title: Transient lymphopenia breaks costimulatory blockade-based peripheral tolerance and initiates cardiac allograft rejection.
abstract: Lymphopenia is induced by lymphoablative therapies and chronic viral infections. We assessed the impact of lymphopenia on cardiac allograft survival in recipients conditioned with peritransplant costimulatory blockade (CB) to promote long-term graft acceptance. After vascularized MHC-mismatched heterotopic heart grafts were stably accepted through CB, lymphopenia was induced on day 60 posttransplant by 6.5 Gy irradiation or by administration of anti-CD4 plus anti-CD8 mAb. Long-term surviving allografts were gradually rejected after lymphodepletion (MST = 74 ± 5 days postirradiation). Histological analyses indicated signs of severe rejection in allografts following lymphodepletion, including mononuclear cell infiltration and obliterative vasculopathy. Lymphodepletion of CB conditioned recipients induced increases in CD44(high) effector/memory T cells in lymphatic organs and strong recovery of donor-reactive T cell responses, indicating lymphopenia-induced proliferation (LIP) and donor alloimmune responses occurring in the host. T regulatory (CD4(+) Foxp(3+)) cell and B cell numbers as well as donor-specific antibody titers also increased during allograft rejection in CB conditioned recipients given lymphodepletion. These observations suggest that allograft rejection following partial lymphocyte depletion is mediated by LIP of donor-reactive memory T cells. As lymphopenia may cause unexpected rejection of stable allografts, adequate strategies must be developed to control T cell proliferation and differentiation during lymphopenia.
authors.affiliation: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Iida
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Tanabe
authors.forename: A
authors.initials: A
authors.lastname: Valujskikh
authors.forename: R L
authors.initials: RL
authors.lastname: Fairchild
authors.forename: R
authors.initials: R
authors.lastname: Abe
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061166:Peripheral Tolerance / Q000276:immunology*; D013601:T-Lymphocytes; D023001:Transplantation Tolerance / Q000187:drug effects*; D014916:Whole-Body Irradiation
keywords: Costimulatory blockade; lymphopenia-induced proliferation; memory T cell