Thymosin alpha1: an endogenous regulator of inflammation, immunity, and tolerance.
Thymosin alpha1 (Talpha1), first described and characterized by Allan Goldstein in 1972, is used worldwide for the treatment of some immunodeficiencies, malignancies, and infections. Although Talpha1 has shown a variety of effects on cells and pathways of the immune system, its central role in modulating dendritic cell (DC) function has only recently been appreciated. As DCs have the ability to sense infection and tissue stress and to translate collectively this information into an appropriate immune response, an action on DCs would predict a central role for Talpha1 in inducing different forms of immunity and tolerance. Recent results have shown that Talpha1: (a) primed DCs for antifungal Th1 resistance through Toll-like receptor (TLR)/MyD88-dependent signaling and this translated in vivo in protection against aspergillosis; (b) activated plasmacytoid DCs (pDC) via the TLR9/MyD88-dependent viral recognition, thus leading to the activation of interferon regulatory factor 7 and the promotion of the IFN-alpha/IFN-gamma-dependent effector pathway, which resulted in vivo in protection against primary murine cytomegalovirus infection; (c) induced indoleamine 2,3-dioxygenase activity in DCs, thus affecting tolerization toward self as well as microbial non-self-antigens, and this resulted in vivo in transplantation tolerance and protection from inflammatory allergy. Talpha1 is produced in vivo by cleavage of prothymosin alpha in diverse mammalian tissues. Our data qualify Talpha1 as an endogenous regulator of immune homeostasis and suggest that instructive immunotherapy with Talpha1, via DCs and tryptophan catabolism, could be at work to control inflammation, immunity, and tolerance in a variety of clinical settings.
Romani
Luigina
L
Microbiology Section, Department of Experimental Medicine, and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy. lromani@unipg.it
Bistoni
Francesco
F
Montagnoli
Claudia
C
Gaziano
Roberta
R
Bozza
Silvia
S
Bonifazi
Pierluigi
P
Zelante
Teresa
T
Moretti
Silvia
S
Rasi
Guido
G
Garaci
Enrico
E
Puccetti
Paolo
P
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology; D000818:Animals; D001228:Aspergillosis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007113:Immunity, Innate; D007249:Inflammation / Q000503:physiopathology*; D009181:Mycoses / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D000077596:Thymalfasin; D013947:Thymosin / Q000031:analogs & derivatives* / Q000276:immunology / Q000502:physiology; D013950:Thymus Gland / Q000276:immunology
D013947:Thymosin; D000077596:Thymalfasin