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Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

ABSTRACT: Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-? in vitro, and this reduced IFN-? production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections.

SUBMITTER: Mysore KR

PROVIDER: S-EPMC5790618 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

Mysore Krupa R KR Ghobrial Rafik M RM Kannanganat Sunil S Minze Laurie J LJ Graviss Edward A EA Nguyen Duc T DT Perez Katherine K KK Li Xian C XC

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20171120 2

Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhib ...[more]

PMID: 29068155

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Project description:Clostridioides difficile infection (CDI) has a higher incidence in solid organ transplant recipients than other hospitalized patients and can lead to poor outcomes. Perturbations to the intestinal microbiome are common in patients undergoing liver transplant (LT); however, the impacts of microbial diversity and composition on risk of CDI in this patient population is incompletely understood. Here, we assessed patients in an established, longitudinal LT cohort for development of CDI within 1 year of transplant. Clinical data were compared for patients with and without CDI using univariable models. 16S rRNA sequencing of fecal samples was performed at multiple pre- and posttransplant time points to compare microbiome α- and β-diversity and enrichment of specific taxa in patients with and without CDI. Of 197 patients who underwent LT, 18 (9.1%) developed CDI within 1 year. Pre-LT Child-Pugh class C liver disease, postoperative biliary leak, and use of broad-spectrum antibiotics were significantly associated with CDI. Patients who developed CDI had significantly lower α-diversity than patients without CDI overall and in samples collected at months 1, 3, and 6. Microbial composition (β-diversity) differed between patients with and without CDI and across sampling time points, particularly later in their posttransplant course. We also identified 15 (8%) patients with toxigenic C. difficile colonization who did not develop CDI and may have had additional protective factors. In summary, clinical and microbiome factors are likely to converge to impart CDI risk. Along with enhanced preventive measures, there may be a role for microbiome modulation to restore microbial diversity in high-risk LT patients. IMPORTANCE Liver transplant (LT) recipients have high rates of Clostridioides difficile infection (CDI), which has been associated with poor outcomes, including graft-related complications and mortality, in prior studies. Susceptibility to CDI is known to increase following perturbations in intestinal commensal bacteria that enable germination of C. difficile spores and bacterial overgrowth. In LT patients, changes in the intestinal microbiome resulting from advanced liver disease, surgery, and other clinical factors is common and most pronounced during the early posttransplant period. However, the relationship between microbiome changes and CDI risk after LT remains unclear. In this study, we investigated clinical and microbiome factors associated with development of CDI within the first year after LT. The importance of this work is to identify patients with high-risk features that should receive enhanced preventive measures and may benefit from the study of novel strategies to reconstitute the intestinal microbiome after LT.

Project description:UnlabelledAlthough some studies have examined the epidemiology of bloodstream infections after liver transplantation, they were based in single centers and did not identify bloodstream infections treated in other hospitals.MethodsWe retrospectively examined a cohort of 7912 adult liver transplant recipients from 24 transplant centers using 2004 to 2012 International Classification of Diseases, Ninth Revision, Clinical Modification billing data from 3 State Inpatient Databases, and identified bloodstream infections, inpatient death, and cumulative 1-year hospital costs. Multilevel Cox regression analyses were used to determine factors associated with bloodstream infections and death.ResultsBloodstream infections were identified in 29% (n = 2326) of liver transplant recipients, with a range of 19% to 40% across transplant centers. Only 63% of bloodstream infections occurring more than 100 days posttransplant were identified at the original transplant center. Bloodstream infections were associated with posttransplant laparotomy (adjusted hazard ratio [aHR], 1.52), prior liver transplant (aHR, 1.42), increasing age (aHR, 1.07/decade), and some comorbidities. Death was associated with bloodstream infections with and without septic shock (aHR, 10.96 and 3.71, respectively), transplant failure or rejection (aHR, 1.41), posttransplant laparotomy (aHR, 1.40), prior solid-organ transplant (aHR, 1.48), increasing age (aHR, 1.15/decade), and hepatitis C cirrhosis (aHR, 1.20). The risk of bloodstream infections and death varied across transplant centers. Median 1-year cumulative hospital costs were higher for patients who developed bloodstream infections within 1 year of transplant compared with patients who were bloodstream infection-free (US $229 806 vs US $111 313; P < 0.001).ConclusionsBloodstream infections are common and costly complications after liver transplantation that are associated with a markedly increased risk of death. The incidence and risk of developing bloodstream infections may vary across transplant centers.

Dataset Information

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

Publications

Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

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