Pierre Reusser

Cytomegalovirus (CMV)—Specific T Cell Immunity after Renal Transplantation Mediates Protection from CMV Disease by Limiting the Systemic Virus Load

The role of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTLs) and T helper cells (Th) in controlling CMV infection, as detected by antigenemia assay and polymerase chain reaction (PCR) in blood leukocytes, and CMV disease was investigated in 20 renal transplant recipients. Within 3 months after transplant, CMV-specific CTL and Th responses were demonstrable in 11 (55%) and 15 (75%) patients, respectively; CMV infection was detected by antigenemia and PCR in 19 (95%) patients each. During the month of first CMV detection, there was an inverse correlation between CTL response and antigenemia at >/=20 positive cells/105 leukocytes (P=.007) but no association with lower antigenemia levels or PCR positivity. CMV disease developed in 7 (35%) patients and was associated with high-level antigenemia but was inversely correlated with detection of CTLs (P=.04). After renal transplantation, CMV-specific CTLs limit the systemic virus load as reflected by antigenemia levels and thereby mediate protection from CMV disease.

Development of a treatment regimen for human cytomegalovirus (CMV) infection in bone marrow transplantation recipients by adoptive transfer of donor-derived CMV-specific T cell clones expanded in vitro.

CMV infection represents a major cause of morbidity and mortality in immunosuppressed bone marrow transplant (BMT) recipients. Life-threatening CMV infection was found to occur only in patients who did not develop a CMV-specific CD8+ Tc response. Therefore, methods to clone and expand CMV-specific Tc were developed to facilitate analysis of the specificity of the CD8+ Tc response to CMV responsible for protective immunity in seropositive donors, and to permit adoptive transfer of in vitro expanded CMV-specific Tc derived from bone marrow donors into immunocompetent HLA-matched BMT recipients to augment resistance to CMV. The immunodominant class I-restricted Tc response present in healthy seropositive individuals was found to be specific for a conserved CMV antigen introduced into the cytoplasm and presented shortly following viral penetration and uncoating, and did not require endogenous viral gene expression and protein synthesis. Thus, the protective immune response to CMV mediates lysis of virally-infected cells prior to virion assembly. Processing of viral proteins and access to presentation in the context of class I MHC molecules immediately following infection of target cells was selective for internal virion proteins, such as the tegument protein pp65. By contrast, presentation by infected cells of GB, the major CMV envelope protein, or IE, the major regulatory protein, was delayed due to a requirement for endogenous synthesis in infected cells, and CD8+ Tc specific for these proteins were detected in low frequency as compared to the immundominant response.