Clinical significance of CMV-specific T helper responses in lung transplant recipients

Cytomegalovirus (CMV) disease continues to be a major problem for lung transplant patients who generate an inefficient immune response to control this viral infection. Both T helper and cytotoxic T cells are thought to play an important role in prevention and control of CMV disease. We investigated the clinical significance of CMV-specific memory responses in lung transplant recipients.

Peripheral blood samples (140) were collected from 99 lung transplant recipients. Patients were grouped according to their pre-transplant CMV serological status as recipient/donor (R-/D+, 25 patients), 28 R+/D+ patients, 35 R+/D- patients and 11 R-/D- patients. Memory responses to CMV whole antigen, 5 CMV proteins, and tetanus toxoid (TT) were measured in a 6-day proliferative assay. Results were expressed as the stimulation index (SI = experimental cpm/background cpm), and were considered positive if the SI was >3 and the cpm values were over 1,000.

The frequency of positive CMV memory responses was similar in three groups: 64% for R-/D+, 63% for R+/D+ and 56% for R+/D- except for R-/D- (21%). The memory response to TT was similar for all four groups (70% of samples were positive). The level of responsiveness to individual CMV proteins was much higher in R+/D+ group (65%) than the other two groups (35% for R+/D-, and 31% for R-/D+). We determined the temporal relationship between the presence of CMV-specific memory responses and the diagnosis of CMV disease. In the R-/D+ group, 16 of 17 patients who had CMV disease eventually developed CMV-specific memory. In those patients (n = 3) who failed to develop CMV-specific T helper response for a prolonged time, all had recurrent CMV disease. In the R+/D+ group, 4 of 8 patients with CMV disease exhibited CMV-specific memory responses. Three of 4 patients in whom we observed a persistent absence of CMV-specific memory had multiple episodes of CMV pneumonitis. In the R+/D- group, only one of 4 patients with CMV disease had suppressed CMV-specific memory response after first episode of CMV pneumonitis and had recurrent disease.

In lung transplant recipients, the loss or persistent lack of CMV-specific memory following infection was associated with chronic CMV disease. These data suggest that monitoring T helper memory responses following primary CMV infection or after augmented immunosuppression for treatment of rejection may identify those patients at risk for morbidity associated with recurrent CMV disease.