title: Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.
abstract: Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.
authors: Emory Transplant Center, Emory University, Atlanta, GA, USA.
authors: E K
authors: EK
authors: Page
authors: A J
authors: AJ
authors: Page
authors: J
authors: J
authors: Kwun
authors: A C
authors: AC
authors: Gibby
authors: F
authors: F
authors: Leopardi
authors: J B
authors: JB
authors: Jenkins
authors: E A
authors: EA
authors: Strobert
authors: M
authors: M
authors: Song
authors: R A
authors: RA
authors: Hennigar
authors: N
authors: N
authors: Iwakoshi
authors: S J
authors: SJ
authors: Knechtle
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D007150:Immunohistochemistry; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000276:immunology*; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D008297:Male
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies