title: Age-related changes in spleen of Dark Agouti rats immunized for experimental autoimmune encephalomyelitis.
abstract: The study was undertaken considering age-related changes in susceptibility to experimental autoimmune encephalomyelitis (EAE) and a putative role of spleen in pathogenesis of this disease. The phenotypic and functional characteristics of T splenocytes were examined in young (3-month-old), middle-aged (8-month-old) and aged (26-month-old) Dark Agouti rats immunized for EAE with rat spinal cord in complete Freund's adjuvant. The rat susceptibility to EAE induction, as well as the number of activated CD4+CD134+ lymphocytes retrieved from their spinal cords progressively decreased with aging. To the contrary, in rats immunized for EAE the number of activated CD4+ splenocytes, i.e., CD4+CD134+, CD4+CD25+FoxP3- and CD4+CD40L+ cells, progressively increased with aging. This was associated with age-related increase in (i) CD4+ splenocyte surface expression of CD44, the molecule suggested to be involved in limiting emigration of encephalitogenic CD4+ cells from spleen into blood and (ii) frequency of regulatory T cells, including CD4+CD25+FoxP3+ cells, which are also shown to control encephalitogenic cell migration from spleen into the central nervous system. In favor of expansion of T-regulatory cell pool in aged rats was the greater concentration of IL-10 in unstimulated, Concanavalin A (ConA)- and myelin basic protein (MBP)-stimulated splenocyte cultures from aged rats compared with the corresponding cultures from young ones. Consistent with the age-related increase in the expression of CD44, which is shown to favor Th1 effector cell survival by interfering with CD95-mediated signaling, the frequency of apoptotic cells among CD4+ splenocytes, despite the greater frequency of CD95+ cells, was diminished in splenocyte cultures from aged compared with young rats. In addition, in control, as well as in ConA- and MBP-stimulated splenocyte cultures from aged rats, despite of impaired CD4+ cell proliferation, IFN-γ concentrations were greater than in corresponding cultures from young rats. This most likely reflected increased abundance of IFN-γ-producing cells in splenocyte cultures from aged compared with young rats. The diminished CD4+ cell proliferation in response to ConA and MBP in splenocyte cultures from aged compared with young rats could be, at least partly, associated with an enhanced splenic expression of iNOS mRNA in aged rats. Thus, the study suggests that age-associated changes leading to entrapping of activated CD4+ cells in the spleen could contribute to the restriction in development of EAE in aged rats.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Djikić
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Nacka-Aleksić
authors.affiliation: Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pilipović
authors.affiliation: Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Duško
authors.initials: D
authors.lastname: Kosec
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Nevena
authors.initials: N
authors.lastname: Arsenović-Ranin
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Stojić-Vukanić
authors.affiliation: Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Dimitrijević
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia. Electronic address: Gordana.Leposavic@pharmacy.bg.ac.rs.
authors.forename: Gordana
authors.initials: G
authors.lastname: Leposavić
mesh_terms: D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005620:Freund's Adjuvant / Q000633:toxicity; D004676:Myelin Basic Protein / Q000276:immunology / Q000633:toxicity; D051381:Rats; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D004676:Myelin Basic Protein; D005620:Freund's Adjuvant
keywords: Aging; CD44; EAE; Regulatory cells; Spleen