Comparative study on signal transduction in endothelial cells after anti-a/b and human leukocyte antigen antibody reaction:  implication of accommodation.
BACKGROUND
Recent development of immunosuppressive therapy has provided a platform for clinical human leukocyte antigen (HLA)- and ABO-incompatible kidney transplantation. However, the prognosis seems to be different between the two. Accommodation, the condition of no injury even in the presence of antidonor antibody, is one of the key factors for successful transplantation with antidonor antibody. The purpose of this study was to compare signal transduction between anti-A/B and anti-HLA antibody reaction and to elucidate the mechanisms underlying accommodation.


METHODS
Blood type A- or B-transferase gene was transfected into human EA.hy926 endothelial cells. After cell sorting, A- or B-expressing cells at high levels were obtained. The effects of anti-HLA and anti-A/B antibody binding on complement-mediated cytotoxicity and signal transduction were examined.


RESULTS
Preincubation with anti-HLA antibodies only at low levels (<10% of saturation level) or anti-A/B antibodies at high levels (even at near saturation levels) for 24 hr resulted in resistance to complement-mediated cytotoxicity. Anti-A/B antibody ligation inactivated ERK1/2 pathway and increased complement regulatory proteins such as CD55 and CD59, whereas anti-HLA ligation activated PI3K/AKT pathway and increased cytoprotective genes such as hemeoxygenase-1 and ferritin H.


CONCLUSIONS
Complement inhibition by upregulation of CD55 and CD59 through ERK1/2 inactivation might play a substantial role in accommodation after ABO-incompatible transplantation, which could also explain the intriguing finding of C4d deposition in the graft without rejection.
Department of Applied Immunology, Nagoya University School of Medicine, Nagoya, Japan.
Kenta
K
Iwasaki
Yuko
Y
Miwa
Haruko
H
Ogawa
Satoko
S
Yazaki
Masaki
M
Iwamoto
Tadashi
T
Furusawa
Akira
A
Onishi
Takafumi
T
Kuzuya
Masataka
M
Haneda
Yoshihiko
Y
Watarai
Kazuharu
K
Uchida
Takaaki
T
Kobayashi
D000017:ABO Blood-Group System / Q000276:immunology*; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology* / Q000494:pharmacology; D001052:Apoferritins / Q000502:physiology; D018958:CD55 Antigens / Q000502:physiology; D018957:CD59 Antigens / Q000502:physiology; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000502:physiology; D016377:Organ Transplantation / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*
D000017:ABO Blood-Group System; D000888:Antibodies, Anti-Idiotypic; D018958:CD55 Antigens; D018957:CD59 Antigens; D006680:HLA Antigens; D003165:Complement System Proteins; D001052:Apoferritins; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt