Possible Role of Arginase-1 in Concomitant Tumor Immunity

The expression of Adenovirus serotype 2 or serotype 5 (Ad2/5) E1A in tumor cells reduces their tumorigenicity in vivo by enhancing the NK cell mediated and T cell mediated anti-tumor immune response, an activity that correlates with the ability of E1A to bind p300. We determined if E1A could be used as a molecular adjuvant to enhance antigen-specific T cell responses to a model tumor antigen, ovalbumin (OVA). To achieve this goal, we stably expressed a fusion protein of E1A and OVA (MCA-205-E1A-OVA), OVA (MCA-205-OVA) or a mutant version of E1A unable to bind p300 and OVA (E1A-Δp300-OVA) in the B6-derived, highly tumorigenic MCA-205 tumor cell line. MCA-205-E1A-OVA tumor cells were over 10,000 fold less tumorigenic than MCA-205-OVA, MCA-205-E1A-Δp300-OVA, or MCA-205 in B6 mice. However, immunization of B6 mice with live MCA-205-OVA, MCA-205-E1A-Δp300-OVA and MCA-E1A-OVA tumor cells induced nearly equivalent OVA-specific CD4 T cells and CD8 CTL responses. Further studies revealed that mice with primary, enlarging MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumors on one flank exhibited OVA-specific anti-tumor T cell responses that rejected a tumorigenic dose of MCA-205-OVA cells on the contralateral flank (concomitant tumor immunity). Next we found that tumor associated macrophages (TAMs) in progressive MCA-205-OVA tumors, but not MCA-205-E1A-OVA tumors that expressed high levels of arginase-1, which is known to have local immunosuppressive activities. In summary, immunization of mice with MCA-205 cells expressing OVA, E1A-Δp300-OVA or E1A-OVA induced equivalent OVA-specific CD4 and CD8 anti-tumor responses. TAMs found in MCA-205-OVA, but not MCA-205-E1A-OVA, tumors expressed high levels of arginase-1. We hypothesize that the production of arginase-1 by TAMs in MCA-205-OVA or MCA-205-E1A-Δp300-OVA tumor cells leads to an ineffective anti-tumor immune response in the tumor microenvironment, but does not result in inhibition of a systemic anti-tumor immunity.     

热休克蛋白-多肽复合物在肿瘤和传染性疾病免疫中的作用

热休克蛋白家族中的许多成员如gp96\,HSP90\,HSP70等具有排斥和治疗肿瘤及传染性疾病的免疫原性,进一步研究发现热休克蛋白作为分子伴侣可结合细胞中的肽库,它本身没有抗原性,抗原性由结合的短肽所决定。热休克蛋白将结合的短肽呈递给I类MHC分子,进而激活特异性CTL和记忆性T细胞,引发机体细胞免疫反应。据最新发现gp96还可能有与MHC一样的功能,可直接将结合的多肽抗原呈递给T细胞。近年来对哺乳动物的二种主要热休克蛋白gp96和HSP70的免疫机制和作为治疗性疫苗的优越性进行了详细研究,这为乙型肝炎和乙肝继发性肝癌的免疫治疗提供了新思路。     

肿瘤抑制因子p53功能及其抗病毒作用研究进展

肿瘤抑制因子p53 作为基因组的守护者,能通过细胞周期调控和促进细胞凋亡而阻止癌细胞及机体肿瘤的发生,p53还能参与DNA损伤修复、调节机体代谢及调节繁殖生育等功能。除此以外,近年来研究发现,p53能通过促进病毒感染的细胞凋亡而起到抗病毒作用以及p53受IFN的调控和p53作为转录调控因子还能直接转录激活IRF9、IRF5、ISG15和TLR3等抗病毒基因,从而确定了p53在抗病毒反应中起到重要作用。这表明p53可能参与先天性免疫、获得性免疫及炎症反应而起到抗病毒的作用。     

Role of the Innate Immune Response and Tumor Immunity Associated with Simian Virus 40 Large Tumor Antigen

We examined properties of the innate immune response against the tumor-specific antigen simian virus 40 (SV40) large tumor antigen (Tag) following experimental pulmonary metastasis in naive mice. Approximately 14 days after mKSA tumor cell challenge, expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), and RANTES was upregulated in splenocytes harvested from mice, as assessed by flow cytometry and antibody array assays. This response was hypothesized to activate and induce tumor-directed NK cell lysis since IL-2-stimulated NK cells mediated tumor cell destruction in vitro. The necessary function of NK cells was further validated in vivo through selected antibody depletion of NK cells, which resulted in an overwhelming lung tumor burden relative to that in animals receiving a control rabbit IgG depletion regimen. Interestingly, mice achieved increased protection from experimental pulmonary metastasis when NK cells were further activated indirectly through in vivo administration of poly(I:C), a Toll-like receptor 3 (TLR3) agonist. In a separate study, mice receiving treatments of poly(I:C) and recombinant SV40 Tag protein immunization mounted effective tumor immunity in an established experimental pulmonary metastasis setting. Initiating broad-based immunity with poly(I:C) was observed to induce a Th1 bias in the SV40 Tag antibody response that led to successful antitumor responses not observed in animals treated only with poly(I:C) or SV40 Tag. These data have direct implications for immunotherapeutic strategies incorporating methods to elicit inflammatory reactions, particularly NK cell-driven lysis, against malignant cell types that express a tumor-specific antigen such as SV40 Tag.Considerable interest has been directed toward the role innate immunity plays in reducing malignant growth and progression. Although the innate system by broad definition is not endowed with the antigen specificity and memory recall of adaptive immunity, natural killer (NK) cells are an innate effector population that shares most properties with the adaptive arm of the immune system, excluding receptor rearrangement (28). Interestingly, NK cells can be employed to directly target and destroy malignant cell types through diverse pathways that include tumor major histocompatibility complex class I (MHC-I) loss and upregulation of stress-inducible protein ligands for the NK cell activating receptor NKG2D (24, 29). Much effort is under way in human clinical trials to manipulate NK cell properties for directed therapies against cancer (13, 29).One strategy in eliciting innate immunity in general involves activating the Toll-like receptor (TLR) family, which are preferentially expressed by innate effectors such as NK cells, macrophages, and dendritic cells (DCs) (26). TLR ligands include a variety of pathogen-associated molecular patterns with differing downstream responses based on the cell type involved and specific TLR activated. In TLR-expressing cells, signal transduction pathways follow a MyD88-independent course to produce type I interferons (IFNs) (e.g., TLR3) or a MyD88-dependent pathway that results in the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and IL-6 and expression of costimulatory molecules such as CD40, CD80, and CD86 (e.g., TLR4 and TLR9) (2, 12, 23, 26). In the case of TLR3, activation by poly(I:C) causes DCs and additional accessory cells to secrete type I interferons and IL-12, activating NK cells and prompting NK cell secretion of IFN-γ among other effects (14, 20). Ultimately, modulation of TLR activation results in the generation of a range of cytokines that promote inflammation, Th1 bias, and NK cell-directed killing that can be utilized in a beneficial manner for tumor treatment strategies.TLR agonist incorporation alongside vaccine strategies has resulted in promising results in mouse models of cancer (12). Indeed, the TLR7 agonist imiquimod is an effective FDA-approved topical compound used to treat superficial basal-cell carcinoma and external genital warts (9). However, to our knowledge, modulating TLR activity while also incorporating recombinant simian virus 40 (SV40) large tumor antigen (Tag) protein immunizations in a therapeutic tumor setting has not been previously reported. SV40 Tag is a clinically relevant tumor-specific antigen that has been shown to be expressed by a number of human malignancies, including malignant pleural mesothelioma (MPM), and represents a potential target for immunotherapeutic strategies.Our laboratory has previously defined a unique role for antibody-dependent cell-mediated cytotoxicity (ADCC) reactions—specific against SV40 Tag—promoting cytotoxic T-lymphocyte (CTL) activity in response to neoantigens through cross-presentation of tumor cell debris in a model of experimental pulmonary metastasis (16, 17). In this report, we analyze the role of innate immunity in mediating tumor cell lysis during the early course of tumorigenesis in the absence of vaccination. Overall, we find that activated NK cells are necessary effector cells in achieving antitumor reactions and providing partial tumor immunity during the onset of tumorigenesis and that these functioning NK cells are likely activated in vivo due to inflammation as a result of tumor growth and progression. The burden of tumor challenge could be further reduced in naive animals with the indirect activation of NK cells using poly(I:C) as a TLR3 agonist prior to and during malignant dissemination. Interestingly, in an established pulmonary tumor setting, therapeutic treatment of mice with poly(I:C) and recombinant SV40 Tag resulted in enhanced protection that was not observed using poly(I:C) or SV40 Tag alone. One effect of instituting poly(I:C) treatment alongside SV40 Tag immunizations was a Th1 skewing of the SV40 Tag IgG antibody response that correlated with therapeutic tumor protection.Our results have direct implications for the prevention and treatment of malignancies, such as MPM, that express the SV40 Tag oncoprotein. Combining specific aspects of innate and adaptive immunity by targeting both NK cells and humoral activity against SV40 Tag, respectively, represents a novel and clinically significant immunotherapeutic strategy for potential use in patients.     

Focus: Vaccines: Myocarditis Following COVID-19 Vaccination: A Systematic Review of Case Reports

Introduction: COVID-19, the infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), often presents with a spectrum of symptoms at varying levels of severity, ranging from asymptomatic patients to those with fatal complications, such as myocarditis. With increased availability of COVID-19 vaccines, the awareness of possible side effects has expanded as reports surface. This study reviewed cases of myocarditis following COVID-19 vaccination and with existing literature on COVID-19 infection-induced myocarditis to compare clinical courses and analyze possible mechanisms of action. Methods: A systematic review of literature was conducted to identify published case reports (as of February 3, 2022) pertaining to the development of myocarditis following COVID-19 vaccination with either Pfizer or Moderna for an in-depth analysis. Additional subgroup analyses were conducted based on age, past medical history, vaccine manufacturer, and dose number. Results: There were 53 eligible case reports that were included in this study. Patients were mostly male with a median age of 24 years, and the most reported symptom upon presentation was chest pain. Seventy percent of the cases involved the Pfizer vaccine with a majority of myocarditis developing subsequent to second dose. Resolution of symptoms was achieved in all but one patient. Clinical severity, as measured primarily by left ventricular ejection fraction, appeared to be worse among adult patients than pediatric, as well as for patients with comorbidities. Conclusion: This study revealed an observable association between COVID-19 vaccines and myocarditis. However, the clinical course and prognosis seem favorable and less prevalent than those conferred from natural infection.     

Focus: Vaccines: The Cost of Ignoring Vaccines

This perspectives piece focuses on the detrimental cost of ignoring vaccines and refusing vaccination against COVID-19 in the United States. Much of the existing literature regarding the consequences of the unvaccinated emphasizes the impact to population health; however, few academic articles have explored the burden the unvaccinated pose to various sectors of society. This paper analyzes the impact that the unvaccinated have on healthcare systems, the US economy, and global health. Throughout the COVID-19 pandemic, unvaccinated populations were found to have put significant strain on healthcare systems, depleting medical resources and contributing to high rates of healthcare worker shortages. Furthermore, research suggests that between November and December 2021, over 692,000 preventable hospitalizations occurred in unvaccinated individuals, costing the US economy over $13.8 billion. Lastly, it is proposed that the strong international presence of the US, when coupled with high levels of disease transmissibility in the unvaccinated, provides a significant threat to global health. In conclusion, the unvaccinated have caused impacts far beyond that of population health; they have also posed a burden to healthcare systems, the economy, and global public health.     

Toll样受体与树突状细胞介导的天然免疫和获得性免疫

树突状细胞(dendritic cells,DCs)作为迄今所发现的抗原提呈功能最强的一类抗原提呈细胞,是联结天然免疫和获得性免疫的桥梁。Toll样受体(Toll-like receptors,TLRs)是一类进化保守的胚系编码的模式识别受体,在DCs的抗原识别、递呈及激活T细胞等方面具有重要作用,是机体受外来抗原入侵后作出适当免疫反应的调控点。现就TLRs在不同DCs亚群中的分布、与DCs介导的天然免疫和获得性免疫的关系及DCs功能可塑性的分子基础作一综述。     

The Role of PP2A A Subunits in Tumor Suppression

The protein phosphatase 2A (PP2A) family of heterotrimeric serine-threonine phosphatases participates in human cell transformation. Each functional PP2A complex contains one structural A subunit (Aα or Aβ), and mutations of both are found to occur at low frequency in human tumors. We have shown that Aα functions as haploinsufficient tumor suppressor gene by regulating in part phosphatidylinositol 3-kinase (PI3K signaling). In contrast, loss of Aβ function due to biallelic alterations contributes to cancer progression through dysregulation of small GTPase RalA activity. These observations provide evidence that dysfunction of particular PP2A complexes regulate specific phosphorylation event necessary for cancer initiation.     

The Role of PP2A A Subunits in Tumor Suppression

The protein phosphatase 2A (PP2A) family of heterotrimeric serine-threonine phosphatases participates in human cell transformation. Each functional PP2A complex contains one structural A subunit (Aα or Aβ), and mutations of both are found to occur at low frequency in human tumors. We have shown that Aα functions as haploinsufficient tumor suppressor gene by regulating in part phosphatidylinositol 3-kinase (PI3K) signaling. In contrast, loss of Aβ function due to biallelic alterations contributes to cancer progression through dysregulation of small GTPase RalA activity. These observations provide evidence that dysfunction of particular PP2A complexes regulate specific phosphorylation event necessary for cancer initiation.Key Words: protein phosphatase 2A, RalA, cancer, transformationReversible phosphorylation plays a key role in the regulation of signaling pathways relevant to cell transformation. Dysregulation of several kinase oncogenes have been shown to be required for cancer development, and several targeted therapies focused on inhibiting particular kinases have now been approved for clinical use. Although it is clear that phosphorylation is also regulated by phosphatases, initial biochemical studies suggested that unlike kinases, phosphatases act promiscuously and constitutively in vitro. However, recent work indicates that phosphatases play essential roles in malignant transformation by acting on specific substrates in vivo.Protein phosphatase 2A (PP2A) is a family of serine-threonine phosphatases implicated in the control of a diverse array of cellular processes. The PP2A core enzyme consists of a catalytic C subunit and a structural A subunit. In mammals, two distinct genes encode closely related versions of both the PP2A A and C subunits. The AC dimer recruits a third regulatory B subunit that has been predicted to dictate the substrate specificity and function of the PP2A heterotrimeric complex. Four unrelated families of B subunits have identified to date: B/B55/PR55/PPP2R2, B′/B56/PR61/PPP2R5, B″/PR72/PPP2R3 and Striatin¹ (Fig. 1). Recent genetic and proteomic studies implicate clear roles for PP2A subunits in regulating physiological functions and one emerging view is that specific PP2A complexes play critical roles in cell transformation by regulating particular substrates.Open in a separate windowFigure 1Disruption of PP2A complexes induces transformation. PP2A is a heterotrimeric protein complex, and several isoforms exist for each of the three subunits, creating a diverse family of related enzymes that regulate specific physiological functions. Alterations of PP2A structural subunits, Aα and Aβ, contribute to spontaneously arising human cancers by distinct mechanisms. Cancer-associated Aα haploinsufficiency may induce human cell transformation by activating PI3K/AKT pathway while PP2A Aβ loss-of-function permits the accumulation of activated RalA.Somatic alterations of the PP2A structural subunit Aβ (PPP2R1B) have been found to occur in colon, lung and breast cancers.^2–5 Notably, point mutations in one Aβ allele are commonly accompanied by loss of the second Aβ allele. We confirmed previous work⁶ that showed cancer-associated Aβ mutants form functionally null alleles.⁷ These studies indicate that Aβ is genetically inactivated in a subset of human cancers. In addition, we found that suppression of Aβ was found to cooperate with H-Ras, telomerase catalytic subunit hTERT and the SV40 Large T antigen to induce transformation of normal human cells while introduction of wild type Aβ into lung carcinoma cells lacking functional Aβ partially reverses this tumorigenic phenotype.⁷ Together, these data provide evidence that PP2A Aβ functions as a tumor suppressor gene.Previous work has shown cancer derived Aβ mutants exhibit markedly impaired ability to form complexes with the catalytic C subunit and the regulatory PR72 subunit.⁶ We have found that Aβ mutants also showed decreased ability to bind to regulatory Bα subunit and several members of B′ family. These data indicate that cancer-associated alterations of PP2A Aβ result in disruption of most if not all PP2A Aβ-containing complexes. Considering that distinct Aβ-B complexes are likely regulate the phosphorylation of particular substrates involved in transformation, further work is required to identify which B subunits participate in malignant transformation.Somatic mutations of the more abundant PP2A structural Aα subunit have also been reported in human cancers, although at low frequency.^2,8 We previously showed that cancer-associated PP2A Aα mutations contribute to cell transformation by creating a state of haploinsufficiency.⁹ Although these two distinct PP2A structural isoforms, Aα and Aβ, are 86% identical,¹⁰ it was unclear whether these two isoforms share overlapping functions.¹¹ We found that overexpression of Aα failed to revert the tumorigenic phenotype induced by Aβ suppression, suggesting that PP2A complexes containing Aα or Aβ are functionally distinct.To identify substrates specific for PP2A Aβ, we performed large scale immunopurification of PP2A Aα- and Aβ-containing complexes. We have found that PP2A Aβ complex, but not the PP2A Aα complex, binds to and inhibits activity of the small GTPase RalA through direct dephosphorylation at Ser183 and Ser 194. Cancer-associated Aβ mutants are unable to dephosphorylate RalA, suggesting that loss of Aβ function impairs the formation of complexes with RalA and deregulates its activity. Consistent with previous reports that implicated RalA in regulation of several signaling pathways relevant to cell transformation,^12–14 loss of function experiments revealed that RalA is crucial for transformation mediated by Aβ dysfunction. These findings strongly suggest that accumulation of phospho-RalA in PP2A Aβ deficient cells promotes tumorigenic phenotype (Fig. 1). However, we cannot exclude that other substrates of PP2A Aβ complexes also contribute to cell transformation.These observations also implicate phosphorylation of RalA as an alternative mechanism that may regulate RalA activity and cell transformation. Prior work has shown Aurora A kinase as one kinase that can induce RalA phosphorylation at Ser 194.¹⁵ However, further studies are required to identify the kinase(s) that are responsible for RalA phosphorylation at Ser 183 and Ser 194.While Aβ loss-of-function permits the accumulation of activated RalA, Aα haploinsufficiency seems to induce human cell transformation by activating AKT/PI3K signaling pathway⁹ (Fig. 1). However, it remains unclear whether PP2A A subunits determine the substrate specificity of heterotrimeric complexes by direct substrate binding, or by forming complex with particular set of B and C subunits. In consonance with the latter idea, Aα and Aβ have been reported to have different affinity to Cα, Bα, B''α1 and PR72 subunits.¹⁷ The systematic characterization of PP2A complex composition necessary for RalA dephosphorylation and Akt activation and further structural studies to resolve PP2A in complex with specific substrates will help elucidate the mechanistic details of how PP2A acts as a tumor suppressor.     

Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

Background

Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.

Methods and Findings

We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.

Conclusions

An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. (ClinicalTrials.gov number {type:clinical-trial,attrs:{text:NCT00289341,term_id:NCT00289341}}NCT00289341).

Trial Registration

ClinicalTrials.gov {type:clinical-trial,attrs:{text:NCT00289341,term_id:NCT00289341}}NCT00289341     

过氧化物酶增殖体激活受体与炎症及免疫反应

过氧化物酶增殖体激活受体(pemxisome proliferator-activated receptor,PPAR)作为糖、脂代谢的调节物,是一种细胞核内受体,属Ⅱ型核受体超家族成员,由激活剂活化后可调控多种核内靶基因的表达,影响人体糖脂代谢、细胞发育等过程,也参与调节炎症与免疫反应。PPAR在体内可分为3型,即α、β和γ型。该主要介绍了PPAR的结构、PPAR配基、PPAR激活后在炎症反应等发生发展过程中的作用机制及重要意义。     

Live Recombinant Salmonella Typhi Vaccines Constructed to Investigate the Role of rpoS in Eliciting Immunity to a Heterologous Antigen

We hypothesized that the immunogenicity of live Salmonella enterica serovar Typhi vaccines expressing heterologous antigens depends, at least in part, on its rpoS status. As part of our project to develop a recombinant attenuated S. Typhi vaccine (RASTyV) to prevent pneumococcal diseases in infants and children, we constructed three RASTyV strains synthesizing the Streptococcus pneumoniae surface protein PspA to test this hypothesis. Each vector strain carried ten engineered mutations designed to optimize safety and immunogenicity. Two S. Typhi vector strains (χ9639 and χ9640) were derived from the rpoS mutant strain Ty2 and one (χ9633) from the RpoS⁺ strain ISP1820. In χ9640, the nonfunctional rpoS gene was replaced with the functional rpoS gene from ISP1820. Plasmid pYA4088, encoding a secreted form of PspA, was moved into the three vector strains. The resulting RASTyV strains were evaluated for safety in vitro and for immunogenicity in mice. All three RASTyV strains were similar to the live attenuated typhoid vaccine Ty21a in their ability to survive in human blood and human monocytes. They were more sensitive to complement and were less able to survive and persist in sewage and surface water than their wild-type counterparts. Adult mice intranasally immunized with any of the RASTyV strains developed immune responses against PspA and Salmonella antigens. The RpoS⁺ vaccines induced a balanced Th1/Th2 immune response while the RpoS⁻ strain χ9639(pYA4088) induced a strong Th2 immune response. Immunization with any RASTyV provided protection against S. pneumoniae challenge; the RpoS⁺ strain χ9640(pYA4088) provided significantly greater protection than the ISP1820 derivative, χ9633(pYA4088). In the pre-clinical setting, these strains exhibited a desirable balance between safety and immunogenicity and are currently being evaluated in a Phase 1 clinical trial to determine which of the three RASTyVs has the optimal safety and immunogenicity profile in human hosts.     

Immunity Genes and Susceptibility to Otitis Media: A Comprehensive Review

Otitis media (OM) is a middle ear infection associated with inflammation and pain. This disease frequently afflicts humans and is the major cause of hearing loss worldwide. OM continues to be one of the most challenging diseases in the medical field due to its diverse host targets and wide range of clinical manifestations. Substantial morbidity associated with OM is further exacerbated by high frequency of recurrent infections leading to chronic suppurative otitis media (CSOM). Children have greater susceptibility to, and thus, suffer most frequently from OM, which can cause significant deterioration in quality of life. Genetic factors have been demonstrated, in large part by twin and family studies, to be key determinants of OM susceptibility. In this review, we summarize the current knowledge on immunity genes and selected variants that have been associated with predisposition to OM. In particular, polymorphisms in innate immunity and cytokine genes have been strongly linked with the risk of developing OM. Future studies employing state-of-the-art technologies, including next-generation sequencing (NGS), will aid in the identification of novel genes associated with susceptibility to OM. This, in turn, will open up avenues for identifying high-risk individuals and designing novel therapeutic strategies based on precise targeting of these genes.     

Systematic Review of Mucosal Immunity Induced by Oral and Inactivated Poliovirus Vaccines against Virus Shedding following Oral Poliovirus Challenge

Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5–30 days after a “challenge” dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08–0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59–1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82–1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV.     

Neuroimmunomodulation in Depression: A Review of Inflammatory Cytokines Involved in this Process

Depression is a debilitating mental disease that affects a large number of people globally; however the pathophysiological mechanisms of this disease remain incompletely understood. Some studies have shown that depression is associated with inflammatory activity, and the mode of action of several antidepressants appears to involve immunomodulation. In this case, the induction of a pro-inflammatory state in healthy or depressive subjects induces a ‘sickness behaviour’ resembling depressive symptomatology. Potential mechanisms of pro-inflammatory cytokines are effects on monoamine levels, disruption of the hypothalamic–pituitary–adrenal axis, activation of the pathological microglial cells, such as the macrophages and alterations in neuroplasticity and brain functions. Thus, this review will highlight the role of inflammation in depression, the possible mechanisms involved, and also explore effective treatments that act on the immune system.     

Prognostic Role of Serum Antibody Immunity to p53 Oncogenic Protein in Ovarian Cancer: A Systematic Review and a Meta-Analysis

Objective

Serum p53 autoantibodies (p53-AAbs) are the product of an endogenous immune response against p53 overexpression driven by the ovarian tumour. The p53-AAbs are detectable only in a subset of patients. To date, the evidence of an association between the presence of p53-AAbs and ovarian cancer outcomes has been poorly investigated.

Methods

A systematic literature search was performed to identify eligible studies investigating the association of serum p53-AAbs and overall survival (OS) and disease free survival (DFS). Associations between presence of serum p53-AAbs and baseline tumour characteristics were also evaluated. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were computed to estimate the prognostic impact of serum p53-AAbs. Heterogeneity between studies was assessed.

Results

A total of 583 patients (7 studies) for OS and 356 patients (4 studies) for DFS were included in the meta-analysis. Presence of p53-AAbs was not associated to OS (pooled uni- multivariate HR = 1.09; 95% CI: 0.55–2.16), and a large heterogeneity was found. When only multivariate HRs were pooled together (4 studies), presence of p53-AAbs was significantly associated to a better OS (pooled HR = 0.57; 95% CI: 0.40–0.81), and no significant heterogeneity was observed. A reduced DFS was associated to p53-AAbs (pooled uni- multivariate HR = 1.37; 95% CI: 0.83–2.25), though not significantly and with a moderate heterogeneity.

Conclusions

The prognostic significance of serum p53-AAbs in ovarian cancer was diverging according to uni or multivariate models used. Since the results of this work were based on only few investigations, large prospective studies are needed to better define the role of antibody immunity against p53.