El trasplante de órganos sólidos es una terapia primaria en pacientes con enfermedades en etapa terminal. Aunque se ha logrado una mejora notable debido a los protocolos inmunosupresores todavía hay un alto porcentaje de receptores de trasplantes que sufren rechazo. Las células supresoras derivadas de mieloides (MDSC) representan un grupo heterogéneo de células reguladoras mieloides que podrían desempeñar un papel importante en la inducción de la tolerancia al aloinjerto. En el presente trabajo hemos monitorizado el número y fenotipo de MDSC y realizado estudios in vitro en los que recolectamos sangre de 38 receptores de trasplante de riñón (KTR) y 82 receptores de trasplante pulmonar (LTR) en diferentes momentos. Observamos un aumento en las frecuencias de Mo-MDSCs a corto plazo después del trasplante y 1 año después del trasplante en KTR. Encontramos un aumento en la expansión de Treg después del co-cultivo con Mo-MDSCs. Además, observamos que las Mo-MDSC de KTR que recibieron tacrolimus tenían una mayor actividad supresora en comparación con las que recibieron rapamicina y atribuimos la pérdida de la función supresora a la menor expresión de IDO en las Mo-MDSC expuestas a rapamicina. Describimos por primera vez subpoblaciones circulantes de MDSC de LTR en varios puntos de tiempo y evaluamos la relación de MDSC con los resultados del trasplante de pulmón. Aunque no se observó ningún efecto de los subconjuntos de MDSC en eventos clínicos a corto plazo, nuestros resultados determinan que las frecuencias de Mo-MDSC aumentan después del rechazo celular agudo (ACR), lo que sugiere un posible papel de Mo-MDSC en el desarrollo de la disfunción crónica del aloinjerto pulmonar (CLAD). Además, se han diseñado 4 nuevos paneles de citometría para identificar las MDSC en sangre periférica humana. Futuros estudios prospectivos son necesarios para establecer si la tolerancia a largo plazo debida a la inmunomodulación es dependiente o no de MDSC.
Solid organ transplantation is a primary therapy in patients with end-stage diseases. Although remarkable improvement has been achieved due to the immunosuppressive protocols and the reduction in the incidence of acute rejection (AR) has been reduced, there is still a high percentage of transplant recipients that suffer from AR within the first year after transplantation. Moreover patients that have previously suffered an AR in kidney transplantation, usually show a higher incidence of chronic rejection and as a consequence long-term allograft survival has not improved significantly throughtout the years. Likewise, despite the improvement in the management of lung transplant recipients (LTR), 5-year survival for LTR remains low. An increasing field of research is focused on the study of dysregulation of immune mechanisms underlying allograft failure. In this regard, myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of myeloid regulatory cells that were originally described in cancer. Several studies in animal models point to them as important players in the induction of allograft tolerance, due to their immune modulatory function, but there is a lack of studies regarding their role in human transplantation. To monitor the number and phenotype of MDSCs and to perform in vitro studies we collected blood from 38 kidney transplant recipients (KTR) and 82 LTR at different time points. We observed an increase in Mo-MDSCs frequencies in the short term after transplantation and 1 year after transplantation in KTR. We report an increase in Treg expansion after Mo-MDSCs co-culture. Furthermore, we observed that Mo-MDSCs from KTR receiving tacrolimus had a higher suppressive activity compared to those receiving rapamycin and we attributed the loss of suppressive function to the decreased expression of IDO in Mo-MDSCs exposed to rapamycin. We describe for the first time circulating subsets MDSCs from LTR at several time points and we evaluated the relationship of MDSCs with sort-term lung transplant outcomes. Although no effect of MDSCs subsets on shortterm clinical events was observed, our results determine Mo-MDSCs frequencies are increased after acute cellular rejection (ACR), suggesting a possible role for Mo-MDSC in the development of chronic lung allograft dysfunction (CLAD). Therefore, whether MDSCs subsets play a role as biomarkers of chronic rejection or not, remains unknown and requires further investigations. Finally, the effects of different immunosuppressive drugs on the development and function of MDSCs need to be better characterized and further prospective studies are required to establish whether long-term tolerance to immune modulation transplantation is dependent on MDSCs. In collaboration with the immunomonitoring lab from the group of Experimental Surgery in the Hospital Klinikum of Regensburg (Germany) we set up 4 new cytometry panels. This new strategy for identifying MDSCs in human peripheral blood combines surface markers, function markers and new markers not affected by corticoids.
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