A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection.
BACKGROUND
Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression.


METHODS
Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis.


RESULTS
Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration.


CONCLUSIONS
Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.
Akashi
Satoru
S
Department of Surgery, Nara Medical University School of Medicine, Nara, Japan.
Sho
Masayuki
M
Kashizuka
Hisanori
H
Hamada
Kaoru
K
Ikeda
Naoya
N
Kuzumoto
Yukiyasu
Y
Tsurui
Yoshikazu
Y
Nomi
Takeo
T
Mizuno
Takashi
T
Kanehiro
Hiromichi
H
Hisanaga
Michiyoshi
M
Ko
Saiho
S
Nakajima
Yoshiyuki
Y
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D065100:CCR5 Receptor Antagonists; D039521:CD11c Antigen / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D017690:Cell Transplantation; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation / Q000379:methods*; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D019713:Receptors, CCR5 / Q000737:chemistry*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
D000577:Amides; D065100:CCR5 Receptor Antagonists; D039521:CD11c Antigen; D015704:CD4 Antigens; D016827:CD8 Antigens; C515187:CXCR3 protein, human; C515188:Cxcr3 protein, mouse; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; C119369:TAK 779