Dynamic establishment and maintenance of the human intestinal B cell population and repertoire following transplantation in a pediatric-dominated cohort.

Introduction: It is unknown how intestinal B cell populations and B cell receptor (BCR) repertoires are established and maintained over time in humans. Following intestinal transplantation (ITx), surveillance ileal mucosal biopsies provide a unique opportunity to map the dynamic establishment of recipient gut lymphocyte populations in immunosuppressed conditions. Methods: Using polychromatic flow cytometry that includes HLA allele group-specific antibodies distinguishing donor from recipient cells along with high throughput BCR sequencing, we tracked the establishment of recipient B cell populations and BCR repertoire in the allograft mucosa of ITx recipients. Results: We confirm the early presence of naïve donor B cells in the circulation (donor age range: 1-14 years, median: 3 years) and, for the first time, document the establishment of recipient B cell populations, including B resident memory cells, in the intestinal allograft mucosa (recipient age range at the time of transplant: 1-44 years, median: 3 years). Recipient B cell repopulation of the allograft was most rapid in infant (<1 year old)-derived allografts and, unlike T cell repopulation, did not correlate with rejection rates. While recipient memory B cell populations were increased in graft mucosa compared to circulation, naïve recipient B cells remained detectable in the graft mucosa for years. Comparisons of peripheral and intra-mucosal B cell repertoires in the absence of rejection (recipient age range at the time of transplant: 1-9 years, median: 2 years) revealed increased BCR mutation rates and clonal expansion in graft mucosa compared to circulating B cells, but these parameters did not increase markedly after the first year post-transplant. Furthermore, clonal mixing between the allograft mucosa and the circulation was significantly greater in ITx recipients, even years after transplantation, than in deceased adult donors. In available pan-scope biopsies from pediatric recipients, we observed higher percentages of naïve recipient B cells in colon allograft compared to small bowel allograft and increased BCR overlap between native colon vs colon allograft compared to that between native colon vs ileum allograft in most cases, suggesting differential clonal distribution in large intestine vs small intestine. Discussion: Collectively, our data demonstrate intestinal mucosal B cell repertoire establishment from a circulating pool, a process that continues for years without evidence of stabilization of the mucosal B cell repertoire in pediatric ITx patients.

Innate and Adaptive Immune Responses in Intestinal Transplant Rejection: Through the Lens of Inflammatory Bowel and Intestinal Graft-Versus-Host Diseases.

Intestinal transplantation is a life-saving procedure utilized for patients failing total parenteral nutrition. However, intestinal transplantattion remains plagued with low survival rates and high risk of allograft rejection. The authors explore roles of innate (macrophages, natural killer cells, innate lymphoid cells) and adaptive immune cells (Th1, Th2, Th17, Tregs) in inflammatory responses, particularly inflammatory bowel disease and graft versus host disease, and correlate these findings to intestinal allograft rejection, highlighting which effectors exacerbate or suppress intestinal rejection. Better understanding of this immunology can open further investigation into potential biomolecular targets to develop improved therapeutic treatment options and immunomonitoring techniques to combat allograft rejection and enhance patient lives.

B-Cell Induction Therapies in Intestinal Transplantation.

Despite advancements in short-term outcomes since the inception of intestinal transplant, significant long-term graft failure persists. Early successes are attributed to the utilization of tacrolimus for maintenance therapy, coupled with T-cell modulating induction regimens, which effectively reduce the incidence of acute cellular rejection. However, the challenge of chronic allograft injury remains unresolved. There is increasing evidence indicating a correlation between donor-specific antibodies and the survival of visceral allografts. Strategies aimed at reducing the presence or load of these antibodies may potentially enhance long-term outcomes. Consequently, our focus is now turning toward B-cell induction therapies as a possible solution.

Living Donor Intestinal Transplantation.

This study explores intestinal transplantation (ITx) as a viable treatment option for intestinal failure (IF). Historical development, donor and recipient considerations, surgical techniques, immunosuppression, and outcomes, are reviewed with particular emphasis to the value of living donor ITx. The review highlights the evolution of ITx and emphasizes the ongoing need for patient-specific selection processes. In the realm of pediatric ITx, the article underlines the significance of early intervention to mitigate IF-related liver disease. Overall, it provides a comprehensive overview of this life-saving procedure.

Intestinal Re-Transplantation.

The history of intestinal transplantation can be traced back to the turn of the twentieth century. Although advancements have been made, the intestine still presents a greater challenge to transplantation than does that of other solid organs, experiencing higher rates of graft rejection and lower long-term survival. Increasingly, intestinal re-transplantation (re-ITx) is seen as a viable option and is now the fourth most common indication for ITx. Changes to immunosuppression protocols, technical modifications, and infectious disease monitoring have contributed to improved outcomes. The authors review the literature on re-ITx in regard to the history, management considerations, and future directions.

Intestinal Transplantation in the Developing World.

Intestinal failure (IF) remains as a life-threatening medical condition worldwide, but the disparity on the type and quality of medical care available, together with the different limitations to access among individual countries or regions, turned IF assessment and therapy into a difficult matter, which becomes a major hazard for the developing world. This article aims to provide an update regarding definitions used, the current general worldwide data, the developments, achievements, and the different access alternatives in Latin-America, Middle East, and Asia to exemplify what can be done to help patients with IF.

Update on Maintenance Immunosuppression in Intestinal Transplantation.

Outcomes in intestinal transplantation remain hampered by higher rates of rejection than any other solid organs. However, maintenance immunosuppression regimens have largely remained unchanged despite advances in therapies for induction and treatment of rejection and graft-versus-host disease. Recently, there have been a small number of new maintenance therapies attempted, and older agents have been used in new ways to achieve better outcomes. The authors herein review the traditional maintenance therapies and their mechanisms and then consider updates in new therapies and new ways of using old therapies for maintenance immunosuppression after intestinal transplantation.

Impact of Recipient and Donor Body Mass Index on Survival Outcomes After Intestinal Transplantation: A United Network for Organ Sharing Database Analysis.

BACKGROUND Long-term patient survival after intestinal transplantation (IT) remains low compared with other organ transplants despite years of advancement in clinical experience. While patients with extremely high or low body mass index (BMI) are often considered ineligible for IT, the impact of BMI on post-transplant IT survival remains understudied. MATERIAL AND METHODS Using the United Network for Organ Sharing Standard Transplant database, we conducted a retrospective cohort study on patients who underwent IT between April 11, 1994, and September 29, 2021. We assessed the association of recipient and donor BMI at transplant with post-transplant mortality using Kaplan-Meier survival curves and univariate and multivariate Cox regression analyses. RESULTS A total of 1541 patients were included in our final sample. Of these patients, 806 were females (52.5%) and most were in the normal-weight BMI subgroup (54.2%). Obese class II (mean; 36.8±10.92 years) and underweight patients (mean; 37.6±13.37 years) were significantly younger than patients in other BMI categories. The adjusted multivariate model demonstrated an increased risk of mortality in underweight IT recipients compared to normal-weight IT recipients (aHR=1.25, 95% confidence interval [CI], 1.02-1.54; P=0.032).There was no significant association between donor BMI categories and survival in IT recipients. CONCLUSIONS Recipient BMI below normal is associated with an increased risk of mortality after intestinal transplantation and represents a potentially modifiable patient characteristic to improve survival outcomes.

Bioengineering of Intestinal Grafts.

Intestinal failure manifests as an impaired capacity of the intestine to sufficiently absorb vital nutrients and electrolytes essential for growth and well-being in pediatric and adult populations. Although parenteral nutrition remains the mainstay therapeutic approach, the pursuit of a definitive and curative strategy, such as regenerative medicine, is imperative. Substantial advancements in the field of engineered intestinal tissues present a promising avenue for addressing intestinal failure; nevertheless, extensive research is still necessary for effective translation from experimental benchwork to clinical bedside applications.

Chimerism-Mediated Tolerance in Intestinal Transplantation.

In this review, the authors outlined concepts and strategies to achieve immune tolerance through inducing hematopoietic chimerism after solid organ transplantation and introduced challenges and opportunities in harnessing two-way alloresponses to improve outcomes after intestinal transplantation (ITx). Next, the authors discussed the dynamics and phenotypes of peripheral blood and intestinal graft T-cell subset chimerism and their association with outcomes. The authors also summarized studies on other types of immune cells after ITx and their potential participation in chimerism-mediated tolerance. The authors further discussed strategies and future directions to promote chimerism-associated tolerance after ITx to overcome rejection and minimize immunosuppression.

Evaluation of pediatric patients for intestinal transplantation in the modern era.

OBJECTIVES: To review recent evaluations of pediatric patients with intestinal failure (IF) for intestinal transplantation (ITx), waiting list decisions, and outcomes of patients listed and not listed for ITx at our center. METHODS: Retrospective chart review of 97 patients evaluated for ITx from January 2014 to December 2021 including data from referring institutions and protocol laboratory testing, body imaging, endoscopy, and liver biopsy in selected cases. Survival analysis used Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Patients were referred almost entirely from outside institutions, one-third because of intestinal failure-associated liver disease (IFALD), two-thirds because of repeated infective and non-IFALD complications under minimally successful intestinal rehabilitation, and a single patient because of lost central vein access. The majority had short bowel syndrome (SBS). Waiting list placement was offered to 67 (69%) patients, 40 of whom for IFALD. The IFALD group was generally younger and more likely to have SBS, have received more parenteral nutrition, have demonstrated more evidence of chronic inflammation and have inferior kidney function compared to those offered ITx for non-IFALD complications and those not listed. ITx was performed in 53 patients. Superior postevaluation survival was independently associated with higher serum creatinine (hazard ratio [HR] 15.410, p = 014), whereas inferior postevaluation survival was associated with ITx (HR 0.515, p = 0.035) and higher serum fibrinogen (HR 0.994, p = 0.005). CONCLUSIONS: Despite recent improvements in IF management, IFALD remains a prominent reason for ITx referral. Complications of IF inherent to ITx candidacy influence postevaluation and post-ITx survival.

Indications and successes of intestinal transplantation in children in the 21st century: A retrospective cohort study.

AIMS: To report the results and successes of intestinal transplantation (ITx) in the most active European centres, to emphasize that, although it is a difficult procedure, it should remain a therapeutic option for children with total, definitive and complicated intestinal failure when intestinal rehabilitation fails. METHODS: We retrospectively collected data about all patients less than 18 receiving an ITx from 2010 to 2022 in 8 centres, and outcomes in July 2022. RESULTS: ITx was performed in 155 patients, median age 6.9 years, in 45% for short bowel syndromes, 22% congenital enteropathies, 25% motility disorders, and 15% re-transplantations. Indications were multiple in most patients, intestinal failure-associated liver disease in half. The graft was in 70% liver-containing. At last follow up 64% were alive, weaned from parenteral nutrition, for 7.9 years; 27% had died and the graft was removed in 8%, mostly early after ITx. DISCUSSION: ITx, despite its difficulties, can give a future to children with complicated intestinal failure. It should be considered among the therapeutic options offered to patients with a predicted survival rate lower than that after ITx. Patients should be early discussed within multidisciplinary teams in ITx centres, to avoid severe complications impacting the results of ITx, or even to avoid ITx.

The Role of Colon in Isolated Intestinal Transplantation: Description of 4 Cases.

Intra-abdominal desmoid tumors are a rare and complex clinical problem. These tumors are locally invasive, and surgical ablation represents the mainstay of treatment. When localized at the root of the mesentery, their resection may require extensive excision of the intestine resulting in intestinal failure and life-long total parenteral nutrition. Intestinal transplantation, either autotransplantation or allotransplantation, has been used as a viable option to treat this group of patients. Herein, we describe a series of 4 patients with unresectable intra-abdominal desmoid tumor who underwent cadaveric isolated intestinal and ascending colon transplantation.

Immune cell profiling in intestinal transplantation.

Since the first published case study of human intestinal transplantation in 1967, there have been significant studies of intestinal transplant immunology in both animal models and humans. An improved understanding of the profiles of different immune cell subsets is critical for understanding their contributions to graft outcomes. While different studies have focused on the contribution of one or a few subsets to intestinal transplant, no study has integrated these data for a comprehensive overview of immune dynamics after intestinal transplant. Here, we provide a systematic review of the literature on different immune subsets and discuss their roles in intestinal transplant outcomes on multiple levels, focusing on chimerism and graft immune reconstitution, clonal alloreactivity, and cell phenotype. In Sections 1, 2 and 3, we lay out a shared framework for understanding intestinal transplant, focusing on the mechanisms of rejection or tolerance in the context of mucosal immunology and illustrate the unique role of the bidirectional graft-versus-host (GvH) and host-versus-graft (HvG) alloresponse. In Sections 4, 5 and 6, we further expand upon these concepts as we discuss the contribution of different cell subsets to intestinal transplant. An improved understanding of intestinal transplantation immunology will bring us closer to maximizing the potential of this important treatment.

Biologicals in the prevention and treatment of intestinal graft rejection: The state of the art Biologicals in Intestinal Transplantation.

Intestinal transplantation is the standard treatment for patients with intestinal failure with severe complications due to parenteral nutrition; however, rejection leads to graft failure in approximately half of both adult and pediatric recipients within 5 years of transplantation. Although intensive immunosuppressive therapy is used in an attempt to reduce this risk, commonly used treatment strategies are generally practice- and/or expert-based, as head-to-head comparisons are lacking. In this ever-developing field, biologicals designed to prevent or treat rejection are used increasingly, with both infliximab and vedolizumab showing potential in the treatment of acute cellular rejection in individual cases and in relatively small patient cohorts. To help advance progress in clinical care, we review the current use of biologicals in intestinal transplantation, and we provide future perspectives to guide this progress.

New insights in immunomodulation for intestinal transplantation.

Tolerance is the Holy Grail of solid organ transplantation (SOT) and remains its primary challenge since its inception. In this topic, the seminal contributions of Thomas Starzl at Pittsburgh University outlined foundational principles of graft acceptance and tolerance, with chimerism emerging as a pivotal factor. Immunologically, intestinal transplantation (ITx) poses a unique hurdle due to the inherent characteristics and functions of the small bowel, resulting in increased immunogenicity. This necessitates heavy immunosuppression (IS) while IS drugs side effects cause significant morbidity. In addition, current IS therapies fall short of inducing clinical tolerance and their discontinuation has been proven unattainable in most cases. This underscores the unfulfilled need for immunological modulation to safely reduce IS-related burdens. To address this challenge, the Leuven Immunomodulatory Protocol (LIP), introduced in 2000, incorporates various pro-tolerogenic interventions in both the donor to the recipient, with the aim of facilitating graft acceptance and improving outcome. This review seeks to provide an overview of the current understanding of tolerance in ITx and outline recent advances in this domain.

Indications for Intestinal Transplantation.

Outcomes for patients with chronic intestinal failure have improved with organization of experts into multidisciplinary teams delivering care in intestinal rehabilitation programs. There have been improvements in understanding of intestinal failure complications as well as development of newer therapies that have amplified the improvements in survival. In spite of this encouraging trend, patients who fail PN are often referred too late for intestinal transplantation. The author proposes a more rational framework that might allow earlier identification of intestinal failure patients at risk for PN-failure, who could appropriately be considered earlier for intestinal transplantation with improvements in overall outcomes.