations in cryoglobulin positive heroin addicts. A total of 363 heroin addicts were analyzed after previously completed questionnaire; biochemical analyses of blood and urine; creatinine clearance (eC(Cr)) by Cockcroft-Gault formula; proteinuria; 24-hour proteinuria (Uprot/Ucreat); ECG; toxicological analyses; complement (C3, C4); immunoglobulins IgA, IgG, IgM; rheumatoid factor; cryoglobulins; circulating immune complexes; antiphospholipid antibodies (anti ß2GP1: IgA, IgG, IgM); antinuclear antibodies. Male patients were predominating (82.09%). Of them 161 were using intravenous heroin (45.4%). IgA was statistically significantly lower in intravenous heroin addicts. Intravenous heroin addicts contrary to those who inhaled heroin had highly significant levels of IgG, IgM, IgG, antiß2GP1 cryoglobulins; significantly higher mean values of: RF, anti ß2GP1 IgA and IgM. Cryoglobulin positive (CP) heroin addicts compared to cryoglobulin negative (CN) presented significantly more frequently with clinical signs of arthralgia, vasculitis, hematuria; whereas highly significantly were manifested respiratory difficulties, neurological disorders, Raynaud phenomenon, proteinuria, 24-hour proteinuria, highly significantly lower mean values of renal clearance. Intravenous heroin addicts compared to the non-parenteral heroin addicts have shown greater changes in certain parameters of humoral immunity. CP heroin addicts have presented with more frequent clinical manifestations than CN heroin addicts.
Assuntos
Autoanticorpos/imunologia , Crioglobulinemia/imunologia , Crioglobulinas/imunologia , Dependência de Heroína/imunologia , Heroína/administração & dosagem , Imunidade Humoral , Administração por Inalação , Adolescente , Adulto , Autoanticorpos/sangue , Crioglobulinemia/sangue , Crioglobulinas/análise , Feminino , Dependência de Heroína/sangue , Humanos , Injeções Intraventriculares , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Adulto JovemRESUMO
There is an increasing body of evidence that heroin addiction is associated with severe alterations in immune function, which might contribute to an increased risk to contract infectious diseases like hepatitis B and C or HIV. However, the impact of heroin consumption on the CD4(+) T cell compartment is not well understood. Therefore, we analyzed the frequency and functional phenotype of CD4(+) T cells as well as immune-suppressive CD4(+)CD25(high) regulatory T cells (Tregs) isolated from the peripheral blood of opiate addicts currently abusing heroin (n=27) in comparison to healthy controls (n=25) and opiate addicts currently in opioid maintenance treatment (OMT; n=27). Interestingly, we detected a significant increase in the percentage of CD4(+)CD25(high) Tregs in the peripheral blood of heroin addicted patients in contrast to patients in OMT. The proliferative response of CD4(+) T cells upon stimulation with anti-CD3 and anti-CD28 antibodies was significantly decreased in heroin users, but could be restored by depletion of CD25(high) regulatory T cells from CD4(+) T cells to similar values as observed from healthy controls and patients in OMT. These results suggest that impaired immune responses observed in heroin users are related to the expansion of CD4(+)CD25(high) Tregs and more importantly, can be restored by OMT.