The role of the alternative complement pathway in early graft loss after intraportal porcine islet xenotransplantation.
BACKGROUND
Intraportal islet transplantation (ITx) causes instant blood-mediated inflammatory reaction (IBMIR), resulting in an early loss of transplanted islets. Porcine islets, transplanted intraportally into nonhuman primates (NHPs), induce complement activation, contributing to the development of IBMIR; however, the exact mechanism is not clear.


METHODS
Complement activation were compared after incubation of purified adult porcine islets in 20% human serum with or without complement inhibitors, C1 esterase inhibitor (C1E-inh), anti-factor B, and purified human factor H. Intraportal porcine ITx was performed in diabetic NHPs to which cobra venom factor (CVF), factor H, or none of complement inhibitor was administered during the peritransplant period. The extent of complement activation and function of islet grafts were monitored after ITx.


RESULTS
The incubation of porcine islets with human serum resulted in generation of C3a, C4d, and factor Bb in the fluid phase. However, the generation of C3a after incubation was suppressed by anti-factor B or factor H, but not by C1E-inh. Moreover, in NHPs with porcine ITx, the administration of CVF or factor H ameliorated the increase in plasma C3a and factor Bb levels, as well as early release of porcine C-peptide after ITx. Furthermore, the functional survival of islet grafts was prolonged in the recipients of the CVF group compared to those in the control group.


CONCLUSIONS
The alternative complement pathway contributes to the development of IBMIR and the early loss of grafts in NHPs with porcine ITx. Complement inhibition during the peritransplant period may be beneficial for the survival of islet grafts.
1 Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Republic of Korea. 2 Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. 3 Xenotransplantation Research Center, Seoul National University Hospital, Seoul, Republic of Korea. 4 Green Cross Corp., Yongin, Republic of Korea. 5 Department of Microbiology and Immunology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. 6 Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. 7 Address correspondence to: Hee Jung Kang, Department of Laboratory Medicine, Hallym University College of Medicine, 896 Pyeongchon-dong, Dongan-gu, Anyang-si, Gyeonggi-do 431-070, Republic of Korea; Chung-Gyu Park, Department of Microbiology and Immunology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
Hee Jung
HJ
Kang
Haneulnari
H
Lee
Jeong-Mi
JM
Ha
Jae-Il
JI
Lee
Jun-Seop
JS
Shin
Ki-Yong
KY
Kim
Ji Yoon
JY
Park
Jung-Sik
JS
Kim
Sang Il
SI
Min
Chung-Gyu
CG
Park
Seong Hoe
SH
Park
Sang Joon
SJ
Kim
D000818:Animals; D003170:Complement Pathway, Alternative / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival; D064593:Heterografts; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D013552:Swine