Treatment of experimental autoimmune prostatitis in nonobese diabetic mice by the vitamin D receptor agonist elocalcitol.
On the basis of on the marked inhibitory activity of the vitamin D receptor agonist Elocalcitol on basal and growth factor-induced proliferation of human prostate cells and on its potent anti-inflammatory properties, we have tested its capacity to treat experimental autoimmune prostatitis (EAP) induced by injection of prostate homogenate-CFA in nonobese diabetic (NOD) mice. Administration of Elocalcitol, at normocalcemic doses, for 2 wk in already established EAP significantly inhibits the intraprostatic cell infiltrate, leading to a profound reduction in the number of CD4(+) and CD8(+) T cells, B cells, macrophages, dendritic cells, and I-A(g7)-positive cells. Immunohistological analysis demonstrates reduced cell proliferation and increased apoptosis of resident and infiltrating cells. Significantly decreased production of the proinflammatory cytokines IFN-gamma and IL-17 is observed in prostate-draining lymph node T cells from Elocalcitol-treated NOD mice stimulated by TCR ligation. In addition, Elocalcitol treatment reduces IFN-gamma production by prostate-infiltrating CD4(+) T cells and draining lymph node T cells specific for an immunodominant peptide naturally processed from prostate steroid-binding protein, a prostate-specific autoantigen. Finally, CD4(+) splenic T cells from Elocalcitol-treated NOD mice show decreased ability, upon adoptive transfer into NOD.SCID recipients, to induce autoimmune prostatitis, paralleled by a reduced capacity to produce IFN-gamma in response to prostate steroid-binding protein. The results indicate that Elocalcitol is able to interfere with key pathogenic events in already established EAP in the NOD mouse. These data show a novel indication for vitamin D receptor agonists and indicate that treatment with Elocalcitol may inhibit the intraprostatic inflammatory response in chronic prostatitis/chronic pelvic pain syndrome patients.
Penna
Giuseppe
G
BioXell, Via Olgettina 58, I-20132 Milan, Italy.
Amuchastegui
Susana
S
Cossetti
Chiara
C
Aquilano
Francesca
F
Mariani
Roberto
R
Sanvito
Francesca
F
Doglioni
Claudio
C
Adorini
Luciano
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000188:drug therapy; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D007107:Immune System / Q000473:pathology; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011472:Prostatitis / Q000188:drug therapy* / Q000473:pathology; D018167:Receptors, Calcitriol / Q000819:agonists*
C487049:BXL628; D018167:Receptors, Calcitriol; D007371:Interferon-gamma; D002117:Calcitriol