Paving the Way Toward a Better Understanding of Viral T Cell Interactions after Stem Cell Transplantation

In recent years, many viruses, such as adenovirus, BK virus, or human herpesvirus type 6, have taken their place in what seems to be a growing list of pathogens that can potentially affect patients after allogeneic stem cell transplantation (alloSCT), and viruses have become a more frequent cause of morbidity and mortality after transplantation. As a consequence, virological monitoring with sensitive assays and the subsequent introduction of preemptive therapy has become a routine strategy in the management of stem cell transplant recipients. Immune reconstitution remains a pivotal issue after transplantation. After myeloablative cytoreductive therapy and alloSCT, a period of deep cellular immunodeficiency follows until the donor-derived immune system has sufficiently regenerated. As a result of the lack of immunosurveillance, endogenous viruses, such as cytomegalovirus and Epstein-Barr virus (EBV), may reactivate and cause disease. Specific T cell depletion of stem cell grafts and the use of antithymocyte globulin as part of the conditioning regimen further reduce the number of T lymphocytes transferred with the graft, which otherwise would have contributed to the first phase of T cell regeneration after transplantation. Moreover, interventions aimed at the prevention of graft-versus-host disease and the reduction of its severity greatly reduce the rate of T cell reconstitution (including that of virus-specific T cells) and therefore increase the frequency and severity of viral reactivations [1, 2].

Cytomegalovirus and EBV have long been major contributors to morbidity among patients who have undergone transplantation. As such, these viruses have been subjected to intensive studies to discover and assess tolerable and effective treatment tools.

For cytomegalovirus, an effective and sensitive detection system has been created that uses viral load as determined by PCR and pp65-positive antigenemia; this method discovers early reactivations and leads to successful preemptive treatment in many cases. The primary concern regarding EBV infection in these circumstances is the development of EBV-driven post-transplant lymphoproliferative disorder (PTLD), which is associated with uncontrolled proliferation of B cells [3]. Thus far, studies of EBV reactivation have been limited to molecular monitoring of EBV load in peripheral blood or plasma of stem cell transplant recipients. These studies have demonstrated the reliability of EBV load as a predictive parameter to identify individuals who will proceed to PTLD [4]. Following this approach, it has been shown that this kind of early monitoring, combined with preemptive therapy with anti-CD20 monoclonal antibodies (rituximab), improves outcome in patients at high risk for PTLD [5].

In the current issue of Clinical Infectious Diseases, Annels et al. [6] describe a comprehensive tool that combines the monitoring of the viral load of the infectious agent with the corresponding response capacity of the infected body. This, for the first time, gives us a fine-tuning system for the management of EBV reactivation. In view of the risk of graft-versus-host disease, the opportunity to separate different populations of T cells will allows us to add back EBV-specific T cells with the stem cell graft without increasing the risk of graft-versus-host disease. This will hold true even in haploidentically mismatched transplantations, in which we anticipate a high rate of aggressive graft-versus-host disease, when a whole alloreactive donor lymphocyte population is given as a result of donor-recipient mismatching. In such situations, this technique will allow us to benefit from the advantages of such a transplantation, while avoiding the price of graft-versus-host disease. Furthermore, for the first time, there is a quantitative tool to recognize and evaluate different subgroups of patients with different qualities of T cell reconstitution, and this has implications far beyond the narrow subject of EBV reactivation. It will also pave the way to exploring more deeply the relationship between the infectious agent and the immune system, as well as how a given infection influences rehabilitation of the T cell lineages.

Anti-EBV treatment may interfere with engraftment. Therefore, avoiding such medications for patients who show self-reconstitution of EBV-specific T cells will further facilitate durable engraftment, which, in turn, will enhance the anti-EBV status of such transplant recipients.

Selective in vitro restoration of anti-EBV cellular immunity is yet another attractive alternative approach for dealing with EBV reactivations after transplantation. In vitro co-culturing of donor T cells with EBV antigens will potentially generate an EBV-specific donor-derived T cell clone, which, in turn, will be transferred to the recipient, creating accurate shielding against the hazardous infection. Application of such an EBV-specific adoptive cellular therapy, following the initial proof of principle (elegantly made by Annels et al. [6]), will provide a powerful tool for better controlling this life-threatening disease.

The future harbors many challenges that are yet to be addressed. However, making a new technical approach available by combining viral load as determined by PCR with T cell reconstitution, as was demonstrated by Annels et al. [6], opens a new horizon for the exploration of viral infections. Evaluating the interrelationship between viruses and T cells with regard to fundamental processes and modalities is expected to shed light on the mechanisms underlying immunity in different physiological and pathological states, to create a better understanding of such processes, and to enable the design of innovative potential future strategies and medications.

• Received February 12, 2006.
• Accepted February 15, 2006.

• © 2006 by the Infectious Diseases Society of America