T cell immunodeficiency and severe herpes virus infections after allogeneic stem cell transplantation

Abstract

Recipients of stem cell transplants (SCT) are severely immunocompromised at least during the first 6 months post-transplant. In the introduction of this thesis this immunodeficiency is further described. During the neutropenic period patients are at risk for developing bacterial and fungal infections. Once neutropenia has recovered, opportunistic viral infections are a major threat. Both the Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) are herpes viruses and share the phenomenon that primary infection is followed by latent infection. In immunocompetent individuals latent infection of these viruses is controlled by T cell immunity. However, in immunocompromised patients herpes viruses frequently show reactivations, regularly resulting in herpes virus related disease. In this thesis, T cell immunodeficiency and EBV and CMV infections after allogeneic SCT are studied. It is shown that several important changes in transplantation procedure have resulted in a more favourable outcome, especially among recipients of grafts from matched unrelated donors (MUD). B cell depletion -in addition to T cell depletion (TCD)- of grafts, a reduced dosage of Antithymocyteglobulin (ATG) and high resolution DNA typing of HLA-antigens all have contributed to this better outcome. The reduced ATG dose and sequence based typing of HLA-antigens may have improved immune recovery in MUD recipients, thereby eliminating CMV-seropositivity as an adverse risk factor for overall survival and transplant related mortality. In recipients of matched related donor (MRD) grafts pre-emptive treatment of CMV reactivations alone was sufficient to eliminate CMV-seropositivity as an adverse risk factor for outcome. The optimal dose of ATG is unknown, however, considering the immunosuppressive and direct toxic effects of ATG, the lowest possible dose should be used. In the setting of SCT with (partially) TCD grafts from MUDs, using limited post-transplant immunosuppression with cyclosporine A, a total dose of 6-8 mg/kg is recommended. A further decrease greatly increases the risk of severe graft-versus-host disease. The future aim is to further improve immune reconstitution post-transplant and to implement new methods for monitoring, prevention and treatment of opportunistic infections. With respect to prevention of EBV-lymphoproliferative disorders, it is important to know the most frequent transmission route of EBV re-infections. Further studies using LMP-1 fingerprinting for strain identification of patient, donor and partner samples are necessary.