title: Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.
abstract: The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Gaoping
authors.initials: G
authors.lastname: Zhao
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
authors.forename: James I
authors.initials: JI
authors.lastname: Kim
authors.forename: Kang Mi
authors.initials: KM
authors.lastname: Lee
authors.forename: Matthew R
authors.initials: MR
authors.lastname: O'Connor
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duff
authors.forename: Maozhu
authors.initials: M
authors.lastname: Yang
authors.forename: Ji
authors.initials: J
authors.lastname: Lei
authors.forename: James F
authors.initials: JF
authors.lastname: Markmann
authors.forename: Shaoping
authors.initials: S
authors.lastname: Deng
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002369:Castration; D004703:Endocrine System / Q000502:physiology*; D006066:Gonads / Q000187:drug effects / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D016729:Leuprolide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013934:Thymectomy; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D017493:Leukocyte Common Antigens; D016729:Leuprolide