Biology Reference
In-Depth Information
evidence has been presented to suggest that prophylactic use of the antiviral
ganciclovir in the immediate posttransplantation period can retard the development
of CAV and prolong graft function (Valantine et al. 1999; Valantine 2004; Fishman
et al. 2007). Similarly, extending the duration of treatment with prophylactic anti-
viral agents has been suggested as an intervention to prevent late-onset HCMV dis-
ease and the associated graft rejection in renal and liver allograft recipients
(Razonable et al. 2001). Models of CAV have been developed in the rat and clearly
implicate CMV as an important cofactor in disease. In agreement with the results
of clinical trials in humans, treatment with antivirals at the time of virus infection
in these animal models modified disease (Lemstrom et al. 1993, 1997; Koskinen
et al. 1999; De La Melena et al. 2001).
The pathogenesis of CMV-associated chronic allograft rejection in humans is
incompletely defined perhaps because of the complexity of the disease, the patient
populations and the potent immunosuppressive agents that are required for their
clinical management. Approximately 5%-20% of solid organ allografts are lost as
a result of chronic rejection but other causes such as noncompliance with antirejec-
tion medications or donor-recipient MHC matching likely contribute to graft loss
in these patients (Morris et al. 1993). Therefore, it has been difficult to perform
well-controlled studies in these patients. However, the overwhelming majority of
epidemiological studies have identified HCMV as an important risk factor for
chronic rejection and graft loss and persistent virus excretion as a key risk factor
for chronic rejection episodes associated with HCMV infection (Everett et al. 1992;
Evans et al. 2000). Several risk associations of chronic graft rejection have been
identified in allograft recipients, including:
1. HCMV infection in donor
2. HCMV infection and disease in the recipient in the 1
st
year after transplantation
3. Transplantation of an allograft from a noninfected donor into a HCMV-infected
recipient
4. Prolonged viral replication
5. Episodes of acute rejection (Falagas et al. 1998; Evans et al. 1999, 2000; Tong
et al. 2002; Fateh-Moghadam et al. 2003; Sola et al. 2003; Sagedal et al. 2004;
Chen et al. 2005; Helantera et al. 2006; Potena et al. 2006; Reischig et al. 2006;
Stoica et al. 2006; Hussain et al. 2007)
Persistence of virus replication in these patients likely is reflective of the failure
of host immunological response to control HCMV infection rather than an arbitrary
absolute level of virus replication as estimated by viral load in the blood. Clinical
observations have suggested that both virus replication and graft rejection are
necessary for accelerated vascular disease. Thus, if CMV promotes inflammatory
vascular disease and atherosclerosis in the normal host, these mechanisms could be
greatly amplified in allograft recipients secondary to an ongoing allogenic response,
and the course of vascular disease in these patients could be expected to be accelerated.
This appears to be the case in experimental animal models as well as in allograft
recipients, findings that have been used to argue for a link between CMV replication,
viral gene expression and inflammation.
