Early renal graft function deterioration in recipients with preformed anti-MICA antibodies: partial contribution of complement-dependent cytotoxicity.
BACKGROUND
We previously reported that preformed anti-MHC class I-related chain A (MICA) antibodies increase the risk for renal graft rejection and enhance the deleterious effect of PRA(+) status early after transplantation.


METHODS
We studied 727 kidney recipients. Days to reach optimal serum creatinine level, estimated glomerular filtration rate (eGFR) at Month 3 and chronic kidney disease (CKD) stages were recorded. Anti-MICA specificities and C1q binding were tested by solid-phase assay. Complement-dependent cytotoxicity (CDC) and flow cytometry (FC) cross-matches with HeLa and PMA/CD28-T-blasts were performed.


RESULTS
PRA(+)MICA(+) recipients exhibited longer time to reach optimal serum creatinine level after transplantation (P = 0.005) and had the lowest eGFR at Month 3 (P = 0.006). PRA(+)MICA(+) status independently increased the risk for CKDT stage 5 at Month 3 [hazard ratio (HR) 4.92, P = 0.030]. Pre-transplant anti-MICA antibodies were polyspecific and showed stronger reactions when coexisting with anti-HLA antibodies (mean standard fluorescent intensity 112 157 ± 44 426 in HLA(+)MICA(+) sera versus 49 680 ± 33 116 in HLA(-)MICA(+) sera, P = 0.0006). Anti-AYVE supereplet reactivity was significantly higher in HLA(+)MICA(+) versus HLA(-)MICA(+) patients (P < 0.001) and significantly superior than anti-CMGWS supereplet within HLA(+)MICA(+) patients (P = 0.001). Three of 13 anti-MICA(+) pre-transplant sera were positive for the C1q binding assay; one of them (serum 3) exclusively recognized AYVE supereplet with a strong reactivity against MICA*027 antigen (same as MICA*008). Anti-MICA antibodies in anti-HLA-absorbed serum 3 bound native MICA molecules in MICA*008(+) HeLa and PMA/CD28-T-blasts and mediated cell death by activating complement.


CONCLUSIONS
Preformed anti-MICA antibodies may occasionally be cytotoxic by fixing and activating complement. This way they might contribute to worse early kidney graft function.
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Elena
E
Sánchez-Zapardiel
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
María José
MJ
Castro-Panete
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Esther
E
Mancebo
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Pablo
P
Morales
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain Research Institute I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Rocío
R
Laguna-Goya
Research Institute I+12, Hospital Universitario 12 de Octubre, Madrid, Spain Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.
José María
JM
Morales
Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Jacqueline
J
Apaza
Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Amado
A
de Andrés
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain.
Paloma
P
Talayero
Department of Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain Research Institute I+12, Hospital Universitario 12 de Octubre, Madrid, Spain School of Medicine, Universidad Complutense de Madrid, Madrid, Spain Section of Immunology, Universidad San Pablo CEU, Madrid, Spain.
Estela
E
Paz-Artal
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D003167:Complement Activation; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000503:physiopathology; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D051436:Renal Insufficiency, Chronic / Q000453:epidemiology / Q000276:immunology / Q000601:surgery*; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D001323:Autoantibodies; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A
anti-MICA antibodies; cytotoxicity; pretransplantation; renal transplant