Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.

Zhao G, Moore DJ, Kim JI, Lee KM, O'Connor MR, Duff PE, Yang M, Lei J, Markmann JF, Deng S
Sci Transl Med. 2011 3 (87): 87ra52

PMID: 21677198 · PMCID: PMC3767303 · DOI:10.1126/scitranslmed.3002270

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.

MeSH Terms (19)

Aging Animals Antineoplastic Agents, Hormonal Castration Endocrine System Gonads Heart Transplantation Humans Immune System Leukocyte Common Antigens Leuprolide Male Mice Mice, Inbred C3H Mice, Inbred C57BL Thymectomy Thymus Gland Transplantation, Homologous Transplantation Tolerance

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