The correlates of protective immunity to disease-inducing viruses in humans remain to be elucidated. We determined the kinetics and characteristics of cytomegalovirus (CMV)-specific CD4 ؉ and CD8 ؉ T cells in the course of primary CMV infection in asymptomatic and symptomatic recipients of renal transplants. Specific CD8 ؉ cytotoxic T lymphocyte (CTL) and antibody responses developed regardless of clinical signs. CD45RA ؊ CD27 ؉ CCR7 ؊ CTLs, although classified as immature effector cells in HIV infection, were the predominant CD8 effector population in the acute phase of protective immune reactions to CMV and were functionally competent. Whereas in asymptomatic individuals the CMV-specific CD4 ؉ T-cell response preceded CMV-specific CD8 ؉ T-cell responses, in symptomatic individuals the CMV-specific effectormemory CD4 ؉ T-cell response was delayed and only detectable after antiviral therapy.The appearance of disease symptoms in these patients suggests that functional CD8 ؉ T-cell and antibody responses are insufficient to control viral replication and that formation of effector-memory CD4 ؉ T cells is necessary for recovery of infection.

CD8+ T-cell responses against latent viruses can cover considerable portions of the CD8+ T-cell compartment for many decades, yet their initiation and maintenance remains poorly characterized in humans. A key question is whether the clonal repertoire that is raised during the initial antiviral response can be maintained over these long periods. To investigate this we combined next-generation sequencing of the T-cell receptor repertoire with tetramer-sorting to identify, quantify and longitudinally follow virus-specific clones within the CD8+ T-cell compartment. Using this approach we studied primary infections of human cytomegalovirus (hCMV) and Epstein Barr virus (EBV) in renal transplant recipients. For both viruses we found that nearly all virus-specific CD8+ T-cell clones that appeared during the early phase of infection were maintained at high frequencies during the 5-year follow-up and hardly any new anti-viral clones appeared. Both in transplant recipients and in healthy carriers the clones specific for these latent viruses were highly dominant within the CD8+ T-cell receptor Vβ repertoire. These findings suggest that the initial antiviral response in humans is maintained in a stable fashion without signs of contraction or changes of the clonal repertoire.

T cells play a dual role in transplantation: They mediate transplant rejection and are crucial for virus control. Memory T cells generated in response to pathogens can cross‐react to alloantigen, a phenomenon called heterologous immunity. Virus‐specific CD8+ T cells cross‐reacting to donor‐alloantigen might affect alloimmune responses and hamper tolerance induction following transplantation. Here, we longitudinally studied these cross‐reactive cells in peripheral blood of 25 kidney transplant recipients with a cytomegalovirus and/or Epstein‐Barr virus infection. Cross‐reactive T cells were identified by flow cytometry as virus‐specific T cells that proliferate in response to donor cells in a mixed‐lymphocyte reaction. In 13 of 25 patients, we found cross‐reactivity to donor cells for at least 1 viral epitope before (n = 7) and/or after transplantation (n = 8). Cross‐reactive T cells were transiently present in the circulation, and their precursor frequency did not increase following transplantation or viral infection. Cross‐reactive T cells expressed interferon‐γ and CD107a in response to both alloantigen and viral peptide and resembled virus‐specific T cells in phenotype and function. Their presence was not associated with impaired renal function, proteinuria, or rejection. In conclusion, virus‐specific T cells that cross‐react to donor‐alloantigen are transiently detectable in the circulation of kidney transplant recipients.

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

After solid organ transplantation, patients are susceptible to infection caused by uncommon pathogens due the immunosuppressive drug therapy. Here, we report the first case of disseminated Mycobacterium genavense infection in a HIV seronegative renal transplant patient. The most striking clinical feature was a decreased consciousness. Blood results revealed hyperammonemia with otherwise normal liver function. Occurrence of hyperammonemia and massive M. genavense infection has not been reported before.