Université Paris-Sud, Inserm U802, Hématologie immunologie biologique, Traitement de l’hémophilie et thérapie transfusionnelle, CHU Bicêtre AP-HP, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, Inserm U762, 75010 Paris, Cliniques universitaires Saint Luc, UCL-ICP, Hematological Section of the Genetic Center, Bruxelles, Belgique
Immunosuppression is a well-known risk factor of lymphoproliferation. However, it is difficult to distinguish the effects of the underlying diseases and of the immunosuppressive or immunomodulatory drugs. In the context of chronic inflammatory diseases, the influence of these drugs on the incidence of lymphoproliferations is debated. Methotrexate may be responsible for the increased incidence of Hodgkin’s lymphoma observed in rheumatoid polyarthritis. Moreover, the recent development of immunomodulators such as infliximab (anti-TNFα) justifies long-term surveillance for lymphoproliferative diseases in this population. In contrast, lymphoproliferative disorders (PTLD) are well known complications of transplantation-related immunodepression. Their incidence and interval following transplantation vary according to the transplanted organ and to the immunosuppressive regimen. Campath (anti-52 antibody) and anti-thymocyte immunoglobulin in particular has been shown to increase their risk. The effect that immunosuppressive agents with anti-neoplastic properties such as Sirolimus have on the risk of PTLD needs further evaluation. The molecular pathogenesis of these lymphoproliferative disorders occurring in the context of immunosuppression involves oncogenic viruses, mainly Epstein-Barr virus (EBV), chronic antigenic stimulation and genetic alterations. EBV, which infects and persists in B lymphocyte, plays a major role in the development of lymphoproliferative disorders. The monitoring of EBV viral load and of EBV specific immunity contributes to an early diagnosis and to a better follow-up of PTLD. The genetic abnormalities observed in PTLD include aberrant somatic mutations of proto-oncogenes, loss of heterozygosity usually targeting tumour suppressor genes and in a fraction of post-transplant lymphoproliferative disorders, high micro satellite instability as a consequence of DNA mismatch repair system deficiency. These genetic alterations mostly occur late in the course of post-transplantation.