Peripheral Blood Epstein–Barr Viral Nucleic Acid Surveillance as a Marker for Posttransplant Cancer Risk

Several viruses, such as Epstein–Barr virus, are now known to be associated with several human cancers, but not all patients with these viral infections develop cancer. In transplantation, such viruses often have a prolonged time gap from infection to cancer development, and many are preceded by a period of circulating and detectable nucleic acids in the peripheral blood compartment. The interpretation of a viral load as a measure of posttransplant risk of developing cancer depends on the virus, the cancer and associated pathogenic factors. This review describes the current state of knowledge regarding the utility and limitations of peripheral blood nucleic acid testing for Epstein–Barr virus in surveillance and risk prediction for posttransplant lymphoproliferative disorders.     

PI3Kδ Inhibition Augments the Efficacy of Rapamycin in Suppressing Proliferation of Epstein−Barr Virus (EBV)+ B Cell Lymphomas

Posttransplant lymphoproliferative disorder (PTLD) continues to be a devastating and potentially life‐threatening complication in organ transplant recipients. PTLD is associated with EBV infection and can result in malignant B cell lymphomas. Here we demonstrate that the PI3K/Akt/mTOR pathway is highly activated in EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with the mTORC1 inhibitor Rapamycin (RAPA) partially inhibited the proliferation of EBV+ B cell lines. Resistance to RAPA treatment correlated with high levels of Akt phosphorylation. An mTORC1/2 inhibitor and a PI3K/mTOR dual inhibitor suppressed Akt phosphorylation and showed a greater anti‐proliferative effect on EBV+ B lymphoma lines compared to RAPA. EBV+ B cell lymphoma lines expressed high levels of PI3Kδ. We demonstrate that PI3Kδ is responsible for Akt activation in EBV+ B cell lymphomas, and that selective inhibition of PI3Kδ by either siRNA, or a small molecule inhibitor, augmented the anti‐proliferative effect of RAPA on EBV+ B cell lymphomas. These results suggest that PI3Kδ is a novel, potential therapeutic target for the treatment of EBV‐associated PTLD and that combined blockade of PI3Kδ and mTOR provides increased efficacy in inhibiting proliferation of EBV+ B cell lymphomas.     

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV‐associated posttransplant lymphoproliferative disorder and worse survival

Epstein‐Barr virus (EBV)–associated posttransplant lymphoproliferative disorder (EBV‐PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single‐center retrospective study to evaluate the risks for PTLD in LTRs over a 7‐year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan‐Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)‐LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33‐8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10‐6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57‐76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan‐Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.     

The Role of Antiviral Prophylaxis for the Prevention of Epstein–Barr Virus–Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review

The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein–Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta‐analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV‐associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58–1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high‐risk EBV‐naive patients has no effect on the incidence of PTLD in SOT recipients.     

The Impact of EBV Status on Characteristics and Outcomes of Posttransplantation Lymphoproliferative Disorder

We examined the associations of Epstein–Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 (58 [33%] EBV‐negative; 118 [67%] EBV‐positive). The proportion of EBV‐negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (p < 0.001). EBV‐negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high‐risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV‐positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV‐negative versus EBV‐positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV‐negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV‐negative PTLD.     

Impact of selective CD28 blockade on virus‐specific immunity to a murine Epstein‐Barr virus homolog

CTLA‐4Ig (belatacept) blocks the CD80/CD86 ligands for both CD28 and CTLA‐4; thus, in addition to the intended effect of blocking CD28‐mediated costimulation, belatacept also has the unintended effect of blocking CTLA‐4–mediated coinhibition. Recently, anti‐CD28 domain antibodies (dAb) that selectively target CD28 while leaving CTLA‐4 intact were shown to more effectively inhibit alloimmune responses and prolong graft survival. However, the impact of selective CD28 blockade on protective immunity has not been extensively investigated. Here, we sought to compare the impact of CTLA‐4Ig vs anti‐CD28dAb on CD8⁺ T cell immunity to a transplant‐relevant pathogen, a murine homolog of Epstein‐Barr virus. Mice were infected with murine gammaherpesvirus‐68 (MHV) and treated with vehicle, CTLA‐4Ig, or anti‐CD28dAb. Although anti‐CD28dAb resulted in a decrease in virus‐specific CD8⁺ T cell numbers as compared to CTLA‐4Ig, cytolytic function and the expression of markers of high‐quality effectors were not different from CTLA‐4Ig treated animals. Importantly, MHV‐68 viral load was not different between the treatment groups. These results suggest that preserved CTLA‐4 coinhibition limits MHV‐specific CD8⁺ T cell accumulation, but the population that remains retains cytolytic function and migratory capacity and is not inferior in its ability to control viral burden relative to T cell responses in CTLA‐4Ig‐treated animals.     

DNA methylation modulates allograft survival and acute rejection after renal transplantation by regulating the mTOR pathway

Acute rejection (AR) can lead to allograft dysfunction following renal transplantation, despite immunosuppressive treatments. Accumulating evidence points out a role for epigenetic modification in immune responses. However, the mechanism and contribution of DNA methylation in allograft survival remain unclear. In this study, we followed up patients who successively experienced end-stage renal disease, renal transplantation with allograft function or dysfunction, and hemodialysis. Peripheral blood mononuclear cells were collected at different time points for analysis of the DNA methylation. Epigenetic modifier analysis was also performed to explore its effect of methylation in a mouse model of AR. Compared with the allograft-stable cohort, patients who experienced AR-induced allograft dysfunction demonstrated more changes in methylation patterns. Pathway analysis revealed that the hypermethylated areas in the allograft dysfunction group were associated with genes related to the mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, in the mouse AR model, treatment with the DNA methyltransferase inhibitor—decitabine regulated the Th1/2/17/regulatory T cell (Treg cell) immune response via its demethylating role in the suppressing the activity of the mTOR pathway, which ultimately ameliorated renal allograft-related inflammatory injuries. These results revealed that changes in methylation accompany AR-induced allograft dysfunction after renal transplantation. Epigenetics may provide new insights into predicting and improving allograft survival.     

Comparing everolimus‐based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from 6 months after heart transplantation: The randomized MANDELA study

In the 12‐month, open‐label MANDELA study, patients were randomized at month 6 after heart transplantation to (1) convert to calcineurin inhibitor (CNI)‐free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI‐free, n = 71), or to (2) continue reduced‐exposure CNI, with EVR and steroids (EVR/redCNI, n = 74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI‐free patients at randomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 posttransplant postrandomization) with superiority of the CNI‐free group vs EVR/redCNI: mean 64.1 mL/min/1.73 m² vs 52.9 mL/min/1.73 m²; difference + 11.3 mL/min/1.73 m² (P < .001). By month 18, estimated GFR had increased by ≥ 10 mL/min/1.73 m² in 31.8% and 55.2% of EVR/redCNI and CNI‐free patients, respectively, and by ≥ 25 mL/min/1.73 m² in 4.5% and 20.9%. Rates of biopsy‐proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI vs the CNI‐free regimen (P = .015); 6 of 15 episodes in CNI‐free patients occurred with EVR concentration < 5 ng/mL. Rates of adverse events and associated discontinuations were comparable. EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One‐year renal function can be improved by early conversion to EVR‐based CNI‐free therapy but requires close EVR monitoring. Clinical trials registry: ClinicalTrials.gov NCT00862979.     

Distinct immunopathological mechanisms of EBV-positive and EBV-negative posttransplant lymphoproliferative disorders

EBV-positive and EBV-negative posttransplant lymphoproliferative disorders (PTLDs) arise in different immunovirological contexts and might have distinct pathophysiologies. To examine this hypothesis, we conducted a multicentric prospective study with 56 EBV-positive and 39 EBV-negative PTLD patients of the K-VIROGREF cohort, recruited at PTLD diagnosis and before treatment (2013–2019), and compared them to PTLD-free Transplant Controls (TC, n = 21). We measured absolute lymphocyte counts (n = 108), analyzed NK- and T cell phenotypes (n = 49 and 94), and performed EBV-specific functional assays (n = 16 and 42) by multiparameter flow cytometry and ELISpot-IFNγ assays (n = 50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival (PFS) was poorer in patients with a CD4 lymphopenia (CD4⁺<300 cells/mm³, p <  .001). EBV-positive PTLD patients presented a profound NK-cell lymphopenia (median = 60 cells/mm³) and a high proportion of NK cells expressing PD-1 (vs. TC, p = .029) and apoptosis markers (vs. TC, p < .001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune exhaustion (p = .013 vs. TC) and poorly recognized the N-terminal portion of EBNA-3A viral protein. Altogether, this broad comparison of EBV-positive and EBV-negative PTLDs highlight distinct patterns of immunopathological mechanisms between these two diseases and provide new clues for immunotherapeutic strategies and PTLD prognosis.     

Inhibition of the mTOR pathway: A new mechanism of β cell toxicity induced by tacrolimus

The mechanisms of tacrolimus‐induced β cell toxicity are unknown. Tacrolimus (TAC) and rapamycin (Rapa) both bind to FK506‐binding protein 12 (FKBP12). Also, both molecular structures are similar. Because of this similarity, we hypothesized that TAC can also inhibit the mTOR signalling, constituting a possible mechanism of β cell toxicity. Thus, we studied the effect of TAC and Rapa over the mTOR pathway, v‐maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and insulin secretion and content in INS‐1 β cells treated with or without glucose and palmitate and in islets from lean or obese rats. TAC and Rapa inhibited the mTOR pathway as reflected by lower levels of phospho‐mTOR, phospo‐p70S6K, and phospo‐S6. The effect of Rapa was larger than TAC. Both drugs reduced the levels of MafA, insulin secretion, and content although these effects were larger with TAC. The changes on MafA and insulin metabolism were observed in cells on glucose and palmitate, in obese animals, and were absent in cells on maintenance medium or in lean animals. In silico docking and immunoprecipitation experiments confirmed that TAC can form a stable noncovalent interaction with FKBP12‐mTOR. Thus, the mTOR inhibition may be a mechanism contributing to the diabetogenic effect of TAC.     

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV− PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199–1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751–6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077–0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.     

Outside‐in HLA class I signaling regulates ICAM‐1 clustering and endothelial cell‐monocyte interactions via mTOR in transplant antibody‐mediated rejection

Antibody‐mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long‐term survival of solid organ transplants. AMR is caused by donor‐specific antibodies to HLA, which contribute to TAV by initiating outside‐in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab–mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab–activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM‐1) clustering, and monocyte firm adhesion to HLA I Ab–activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1^?/? recipients of BALB/c cardiac allografts were passively transferred with donor‐specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM‐1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell‐monocyte interactions during AMR.     

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital‐based registry, we identified biopsy‐proven cases of PTLD among children during a 15‐year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow‐up after the diagnosis of PTLD. We studied 82 patients with first‐episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2‐12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan‐Meier survival curves showed that T/A PTLD was associated with decreased all‐cause mortality compared with PTLD at other sites (log‐rank 0.004), even after adjustment for histological subtype (P = .047). PTLD‐related mortality was also decreased among T/A PTLD (log‐rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.     

Evolving Perspectives of mTOR Complexes in Immunity and Transplantation

Since the discovery of Rapamycin (RAPA) and its immunosuppressive properties, enormous progress has been made in characterizing the mechanistic target of rapamycin (mTOR). Use of RAPA and its analogues (rapalogs) as anti‐rejection agents has been accompanied by extensive investigation of how targeting of mTOR complex 1 (mTORC1), the principal target of RAPA, and more recently mTORC2, affects the function of immune cells, as well as vascular endothelial cells, that play crucial roles in regulation of allograft rejection. While considerable knowledge has accumulated on the function of mTORC1 and 2 in T cells, understanding of the differential roles of these complexes in antigen‐presenting cells, NK cells and B cells/plasma cells is only beginning to emerge. Immune cell‐specific targeting of mTORC1 or mTORC2, together with use of novel, second generation, dual mTORC kinase inhibitors (TORKinibs) have started to play an important role in elucidating the roles of these complexes and their potential for targeting in transplantation. Much remains unknown about the role of mTOR complexes and the consequences of mTOR targeting on immune reactivity in clinical transplantation. Here we address recent advances in understanding and evolving perspectives of the role of mTOR complexes and mTOR targeting in immunity, with extrapolation to transplantation.     

Donor apoptotic cell–based therapy for effective inhibition of donor‐specific memory T and B cells to promote long‐term allograft survival in allosensitized recipients

Allosensitization constitutes a major barrier in transplantation. Preexisting donor‐reactive memory T and B cells and preformed donor‐specific antibodies (DSAs) have all been implicated in accelerated allograft rejection in sensitized recipients. Here, we employ a sensitized murine model of islet transplantation to test strategies that promote long‐term immunosuppression‐free allograft survival. We demonstrate that donor‐specific memory T and B cells can be effectively inhibited by peritransplant infusions of donor apoptotic cells in combination with anti‐CD40L and rapamycin, and this treatment leads to significant prolongation of islet allograft survival in allosensitized recipients. We further demonstrate that late graft rejection in recipients treated with this regimen is associated with a breakthrough of B cells and their aggressive graft infiltration. Consequently, additional posttransplant B cell depletion effectively prevents late rejection and promotes permanent acceptance of islet allografts. In contrast, persistent low levels of DSAs do not seem to impair graft outcome in these recipients. We propose that B cells contribute to late rejection as antigen‐presenting cells for intragraft memory T cell expansion but not to alloantibody production and that a therapeutic strategy combining donor apoptotic cells, anti‐CD40L, and rapamycin effectively inhibits proinflammatory B cells and promotes long‐term islet allograft survival in such recipients.     

Transplant Infectious Diseases: A Review of the Scientific Registry of Transplant Recipients Published Data

The Scientific Registry of Transplant Recipients (SRTR) serves to collect data on organ transplants performed in the United States. Although the infectious diseases data are limited and include mostly pretransplant serologies and other nonspecific infection‐related outcomes, this multicenter data collection allows for insightful national data and the ability to monitor trends over time. We reviewed the published concise reports for each organ type in SRTR reports containing data from 2005 to 2014, and summarized our findings with respect to cytomegalovirus (CMV), Epstein‐Barr virus, posttransplant lymphoproliferative disorder (PTLD), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, general infection, and prophylaxis. Our review highlights a few developments. While rates of donor–recipient CMV serology combinations remain fairly constant over time, there are generally more seronegative donors and recipients among living donor transplants. There has been a reduction in PTLD for pediatric transplant recipients. There has also been a slight reduction in anti‐HBV core antibody–positive donor organs and stable reporting of HCV‐positive donor organs and HIV‐positive recipients.     

Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejection‐specific microenvironment in renal allograft biopsies

The role of endothelial cells in the pathophysiology of antibody‐mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166 based on their potential signal‐transducing capacity to mediate back signaling after encounter with either T/NK cells or donor‐specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL‐6, CXCL1,8,10, CCL2, and sICAM‐1. These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection.     

Vendor‐specific microbiome controls both acute and chronic murine lung allograft rejection by altering CD4+Foxp3+ regulatory T cell levels

Despite standardized postoperative care, some lung transplant patients suffer multiple episodes of acute and chronic rejection while others avoid graft problems for reasons that are poorly understood. Using an established model of C57BL/10 to C57BL/6 minor antigen mismatched single lung transplantation, we now demonstrate that the recipient microbiota contributes to variability in the alloimmune response. Specifically, mice from the Envigo facility in Frederick, Maryland contain nearly double the number of CD4⁺Foxp3⁺ regulatory T cells (T_regs) than mice from the Jackson facility in Bar Harbor, Maine or the Envigo facility in Indianapolis, Indiana (18 vs 9 vs 7%). Lung graft recipients from the Maryland facility thus do not develop acute or chronic rejection. Treatment with broad‐spectrum antibiotics decreases T_regs and increases both acute and chronic graft rejection in otherwise tolerant strains of mice. Constitutive depletion of regulatory T cells, using Foxp3‐driven expression of diphtheria toxin receptor, leads to the development of chronic rejection and supports the role of T_regs in both acute and chronic alloimmunity. Taken together, our data demonstrate that the microbiota of certain individuals may contribute to tolerance through T_reg‐dependent mechanisms and challenges the practice of indiscriminate broad‐spectrum antibiotic use in the perioperative period.