Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial

Abstract

Background Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies. Methods This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γ release assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)–specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. Results Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30–9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31–59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89–237.96]). Conclusions Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell–depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation. Clinical Trials Registration NCT02550639.

Use of T Cell Mediated Immune Functional Assays for Adjustment of Immunosuppressive or Anti-infective Agents in Solid Organ Transplant Recipients: A Systematic Review

“…A recent multicenter double-blind randomized clinical trial included adult kidney transplant recipients who were anti-CMV antibody donor positive / recipient positive prior to transplantation ( 44 ). This clinical trial used T-SPOT®.CMV and assigned SOT recipients into the interventional groups.…”

“…The cut-off to discriminate low- and high-risk SOT recipients were 20 spots per 300,000 PBMCs. Both low- and high-risk SOT recipients underwent randomization to receive either anti-CMV prophylaxis (for 3 months) or preemptive antiviral therapy ( 44 ). In addition, T-SPOT®.CMV was done 15 days post-transplantation in both groups.…”

Understanding human γδ T cell biology toward a better management of cytomegalovirus infection

“…61 CMV peptides from the three following open reading frames (UL48, UL83, and UL123) are recognized by more than half of individuals. 48 Interestingly, IE-1 (UL123)-specific CD8 + T cells are associated with less CMV reactivation in SOTR, 62,63 probably because UL123 is the first CMV protein to be expressed in infected cells. In vitro, CMV-specific CD8 + T cells are able to exert antiviral effector functions trough interferon-γ (IFN-γ) production.…”

“…In patients undergoing CMV disease that are resistant to antiviral treatments, second-line therapies are associated with important adverse effects, and no other therapeutic option is currently available 5. Importantly, it has been shown that a quicker immune reconstitution of both αβ and γδ T cell compartments after HCT or a better quality of the αβ and γδ T cell responses in SOTR is correlated with a lower incidence of CMV infection and disease 34,63,[176][177][178]. These observations highlight the importance of an efficient cellular immune response for preventing CMV infection.Adoptive transfer of CMV-reactive T cells therefore represents an attractive approach in both HCTR and SOTR, in order to boost the cellular immune response and achieve long-term protection against CMV infection.…”

“…(Immunotec),63,218 by Jarque and colleagues, and for pp-65 or IE1 at 40 IFN-γ spots/3.10 5 PBMC 219 (Immunotec).At the beginning of transplantation to predict the risk of CMV infection or diseaseIn D + R − patients, T-SPOT > 10 IFN-γ spots/3.10 5 PBMC was found in 30% of patients and was associated with a lower incidence of CMV infection, demonstrating that seronegative recipients could have a protective CMV-specific αβ T CMI 220. In R + patients, at day 0 and more predictively at day 15 post-transplantation, T-SPOT > 20 IFN-γ spots/3.10 5 PBMC for IE1 was highly associated with the absence of any CMV infection in patients who did not receive T-cell-depleting agents as induction therapy 63. Indeed, we have previously shown that R + patients with positive IE1 T-SPOT at day 0 of transplantation,…”