The innate immune response and activation of coagulation in alpha1,3-galactosyltransferase gene-knockout xenograft recipients.
BACKGROUND
The role of the innate immune system in the development of thrombotic microangiopathy (TM) after alpha1,3-galactosyltransferase gene-knockout (GTKO) pig organ transplantation in primates is uncertain.


METHODS
Twelve organs (nine hearts, three kidneys) from GTKO pigs were transplanted into baboons that received no immunosuppressive therapy, partial regimens, or a full regimen based on costimulation blockade. After graft failure, histologic and immunohistologic examinations were carried out.


RESULTS
Graft survival of less than 1 day was prolonged to 2 to 12 days with partial regimens (acute humoral xenograft rejection) and to 5 and 8 weeks with the full regimen (TM). Clinical or laboratory features of consumptive coagulopathy occurred in 7 of 12 baboons. Immunohistochemistry demonstrated IgM, IgG, and complement deposition in most cases. Histopathology demonstrated neutrophil and macrophage infiltrates, intravascular fibrin deposition, and platelet aggregation (TM). Grafts showed expression of primate tissue factor (TF), with increased mRNA levels, and TF was also expressed on baboon macrophages/monocytes infiltrating the graft.


CONCLUSIONS
Our data suggest that (1) irrespective of the presence or absence of the adaptive immune response, early or late xenograft rejection is associated with activation of the innate immune system; and (2) porcine endothelial cell activation and primate TF expression by recipient innate immune cells may both contribute to the development of TM.
Ezzelarab
Mohamed
M
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, PA 15261, USA.
Garcia
Bertha
B
Azimzadeh
Agnes
A
Sun
Hongtao
H
Lin
Chih Che
CC
Hara
Hidetaka
H
Kelishadi
Sean
S
Zhang
Tianshu
T
Lin
Yih Jyh
YJ
Tai
Hao-Chi
HC
Wagner
Robert
R
Thacker
Jnanesh
J
Murase
Noriko
N
McCurry
Kenneth
K
Barth
Rolf N
RN
Ayares
David
D
Pierson
Richard N
RN
Cooper
David K C
DK
D000818:Animals; D030801:Animals, Genetically Modified; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006720:Homozygote; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D010215:Papio; D013552:Swine / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014183:Transplantation, Heterologous / Q000276:immunology*
D007166:Immunosuppressive Agents; D005700:Galactosyltransferases