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Aging is closely related to the main aspects of multiple sclerosis (MS). The average age of the MS population is increasing and the number of elderly MS patients is expected to increase. In addition to neurons, N-methyl-D-aspartate receptors (NMDARs) are also expressed on non-neuronal cells, such as immune cells. The aim of this study was to investigate the role of NMDARs in experimental autoimmune encephalomyelitis (EAE) in young and aged rats. Memantine, a non-competitive NMDAR antagonist, was administered to young and aged Dark Agouti rats from day 7 after immunization. Antagonizing NMDARs had a more favourable effect on clinical disease, reactivation, and apoptosis of CD4+ T cells in the target organ of aged EAE rats. The expression of the fractalkine receptor CX3CR1 was increased in memantine-treated rats, but to a greater extent in aged rats. Additionally, memantine increased Nrf2 and Nrf2-regulated enzymes’ mRNA expression in brain tissue. The concentrations of superoxide anion radicals, malondialdehyde, and advanced oxidation protein products in brain tissue were consistent with previous results. Overall, our results suggest that NMDARs play a more important role in the pathogenesis of EAE in aged than in young rats.

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine with a role in immunity to pathogens, as well as in the pathogenesis of several autoimmune/inflammatory diseases. Biological drugs targeting this cytokine and inhibiting its effects are designed. Until today, five TNF-α inhibitors are approved: infliximab, adalimumab, golimumab (monoclonal antibodies), certolizumab pegol (pegylated antigen-binding fragment of immunoglobulin), and etanercept [TNF receptor type 2-fragment crystallizable (Fc) of immunoglobulin fusion protein]. Their approved biosimilars are on the market, too. They are mainly used for the treatment of rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Although TNF-α inhibitors are present in clinical practice for more than two decades and are established as an efficacious therapeutics, researchers are still occupied by revealing the complex mechanisms of their action. Namely, in addition to binding and neutralisation of soluble TNF-α, these drugs also bind/block transmembrane form of TNF-α (tmTNF-α), trigger diverse intracellular signals in tmTNF-α positive cells (a process named “reverse signalling”) or, if they have an Fc fragment, mediate killing of tmTNF-α-expressing cells by other immune cells or the complement system. Also, TNF-α inhibitors that contain Fc portion of the IgG antibody may affect Fc receptor-expressing cells and have an effector function quite independent of their TNF-α neutralisation capacity., Faktor nekroze tumora (TNF)-a je citokin koji ima značajnu ulogu u patogenezi nekih autoimunskih/inflamatornih bolesti. Shodno tome, dizajnirani su biološki lekovi koji ciljano inhibiraju efekte koje on ostvaruje posredstvom svojih receptora. Do danas je odobreno pet lekova koji inhibiraju TNF-a: infliksimab, adalimumab, golimumab (monoklonska antitela), certolizumab pegol (pegilovani antigen-vezujući fragment imunoglobulina) i etanercept [TNF receptor 2-kristalizujući fragment (Fc) imunoglobulina fuzioni protein]. Takođe, brojni biosimilari ovih lekova su odobreni za primenu. Glavne indikacije za primenu anti-TNF-a lekova su: reumatoidni artritis, inflamatorne bolesti creva, psorijaza. Iako se TNF-a inhibitori više od dve decenije uspešno koriste u kliničkoj praksi, složeni mehanizmi njihovog delovanja još uvek nisu potpuno poznati. Naime, pokazano je da se ovi lekovi, osim vezivanja i neutralizacije solubilnog TNF-a, mogu vezati i za transmembransku formu ovog citokina i blokirati je i/ili pokrenuti prenos signala u ćeliju koja ispoljava ovaj molekul ("reverzni prenos signala"). Takođe, ovi lekovi, ukoliko poseduju Fc fragment, mogu posredovati i u ubijanju ćelija koje ispoljavaju membransku formu TNF-a aktivacijom drugih ćelija imunskog sistema ili sistema komplementa ili modulisati funkciju ćelija koje ispoljavaju receptore za Fc fragmanet i ostvarivati efektorske funkcije nezavisno od njihove sposobnosti da blokiraju/neutrališu TNF-a.

Considering variability in vaccine responsiveness across human populations, in respect to magnitude and quality, and importance of vaccines in the elderly, the influence of recipient genetic background on the kinetics of age-related changes in the serum IgG antibody responses to seasonal trivalent inactivated split-virus influenza bulk (TIV) was studied in BALB/c and C57BL/6 mice showing quantitative and qualitative differences in this responses in young adult ages. With ageing the total serum IgG response to influenza viruses declined, in a strain-specific manner, so the strain disparity observed in young adult mice (the greater magnitude of IgG response in BALB/c mice) disappeared in aged mice. However, the sexual dimorphisms in this response (more prominent in females of both strains) remained in aged ones. The strain-specific differences in age-related decline in the magnitude of IgG response to TIV correlated with the number of germinal centre (GC) B splenocytes. The age-related decline in GC B cell number was consistent with the decrease in the proliferation of B cells and CD4+ cells in splenocyte cultures upon restimulation with TIV. Additionally, the age-related decrease in the magnitude of IgG response correlated with the increase in follicular T regulatory (fTreg)/follicular T helper (fTh) and fTreg/GC B splenocyte ratios (reflecting decrease in fTh and GC B numbers without changes in fTreg number), and the frequency of CD4+ splenocytes producing IL-21, a key factor in balancing the B cell and fTreg cell activity. With ageing the avidity of virus influenza-specific antibody increased in females of both strains. Moreover, ageing affected IgG2a/IgG1 and IgG2c/IgG1 ratios (reflecting Th1/Th2 balance) in male BALB/c mice and female C57BL/6 mice, respectively. Consequently, differently from young mice exhibiting the similar ratios in male and female mice, in aged female mice of both strains IgG2a(c)/IgG1 ratios were shifted towards a less effective IgG1 respons

Extended lifespan and increasing number of the elderly (>65 years) worldwide carries the challenges for the public health system, as this is the population particularly susceptible to infectious diseases. One way to prevent these diseases is vaccination. In order to improve the quality of life of the elderly, to reduce complications, hospitalizations and mortality, many European countries and the United States recommend the vaccination of the elderly with the influenza vaccine, vaccines against Streptococcus pneumoniae and Varicella-zoster virus (VZV), and booster vaccination against tetanus, pertussis and diphtheria. The reason for the greater susceptibility to infectious diseases, and lower efficacy of vaccines in the elderly, are age-associated changes of the immune system. In most European countries seasonal influenza vaccine is recommended for the individuals over 65 years of age. Its efficacy is lower in the elderly than in adults, so strategies are being developed to overcome these problems (including adjuvants in the formulation, increasing the antigen dose, changing the route of immunization, development of vector-based vaccines). Polysaccharide and conjugated vaccines are available against S. pneumoniae, but data regarding their efficacy are inconsistent. The VZV vaccine is an attenuated, live vaccine and has been shown to be effective in reducing the incidence of herpes zoster and post-herpetic neuralgia. Raising awareness of the importance of vaccination in the elderly and the development of vaccines tailored for this population is of great importance for the preservation of their health. © 2019, Pharmaceutical Association of Serbia., Produženje ljudskog veka i povećanje broja starih (stariji od 65 godina) na svetskom nivou nosi sa sobom izazove za javno-zdravstveni sistem jer se radi o populaciji podložnoj infektivnim bolestima. Vakcinacija je jedan od načina prevencije ovih bolesti. U cilju poboljšanja kvaliteta života, smanjenja komplikacija bolesti, hospitalizacija i mortaliteta starih, mnoge evropske države i Sjedinjene Američke Države, kod starih osoba, preporučuju vakcinaciju protiv gripa, pneumokoka, varičela-zoster virusa (VZV), kao i „booster” vakcinacije protiv tetanusa, pertusisa i difterije. Razlog veće podložnosti infektivnim bolestima i manjoj efikasnosti vakcina kod starih su starenjem uslovljene promene koje pogađaju imunski sistem, a koje utiču na njegovu funkciju. Sezonska vakcina protiv gripa se u većini evropskih zemalja preporučuje starijima od 65 godina. Budući da je njena efikasnost niža kod starih nego kod odraslih osoba, razvijaju se strategije koje bi prevazišle ovaj problem (uključivanje adjuvansa u formulaciju, povećanje doze, promena puta unošenja antigena, razvoj vektorskih vakcina). Protiv pneumokoka su dostupne polisaharidna i konjugovana vakcina, a podaci o njihovoj efikasnosti su nekonzistentni. Vakcina protiv VZVje atenuisana, živa vakcina i pokazala se efikasna u smanjenju incidencije herpes zostera i post-herpetične neuralgije.

Elderly patients with rheumatoid arthritis, psoriasis and psoriatic arthritis encompass those with elderly-onset disease, over 60 years of age, but also those with earlier disease onset who entered old age. Considering the age-related changes of the immune system, possible frailty, susceptibility to infection and concomitant comorbidity that implies multiple medicines, the treatment of these diseases in elderly patients can be challenging. Interleukin inhibitors have been shown to be an efficient and safe treatment for these diseases. However, elderly patients with these diseases were often included in the pivotal clinical trials for interleukin inhibitors in numbers insufficient to determine whether they responded differently from younger subjects. The aim of this paper was to review the findings on the efficacy and safety of interleukin inhibitor treatment in elderly patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis.The findings suggest that, for all the interleukin inhibitors reviewed herein, used in elderly patients with rheumatoid arthritis, or with psoriasis and psoriatic arthritis, the efficacy was comparable to younger patients. Furthermore, the incidence of reported adverse events was similar in these two age groups. Severe adverse events, which were related to sarilumab treatment for rheumatoid arthritis and secukinumab treatment for psoriasis, were higher in elderly patients.The reviewed findings suggest that the interleukin inhibitors approved and currently in use in clinical practice for the treatment of rheumatoid arthritis, psoriasis, and psoriatic arthritis can be considered a safe and efficient option for these diseases in elderly patients., Stariji pacijenti koji boluju od reumatoidnog artritisa, psorijaze ili psorijaznog artritisa uključuju one kod kojih je bolest imala kasni početak, nakon 60. godine starosti, ali takođe i one pacijente kod kojih je bolest počela ranije, a koji su ušli u staro doba. Imajući u vidu starenjem uslovljene promene imunskog sistema, moguću slabost starijih, podložnost infekcijama, prateći komorbiditet, koji uključuje i uzimanje više lekova, terapija ovih bolesti kod starijih pacijenata može predstavljati izazov. Inhibitori interleukina su se pokazali kao efikasna i bezbedna terapija ovih poremećaja. Međutim, stariji pacijenti sa ovim bolestima su često bili nedovoljno zastupljeni u ključnim kliničkim ispitivanjima inhibitora interleukina da bi se moglo sa sigurnošću utvrditi da postoji razlika u terapijskom odgovoru kod ovih pacijenata u odnosu na isti kod mlađih pacijenata. Cilj ovog rada bio je da prikaže nalaze od značaja za bezbednost i efikasnost terapije inhibitorima interleukina kod starijih pacijenata sa reumatoidnim artritisom, psorijazom ili psorijaznim artritisom. Nalazi ukazuju da je efikasnost inhibitora interleukina, prikazanih u ovom radu, uporediva kod starijih i mlađih pacijenata. Osim toga, incidencija neželjenih događaja se nije razlikovala između ove dve starosne grupe. Veća incidencija teških neželjenih događaja kod starijih pacijenata u odnosu na mlađe bila je zabeležena u terapiji reumatoidnog artritisa sarilumabom i psorijaze secukinumabom. Terapija reumatoidnog artritisa, psorijaze i psorijaznog artritisa inhibitorima interleukina može se smatrati efikasnom i bezbednom u populaciji starih pacijenata.

The study investigated influence of sex and age on splenic myeloid dendritic cells (DCs) from Dark Agouti rats. Freshly isolated DCs from young males exhibited less mature phenotype and greater endocytic capacity compared with those from age-matched females. Upon LPS stimulation in vitro they were less potent in stimulating allogeneic CD4+ cells in mixed leukocyte reaction (MLR), due to lower expression of MHC II, and greater NO and IL-10 production. In accordance with higher TGF-beta production, young male rat DCs were less potent in stimulating IL-17 production in MLR than those from young females. Irrespective of sex, endocytic capacity and responsiveness of DCs to LPS stimulation in culture, judging by their allostimulatory capacity in MLR decreased with age, reflecting decline in MHC II surface density followed by their greater NO production; the effects more prominent in females. Additionally, compared with LPS-stimulated DCs from young rats, those from sex-matched aged rats were more potent in stimulating IL-10 production in MLR, whereas capacity of DCs from aged female and male rats to stimulate IL-17 production remained unaltered and decreased, respectively. This reflected age-related shift in IL-6/TGF-beta production level ratio in LPS-stimulated DC cultures towards TGF-beta, and sex-specific age-related remodeling CD4+ cell cytokine pathways. Additionally, compared with LPS-stimulated DCs from young rats, those cells from sex-matched aged rats were less potent in stimulating IFN-gamma production in MLR, the effect particularly prominent in MLRs encompassing male rat DCs. The study showed that stimulatory and polarizing capacity of DCs depends on rat sex and age.

Hashimoto autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in the pediatric population. Development of AIT is mediated mainly by cellular immune response directed toward thyroid autoantigens, leading to inflammation and impaired function of thyroid gland. Both thyroid dysfunction and inflammation affect the metabolism of plasma lipoproteins. The alterations in lipid profile worsen with the advancement of hypothyroidism, ranging from discrete changes in euthyroid AIT patients, to atherogenic dyslipidemia in the overt hypothyroidism. In this review, characteristics of dyslipidemia in pediatric AIT patients, and the consequences in respect to the risk for cardiovascular disease (CVD) development are discussed. Additionally, benefit of L-thyroxine treatment on serum lipid profile in pediatric AIT patients is addressed. Finally, potential usefulness of novel lipid biomarkers, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), non-cholesterol sterols, low-density lipoprotein particle size and number, and high-density lipoprotein structure and functionality in AIT patients is also covered. Further longitudinal studies are needed in order to elucidate the long-term cardiovascular outcomes of dyslipidemia in pediatric patients with Hashimoto AIT., article

In the present study, possibilities for using novel nanocomposites based on alginate and silver nanoparticles for wound treatment were investigated in a second-degree thermal burn model in Wistar rats. Silver nanoparticles (AgNPs) were electrochemically synthesized in alginate solutions that were further utilized to obtain the Ag/alginate solution and microfibers for subsequent in vivo studies. Daily applications of the Ag/alginate colloid solution, containing AgNPs, alginate and ascorbic acid (G3), wet Ag/alginate microfibers containing AgNPs (G5) and dry Ag/alginate microfibers containing AgNPs (G6) were compared to treatments with a commercial cream containing silver sulfadiazine (G2) and a commercial Ca-alginate wound dressing containing silver ions (G4), as well as to the untreated controls (G1). Results of the in vivo study have shown faster healing in treated wounds, which completely healed on day 19 (G4, G5 and G6) and 21 (G2 and G3) after the thermal injury, while the period for complete reepitelization of untreated wounds (G1) was 25 days. The macroscopic analysis has shown that scabs fell off between day 10 and 12 after the thermal injury induction in treated groups, whereas between day 15 and 16 in the control group. These macroscopic findings were supported by the results of histopathological analyses, which have shown enhanced granulation and reepithelization, reduced inflammation and improved organization of the extracellular matrix in treated groups without adverse effects. Among the treated groups, dressings based on Ca-alginate (G4-G6) induced enhanced healing as compared to the other two groups (G2, G3), which could be attributed to additional stimuli of released Ca2+. The obtained results indicated potentials of novel nanocomposites based on alginate and AgNPs for therapeutic applications in wound treatments.

Dendritske ćelije (DĆ) su profesionalne antigen-prezentujuće ćelije koje činesponu između urođenog i stečenog imuniteta i imaju važnu ulogu u imunskomodgovoru. Pored toga, DĆ imaju ulogu u uspostavljanju i održavanju imunološketolerancije, kao i u patogenezi autoimunskih bolesti. Istraživanja na polju biologijestarenja ćelija imunskog sistem su pokazala da tokom starenja komponente i urođenog istečenog imuniteta podležu promenama. Podaci vezani za uticaj starenja na DĆ nisukonzistentni i uglavnom se odnose na ćelije humanog porekla, ćelije primata i miševa,dok nema podataka o uticaju starenja na DĆ pacova.Cilj ove doktorske disertacije je bio da se ispita uticaj starenja na fenotipske ifunkcijske karakteristike konvencionalnih DĆ (kDĆ) pacova, kao i mogući značajsojnih razlika za nastanak starenjem uslovljenih promena ovih ćelija. Takođe, cilj je bioi da se utvrdi da li starenjem uslovljene promene kDĆ pacova koreliraju sa promenomosetljivosti pacova na indukciju organ-specifičnih autoimunskih bolesti. Ispitivane susveže izolovane kDĆ i stimulisane in vitro lipopolisaharidom (LPS). KonvencionalneDĆ su izolovane iz slezina pacova uzrasta 3 meseca (mladi odrasli pacovi) i 26 meseci(stari pacovi) Albino Oxford (AO) i Dark Agouti (DA) soja, koji pokazuju različitstepen osetljivosti na indukciju organ-specifične autoimunske bolesti posredovaneTh1/Th17 limfocitima, kao što je eksperimentalni autoimunski encefalomijelitis (EAE).Starenje dovodi do veće zastupljenosti ćelija CD4- fenotipa u populaciji svežeizolovanih kDĆ starih AO pacova za razliku od mladih životinja, kod kojih je brojnijaCD4+ subpopulacija, a ne utiče na zastupljenost ovih subpopulacija kod DA pacova,tako da je kod njih u oba uzrasta dominantna CD4- subpopulacija. Osim toga, svežeizolovane kDĆ starih AO pacova pokazuju nezreliji, a starih DA pacova zreliji fenotip,u odnosu na kDĆ mladih pacova odgovarajućeg soja, a što je procenjeno na osnovunivoa ispoljenosti aktivacionih molekula (CD80, CD86 i CD40). U s, Dendritic cells (DCs) are the professional antigen-presenting cells that form aninterface between innate and adaptive immunity and play an important role in theimmune response. They are also central in the establishment and maintenance ofimmune tolerance, as well as in the pathogenesis of autoimmune diseases. Aging isassociated with the progressive immune system changes, which involve all types ofimmune cells. The data on age-associated DC alterations origin mainly from studies inmice and human, and are largely inconsistent, while there are no data on the influenceof aging on rat DCs.The aim of this thesis was to elucidate the influence of aging on the phenotypicand functional characteristics of conventional DCs (cDCs), and the possible significanceof strain differences in the development of age-related changes. In addition, this thesiswas aimed to investigate a putative correlation between age-related changes in cDCbiology and rat susceptibility to induction of organ-specific autoimmune diseases.Freshly isolated cDCs and cDCs stimulated in vitro with lipopolysaccharide (LPS) wereinvestigated. The cells were isolated from the spleens of 3- (young adult) and 26 monthold(aged) rats of Albino Oxford (AO) and Dark Agouti (DA) strain, which arerelatively resistant (AO) and susceptible (DA) to the induction of Th1/Th17-mediatedorgan-specific autoimmune disease, as it is experimental autoimmune encephalomyelitis(EAE).In AO rats aging increased relative proportion of cells exhibiting CD4-phenotype within population of freshly isolated cDCs, while in young animals CD4+cells represented the predominant subpopulation within cDCs. In DA rats aging did notaffect cDC subset composition, so predominance of CD4- subset within cDCs in rats ofboth ages was found. Aging affected surface phenotype and endocytic capacity offreshly isolated cDCs in a strain-specific manner. Namely, the lower surface density ofactivation markers (CD80, CD86 and CD40) on cDCs from aged AO rats and theirhig