title: Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells.
abstract: Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8(+) memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2(high) CD8(+) effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2(high) cells including CD8(+) TEM while sparing naïve CD8(+) T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2(high) T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach.
authors.affiliation: Department of Surgery, Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Tonsho
authors.forename: S
authors.initials: S
authors.lastname: Boskovic
authors.forename: O
authors.initials: O
authors.lastname: Nadazdin
authors.forename: D
authors.initials: D
authors.lastname: Schoenfeld
authors.forename: K
authors.initials: K
authors.lastname: Cappetta
authors.forename: M
authors.initials: M
authors.lastname: Atif
authors.forename: R-N
authors.initials: RN
authors.lastname: Smith
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.forename: G
authors.initials: G
authors.lastname: Benichou
authors.forename: T
authors.initials: T
authors.lastname: Kawai
mesh_terms: D000077944:Alefacept; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D018801:CD2 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005838:Genotype; D006085:Graft Survival; D007108:Immune Tolerance; D007156:Immunologic Memory / Q000187:drug effects*; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D008285:Major Histocompatibility Complex; D011993:Recombinant Fusion Proteins / Q000737:chemistry*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000379:methods*; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D018801:CD2 Antigens; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D000077944:Alefacept
keywords: Kidney transplantation; memory T cells; mixed hematopoietic chimerism; nonhuman primates; tolerance