BACKGROUND: Tolerogenic dendritic cells (Tol-DCs) play a critical role in inducing and maintaining tolerance. Recognizing that both T-cell inactivation and activation are contingent on signals provided by DCs and that graft-specific activated T cells are major mediators of transplant rejection, we aimed to create an environment favoring Tol-DCs with a novel reagent, human soluble CD83 (hsCD83). METHODS: Life-supporting orthotopic kidney transplantation was performed in a C57BL/6-to-BALB/c mouse model. The study group was treated with hsCD83 (100 μg/mouse/day, postoperative days -1 to +7, intravenously) and compared with untreated controls. RESULTS: Treatment with hsCD83 achieved kidney allograft tolerance (>100 days), with negligible antidonor antibody detected. In contrast, kidney grafts in untreated recipients demonstrated severe rejection after 35 days, characterized by cellular infiltration, interstitial hemorrhage and edema, and glomerular and tubular necrosis, as well as high antidonor antibody titers. In addition, splenic DCs of tolerant recipients exhibited significantly decreased levels of surface major histocompatibility complex class II, CD40, CD80, and intracellular interleukin-12, as well as reduced allogeneic stimulatory capacity. Adoptive transfer of CD11c+ DCs from tolerant hsCD83-treated animals induced kidney allograft tolerance in syngeneic recipients. Blocking indoleamine 2,3-dioxygenase with 1-methyl-tryptophan (15 mg/mouse/day; gavage) prevented the immunosuppressive effect of hsCD83, abrogating hsCD83-induced Tol-DCs and graft tolerance, and leading to acute kidney graft rejection in 22 days. CONCLUSION: hsCD83 alone was capable of inducing kidney allograft tolerance through a mechanism involving Tol-DC generation and, at least in part, indoleamine 2,3-dioxygenase activity. Because sCD83 is of human origin, the therapeutic approach used in our mouse transplant model holds significant promise for clinical transplantation.
BACKGROUND: Tolerogenic dendritic cells (Tol-DCs) play a critical role in inducing and maintaining tolerance. Recognizing that both T-cell inactivation and activation are contingent on signals provided by DCs and that graft-specific activated T cells are major mediators of transplant rejection, we aimed to create an environment favoring Tol-DCs with a novel reagent, human soluble CD83 (hsCD83). METHODS: Life-supporting orthotopic kidney transplantation was performed in a C57BL/6-to-BALB/c mouse model. The study group was treated with hsCD83 (100 μg/mouse/day, postoperative days -1 to +7, intravenously) and compared with untreated controls. RESULTS: Treatment with hsCD83 achieved kidney allograft tolerance (>100 days), with negligible antidonor antibody detected. In contrast, kidney grafts in untreated recipients demonstrated severe rejection after 35 days, characterized by cellular infiltration, interstitial hemorrhage and edema, and glomerular and tubular necrosis, as well as high antidonor antibody titers. In addition, splenic DCs of tolerant recipients exhibited significantly decreased levels of surface major histocompatibility complex class II, CD40, CD80, and intracellular interleukin-12, as well as reduced allogeneic stimulatory capacity. Adoptive transfer of CD11c+ DCs from tolerant hsCD83-treated animals induced kidney allograft tolerance in syngeneic recipients. Blocking indoleamine 2,3-dioxygenase with 1-methyl-tryptophan (15 mg/mouse/day; gavage) prevented the immunosuppressive effect of hsCD83, abrogating hsCD83-induced Tol-DCs and graft tolerance, and leading to acute kidney graft rejection in 22 days. CONCLUSION:hsCD83 alone was capable of inducing kidney allograft tolerance through a mechanism involving Tol-DC generation and, at least in part, indoleamine 2,3-dioxygenase activity. Because sCD83 is of human origin, the therapeutic approach used in our mouse transplant model holds significant promise for clinical transplantation.
Authors: Joe M Horvatinovich; Elizabeth W Grogan; Marcus Norris; Alexander Steinkasserer; Henrique Lemos; Andrew L Mellor; Irina Y Tcherepanova; Charles A Nicolette; Mark A DeBenedette Journal: J Immunol Date: 2017-02-13 Impact factor: 5.422
Authors: Tracy L McGaha; Lei Huang; Henrique Lemos; Richard Metz; Mario Mautino; George C Prendergast; Andrew L Mellor Journal: Immunol Rev Date: 2012-09 Impact factor: 12.988
Authors: Henrique Lemos; Lei Huang; Phillip R Chandler; Eslam Mohamed; Guilherme R Souza; Lingqian Li; Gabriela Pacholczyk; Glen N Barber; Yoshihiro Hayakawa; David H Munn; Andrew L Mellor Journal: J Immunol Date: 2014-05-05 Impact factor: 5.422
Authors: Marina Doebbeler; Christina Koenig; Lena Krzyzak; Christine Seitz; Andreas Wild; Thomas Ulas; Kevin Baßler; Dmitry Kopelyanskiy; Alina Butterhof; Christine Kuhnt; Simon Kreiser; Lena Stich; Elisabeth Zinser; Ilka Knippertz; Stefan Wirtz; Christin Riegel; Petra Hoffmann; Matthias Edinger; Lars Nitschke; Thomas Winkler; Joachim L Schultze; Alexander Steinkasserer; Matthias Lechmann Journal: JCI Insight Date: 2018-06-07
Authors: J Eckhardt; S Kreiser; M Döbbeler; C Nicolette; M A DeBenedette; I Y Tcherepanova; C Ostalecki; A J Pommer; C Becker; C Günther; E Zinser; T W Mak; A Steinkasserer; M Lechmann Journal: Mucosal Immunol Date: 2014-01-15 Impact factor: 7.313
Authors: Andreas B Wild; Lena Krzyzak; Katrin Peckert; Lena Stich; Christine Kuhnt; Alina Butterhof; Christine Seitz; Jochen Mattner; Niklas Grüner; Maximilian Gänsbauer; Martin Purtak; Didier Soulat; Thomas H Winkler; Lars Nitschke; Elisabeth Zinser; Alexander Steinkasserer Journal: JCI Insight Date: 2019-10-17