Avenços en la monitorització immunològica en trasplantament renal
- Autores: Laura Llinàs Mallol
- Directores de la Tesis: Julio Pascual Santos (dir. tes.), Dàlia Raïch Regué (codir. tes.), Marta Crespo Barrio (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2021
- Idioma: catalán
- Tribunal Calificador de la Tesis: Francesc Josep Moreso Mateos (presid.), Frizt Diekman (secret.), Maarten Naesens (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Kidney transplantation (KT) is the best therapeutic option for patients with end-stage renal disease and has the goal to provide long-term stable graft function to those patients. However, graft survival is still limited in time, and antibody-mediated rejection (ABMR) is nowadays recognised as a leading cause of allograft rejection and graft loss. Antibodies directed against HLA antigens present on the donor (HLA-DSA) have been classically associated with ABMR damage. Nevertheless, cases of ABMR without detectable HLA-DSA do exist, and this strengthens the hypothesis that other mechanisms of damage may be playing a role in those cases. The use of immunosuppressive drugs is intended to prevent the immunological rejection of the graft, but its use may be related to the development of serious drawbacks. Changes in the immunosuppression treatment after KT are frequent, but their impact on peripheral blood immune cells and HLA-DSA development has not been elucidated yet. The main aim of this doctoral thesis is to assess whether the immune monitoring of KT recipients in a combined effort comprising HLA and non-HLA antibodies, HLA epitope mismatch analysis and immune cells subpopulations may help to better tailor their immunological risk.
In the first two studies, two changes in immunosuppressive treatment were evaluated: steroid withdrawal and conversion from tacrolimus to mTOR inhibitors. Both immunosuppressive strategies proved to be safe in terms of renal function and HLA-DSA development and triggered a significant redistribution of peripheral blood lymphocyte subsets. Steroid withdrawal mainly impacted the B-cell compartment, whereas conversion to mTOR inhibitors exerted its principal effects in the NK-cell niche. In the third study, we aimed to assess the role of HLA and non-HLA antibodies, together with HLA epitope mismatch analysis in the development of histological ABMR. Nearly a third of histological ABMR cases did not show circulating HLA-DSA at biopsy time, but no non-HLA antibody associated with these cases. Those patients presented lower class II and DRB HLA epitope mismatches compared with ABMR histology cases that presented HLA-DSA, dismissing the possibility of low, undetected HLA-DSA. The detection of pre-transplant antibodies against angiotensin-II type 1 receptor (AT1R) associated with the development of ABMR histology in the presence of HLA-DSA and suggested that HLA-DSA and AT1R antibodies may function in synergy. Finally, the analysis of HLA epitope mismatches proved to be better than the classical HLA antigen mismatches analysis for the prediction of de novo HLA-DSA development.
To conclude, the results presented in this doctoral thesis support that immune monitoring in KT recipients is a useful tool for better immunological risk assessment.
