Alterations in dendritic cell function in aged mice: potential implications for immunotherapy design.
It is known that immune system functions decrease with age, and that adaptive immune responses, especially CD4+ T cell function, seem to be the main affected point in immunity with aging. Dendritic cells (DC) are the major antigen presenting cell (APC), and at least part of the defects observed in adaptive immunity of aged individuals could be due to diminished potential of bone marrow to generate new DC, or defects in DC function. In this study, we investigated if the ability of aged bone marrow (BM) to generate new DC in vitro, as well as aged BM-derived DC responses to lypopolysaccharide (LPS). Because DC are important tools in newly developing anti-tumor therapies, we also studied the ability of aged DC to phagocytose and present antigen from necrotic tumor cells. We found that aged BM generated fewer DC in vitro compared to young BM. While LPS-induced DC maturation is reduced in DC of aged mice, a high TNF-alpha production is observed in aged DC even without LPS stimulation. While phagocytosis of tumor cells is not affected by age, and DC derived from aged BM show a higher TNF-alpha production in response to phagocytosis, presentation of tumor antigens was decreased in aged DC. Because class II upregulation in response to phagocytosis was similar between aged and young DC, this could indicate an age associated processing defect in the exogenous pathway. These findings suggest that age of BM used to generate DC does not impair their phagocytic ability or TNF-alpha production, however leads to a decreased yield in mature DC, reduced response to LPS, and diminished antigen processing/presentation potential. Our results are relevant to optimization DC-based vaccine design for aged populations.
Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Carine
C
Paula
Adriana
A
Motta
Carla
C
Schmitz
Claudia P
CP
Nunes
Ana Paula
AP
Souza
Cristina
C
Bonorino
D000367:Age Factors; D000375:Aging / Q000276:immunology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010587:Phagocytosis; D012107:Research Design; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000951:Antigens, Neoplasm; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4