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Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies.

ABSTRACT: The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMVneg patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMVneg patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137+IFN?+CD4+ and CD137+IFN?+CD8+ memory T cells were present in 46 and 39% of CMVneg patients (n?=?28) although at much lower frequencies compared to CMVpos patients (median 0.01 versus 0.58% for CD4+ and 0.05 versus 0.64% for CD8+ T cells) with a less differentiated CD28-expressing phenotype. In line with these data, CMV-specific proliferative CD4+ and CD8+ T cells were observed in CMVneg patients, which significantly correlated with the frequency of CMV-specific T cells. CMV-specific IgG antibody-secreting cells (ASC) could be detected at low frequency in 36% of CMVneg patients (1 versus 45 ASC/105 cells in CMVpos patients). CMVneg patients with pretransplant CMV-specific CD137+IFN?+CD4+ T cells had a lower risk to develop CMV viremia after transplantation with a CMVpos donor kidney (relative risk: 0.43, P?=?0.03). In conclusion, a solitary CMV-specific T-cell response without detectable anti-CMV antibodies is frequent and clinically relevant as it is associated with protection to CMV infection following transplantation with a kidney from a CMVpos donor.

SUBMITTER: Litjens NHR

PROVIDER: S-EPMC5600906 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies.

Litjens Nicolle H R NHR Huang Ling L Dedeoglu Burç B Meijers Ruud W J RWJ Kwekkeboom Jaap J Betjes Michiel G H MGH

Frontiers in immunology 20170912

The absence of anti-cytomegalovirus (CMV) immunoglobulin G (IgG) is used to classify pretransplant patients as naïve for CMV infection (CMVneg patients). This study assessed whether pretransplant CMV-specific T-cell immunity exists in CMVneg patients and whether it protects against CMV infection after kidney transplantation. The results show that CMV-specific CD137+IFNγ+CD4+ and CD137+IFNγ+CD8+ memory T cells ...[more]

PMID: 28955345

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Project description:IntroductionOpportunistic viral infections cause extensive morbidity and mortality in kidney transplant recipients (KTRs). Low serum albumin levels before and after transplant have been associated with negative outcomes. However, it is uncertain whether serum albumin levels before transplantation are associated with the risk for post-transplantation opportunistic BK polyomavirus (BKV) or cytomegalovirus (CMV).MethodsWe reviewed all KTRs transplanted at our institution between 1 January 2005 and 31 December 2015 with serum albumin measured within 45 days before transplantation in a retrospective observational cohort study. Selected patients were stratified into 3 groups: normal albuminemia (≥3.5 g/dl), moderate hypoalbuminemia (3.49-2.5 g/dl), and severe hypoalbuminemia (<2.5 g/dl). Patients were observed for post-transplantation BKV or CMV according to standard of care.ResultsWe included 1717 patients in this study; 72.3% had normal serum albumin, 26.3% had moderate hypoalbuminemia, and 1.5% had severe hypoalbuminemia. Moderate and severe hypoalbuminemia incurred a higher risk for BKV compared with normal serum albumin levels in univariable analysis (moderate hypoalbuminemia: hazard ratio [HR] = 1.5; 95% confidence interval [CI], 1.14-1.90; P = .003); severe hypoalbuminemia: HR = 2.15; 95% CI, 1.01-4.56; P = 0.05). Although not significant after multivariable adjustment, there was still 18% increased risk in moderate hypoalbuminemia and 64% in severe hypoalbuminemia for BKV compared with the normal albumin group. Moderate hypoalbuminemia was associated with a higher risk for CMV infection than normal serum albumin levels in multivariable analysis, although it was not statistically significant (HR = 1.15; 95% CI, 0.36-3.64; P = 0.81).ConclusionsThese findings suggest that pretransplantation hypoalbuminemia is associated with a higher risk for post-transplantation BKV and possibly CMV. More intense screening is warranted for these viruses in recipients with pretransplant hypoalbuminemia.

Project description:BackgroundCytomegalovirus (CMV) is one of the most important opportunistic infections in transplant recipients. Currently sero-positivity for CMV IgG before solid organ transplantation is the laboratory test of choice for stratifying the risk of CMV reactivation after solid organ transplantation. Theoretically, CMV-specific cell-mediated immune responses before solid organ transplantation should further categorize patients as high or low risk of CMV development. We therefore evaluated the usefulness of the CMV-specific enzyme-linked immunospot (ELISPOT) assay in kidney transplant (KT) candidates for predicting the development of CMV infections after transplantation.Materials and methodsAll adult CMV IgG (+) recipients admitted to the KT institute between March 2014 and June 2014 were enrolled, and CMV infections after KT were observed between March 2014 and December 2014. All patients underwent CMV pp65 and IE1-specific ELISPOT assays before transplantation. CMV infection was defined in the presence of CMV antigenemia, CMV syndrome, or tissue-invasive CMV disease. We used the data to select optimal cut-off values for pp65 and IE1, respectively, on ROC curves.ResultsA total of 69 transplant recipients involving 54 (78%) living-donor KT, 9 (13%) deceased-donor KT, 3 (4%) kidney-pancreas transplants, and 3 (4%) pancreas transplants were enrolled. Of the 69 patients, 27 (39%) developed CMV infections. There was no association between the IE1-specific ELISPOT assay and CMV infection. However, only 15 (31%) of the 48 patients with positive pp65-specific ELISPOT results (>10 spots/2.0 × 105 cells) developed CMV infections, whereas 12 (57%) of the 21 patients with negative pp65-specific ELISPOT results developed CMV infection (P = 0.04).ConclusionNegative pp65-specific ELISPOT assay results before transplantation appear to predict the subsequent development of CMV infections after transplantation in CMV IgG (+) KT recipients. Therefore, risk stratification of CMV IgG (+) recipients using the CMV-specific ELISPOT, together with preventive strategies, may further reduce CMV development.

Project description:BackgroundHuman cytomegalovirus infection is associated with a variety of pathological conditions including retinitis, pneumonia, hepatitis and encephalitis that may be transmitted congenitally, horizontally and parenterally and occurs both as a primary infection and as reactivation in immunocompromised individuals. Currently, there is a need for improved quantitative serological tests to document seropositivity with high sensitivity and specificity.MethodsHere we investigated whether luciferase immunoprecipitation systems (LIPS) would provide a more quantitative and sensitive method for detecting anti-CMV antibodies. Four protein fragments of immunodominant regions of CMV antigens pp150 and pp65 were generated as Renilla luciferase (Ruc) fusion proteins and used in LIPS with two cohorts of CMV positive and negative sera samples previously tested by ELISA.ResultsAnalysis of the antibody responses to two of these antigen fragments, pp150-d1 and pp150-d2, revealed geometric mean antibody titers in the first cohort that were 100-1000 fold higher in the CMV positive sera compared to the CMV negative samples (p < 0.0001) and infection status exactly matched the ELISA results for the 46 samples of the first cohort (100% sensitivity and 100% specificity). Two additional antigen fragments, pp65-d1 and pp65-d2 also showed robust antibody titers in some CMV-infected sera and yielded 50% and 96% sensitivity, respectively. Analysis of a second cohort of 70 samples using a mixture of the 4 antigens, which simplifies data collection and analysis, yielded values which correlated well with the sum of the values from the 4 separate tests (rs = 0.93, p < 0.00001). While comparison of the LIPS results from this second cohort with ELISA showed 100% sensitivity, LIPS detected six additional CMV positive samples that were not detected by ELISA. Heat map analysis revealed that several of the LIPS positive/ELISA negative samples had positive LIPS immunoreactivity with 3-4 of the CMV antigens.ConclusionThese results suggest that LIPS provides a highly robust and quantitative method for studying anti-CMV antibodies and has the potential to more accurately document CMV infection than standard ELISA.

Dataset Information

Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies.

Publications

Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies.

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