Cytomegalovirus (CMV) infection in the period of temporary immunodeficiency after haematoablative treatment and bone marrow transplantation (BMT) is associated with a risk of graft failure and multiple-organ CMV disease. The efficacy of immune system reconstitution is decisive for the prevention of CMV pathogenesis after BMT. Previous data in murine model systems have documented a redundancy in the immune effector mechanisms controlling CMV. CD8 T cells proved to be relevant but not irreplaceable as antiviral effectors. Specifically, in a state of long-term in vivo depletion of the CD8 T-cell subset, CD4 T cells were educed to become deputy effectors controlling CMV by a mechanism involving antiviral cytokines. It is of medical importance to know whether one can trust in this ' flexible defence ' in all clinical settings. It is demonstrated here that reconstitution of CD8 T cells is crucial for the prevention of fatal multipleorgan CMV disease under the specific conditions of BMT.Patients undergoing bone marrow transplantation (BMT) associated with temporary immunodeficiency are at risk of fatal cytomegalovirus (CMV) disease with multiple organ involvement (for reviews see Winston et al., 1990 ; Einsele et al., 1998). Whether or not primary or recurrent CMV infections develop into disease appears to be related to the efficacy of haematopoietic and immune system reconstitution. Specifically, early reappearance of CD8 T cells is of positive prognostic value for recovery (Reusser et al., 1991). Accordingly, restoration of immunity to CMV by adoptive cytoimmunotherapy with antiviral CD8 T-cell lines is in clinical trials (Riddell et al., 1992 ;Walter et al., 1995). In BMT performed across minor or class I major histocompatibility disparities, graft vs. host disease (GvHD) is a further risk factor (Einsele et al., 1998). In a major Author for correspondence : Matthias Reddehase.Fax j49 6131 395604. e-mail Matthias.Reddehase!uni-mainz.de histocompatibility complex (MHC) class II-identical but MHC class I-disparate setting, selective depletion of class I-restricted CD8 T cells might be discussed as a regime for GvHD prophylaxis. However, if CD8 T cells were the only effectors Fig. 1. (A) Lethality of CMV infection after selective T-cell subset depletion. Syngeneic BMT was performed on day 0 with BALB/c mice as BM cell donors and recipients. Recipients were infected with 1i10 5 p.f.u. of purified murine CMV ca. 2 h after BMT. In vivo depletion of T-cell subsets was performed twice, namely on days 7 and 14, by intravenous administration of 1 mg of the respective antibody. Kaplan-Meyer plots show the survival rates for 20 recipients per experimental group as a function of time. (B) Efficacy and specificity of the T-cell subset depletions. Pulmonary infiltrate leukocytes were isolated on day 21 and analysed by three-colour cytofluorometry for the expression of TCR α/β (phycoerythrin fluorescence, FL-2), CD4 (RED613 fluorescence, FL-3) and CD8 (FITC fluorescence, FL-1). Gates were set on lymphocytes and on positive FL-2 in ...

Therapy of cytomegalovirus (CMV) infection in recipients of hematopoietic stem cell transplantation (HSCT) by immune serum transfer did not fulfill the high clinical expectations, although immune sera or immunoglobulin-enriched preparations pooled from many CMV-immune donors are likely to contain virus neutralizing antibodies covering a broad range of virus variants. Likewise, the highest risk of CMV disease in HSCT recipients results from the reactivation of the latently infected recipient's own virus despite pre-transplantation humoral immunity. These findings suggest the conclusion that antiviral antibodies are inefficient in controlling CMV. Rather than B cells and antibodies, T cells, in particular CD8 T cells, are thought to play a major role in resolving established organ infection. In theory, antibodies, though being capable of neutralizing free virions, could fail to prevent cell-bound virus dissemination from the portal of entry to distant target tissues and also could fail in preventing cell-to-cell spread within tissue. Here we have used murine model systems, including B cell deficient C57BL/6 micro(- ) micro(-) (microMT) mutants, to revisit the role of antiviral antibodies in the control of CMV infection and to reevaluate the prospects of an antibody-based immunotherapy from a basic science point of view.

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