Project name: Project category: Kind of research: Country: Principle investigator:

Prognostic impact of different cytotoxic mechanisms of Donor-Specific HLA class-I and -II Antibodies (DSA) in lung transplant recipients: Role of dependent complement activation and Antibody Dependant Cellular Cytotoxicity (ADCC)

France Martine Reynaud-Gaubert
Status: Ongoing

Background: Lung transplantation (LTx) is a valid therapeutic strategy for selected patients with end-stage pulmonary disease. However, post-transplant prognosis is hampered by the occurrence of a chronic lung allograft dysfunction (CLAD) which continues to be highly prevalent and remains the major limitation to long-term survival and functional outcome after LTx. Various risk factors are recognized to contribute to the CLAD, among which acute cellular rejection is considered as the most important. During the last decade, the introduction of highly sensitive solid phase assays, such as luminex technology for HLA antibody (Abs) detection in organ transplantation, participated to recognize that antibody-mediated rejection (AMR) is a major cause of organ allograft injury. Recently, we and other studies showed that the humoral response characterized by both the presence of preformed anti-HLA Abs and the development of de novo anti-HLA Abs, and especially Abs directed against donor-mismatched HLA (DSA) are associated with poor survival and CLAD. However, the mechanisms of cytotoxicity of the DSA contributing to the immunopathogenesis of acute and chronic organ failure are still enigmatic. Thus, a better understanding remains a major challenge to improve management of LTx recipients.

-The aim of the study: To evaluate the prevalence and prognostic impact of two cytotoxic mechanisms (Complement fixation on DSA and/or Antibody Dependant Cellular Cytotoxicity (ADCC)) with regards to overall survival and functional outcome of the allograft.

-Methods: We plan a retrospective monocentre study which includes 138 patients who underwent LT at the Lung Transplant Center in Marseille between 1998 and 2010. Serum samples were serially collected in a routine surveillance during the pre-transplant period and at 1, 3 12 and 24 months after the transplant procedure and were stored at -80°C. Focus is put on markers from sera that regulate humoral responses:
1/Anti-HLA class I and II IgM detection in recipient’ by “Single Antigen” luminex (LSA Labscreen®, OneLambda) for sera positive for IgM by CDC
2/C1q- (C1q screen, OneLambda) and C3d-fixing (C3d, Immucor) DSA detection in recipient’ by “Single Antigen” luminex
3/Assay of serum with DSA induced antibody mediated cytotoxic NK immune activation against lymphocytes with HLA genotyping known.
These parameters (DSA IgG, DSA IgM, C1q- and C3d-fixing DSA, DSA with ADCC mechanism) will be analyzed either independently or in combination, in reference to clinical (survival, CLAD occurrence, acute rejection, infections), biological and pharmacological parameters collected during routine follow up. Univariate and multivariate analysis will be performed using SPSS software version 15.0.

-Expected results:
This study should allow: 1/to better understand the role of anti-HLA DSA in the pathogenesis of CLAD ; 2/ to determine a potential association between the clinical outcome and survival and:
1/ preformed C1q- and C3d-fixing DSA IgG and DSA IgM
2/ de novo C1q and C3d-fixing DSA post-LT and DSA IgM
3/ persistent de novo C1q and C3d-fixing DSA post-LT at M3
4/ ADCC potential of preformed DSA and de novo DSA
These correlations could determine the impact of different cytotoxic mechanisms of DSA on CLAD occurrence and recipient’s survival, allowing better monitoring of humoral response in clinical routine and potential development of specific therapeutic options limiting allograft injury and extend long term survival after lung transplantation.

Project amount (€): 32.000

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