title: Posttransplant peripheral blood donor-specific interferon-γ enzyme-linked immune spot assay differentiates risk of subclinical rejection and de novo donor-specific alloantibodies in kidney transplant recipients.
abstract: Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft function (subclinical rejection) could permit more effective therapy and prevent later development of de novo anti-donor HLA antibodies and/or graft dysfunction. Here we tested whether quantifying posttransplant donor-specific alloreactive T-cells by IFN-γ ELISPOT assay noninvasively detects subclinical T-cell mediated rejection and/or predicts development of anti-donor HLA antibodies. Using an initial cross-sectional cohort of 60 kidney transplant patients with six-month surveillance biopsies, we found that negative donor-specific IFN-γ ELISPOT assays accurately ruled out the presence of subclinical T-cell mediated rejection. These results were validated using a distinct prospective cohort of 101 patients where donor-specific IFN-γ ELISPOT results at both three- and six-months posttransplant significantly differentiated patients with subclinical T-cell mediated rejection at six months, independent of other clinical variables (odds ratio 0.072, 95% confidence interval 0.008-0.653). The posttransplant donor-specific IFN-γ ELISPOT results independently associated with subsequent development of significant anti-donor HLA antibodies (0.085, 0.008-0.862) and with significantly worse two-year function (estimated glomerular filtration rate) compared to patients with a negative test. Thus, posttransplant immune monitoring by donor-specific IFN-γ ELISPOT can assess risk for developing subclinical T-cell mediated rejection and anti-donor HLA antibodies, potentially limiting the need for surveillance biopsies. Our study provides a guide for individualizing immunosuppression to improve posttransplant outcomes.
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Crespo
authors.affiliation: Renal Division, Department of Medicine and the Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cravedi
authors.affiliation: HLA histocompatibility Laboratory, Hospital Clinic de Barcelona, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Martorell
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Luque
authors.affiliation: Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Melilli
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain; Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Jarque
authors.affiliation: Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Meneghini
authors.affiliation: Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Manonelles
authors.affiliation: Renal Division, Department of Medicine and the Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadei
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Lloberas
authors.affiliation: Pathology Department, Bellvitge University Hospital, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Gomà
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain; Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
authors.affiliation: Renal Division, Department of Medicine and the Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Heeger
authors.affiliation: Experimental Nephrology Laboratory, IDIBELL, Barcelona University, Barcelona, Spain; Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona, Spain. Electronic address: obestard@bellvitgehospital.cat.
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D058070:Asymptomatic Diseases; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016009:Chi-Square Distribution; D003430:Cross-Sectional Studies; D003937:Diagnosis, Differential; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000097:blood*; D059425:Interferon-gamma Release Tests; D007518:Isoantibodies / Q000097:blood*; D016030:Kidney Transplantation / Q000009:adverse effects*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic / Q000379:methods*; D015999:Multivariate Analysis; D016017:Odds Ratio; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012372:ROC Curve; D012307:Risk Factors; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006680:HLA Antigens; C573415:IFNG protein, human; D007518:Isoantibodies; D007371:Interferon-gamma
keywords: T-cell alloreactivity; de novo alloantibodies; kidney transplantation; noninvasive biomarkers