Sophoclis Alexopoulos

Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice

T cell Ig mucin (Tim) molecules modulate CD4(+) T cell responses. In keeping with the view that Tim-1 generates a stimulatory signal for CD4(+) T cell activation, we hypothesized that an agonist Tim-1-specific mAb would intensify the CD4(+) T cell-dependant allograft response. Unexpectedly, we determined that a particular Tim-1-specific mAb exerted reciprocal effects upon the commitment of alloactivated T cells to regulatory and effector phenotypes. Commitment to the Th1 and Th17 phenotypes was fostered, whereas commitment to the Treg phenotype was hindered. Moreover, ligation of Tim-1 in vitro effectively deprogrammed Tregs and thus produced Tregs unable to control T cell responses. Overall, the effects of the agonist Tim-1-specific mAb on the allograft response stemmed from enhanced expansion and survival of T effector cells; a capacity to deprogram natural Tregs; and inhibition of the conversion of naive CD4(+) T cells into Tregs. The reciprocal effects of agonist Tim-1-specific mAbs upon effector T cells and Tregs serve to prevent allogeneic transplant tolerance.

Roles of Deletion and Regulation in Creating Mixed Chimerism and Allograft Tolerance Using a Nonlymphoablative Irradiation-Free Protocol

The induction of mixed chimerism (MC) is a powerful and effective means to achieve transplantation tolerance in rodent models. Host conditioning with irradiation or cytotoxic drugs has been used in many protocols for chimeric induction across allogeneic barriers. The deletion of alloreactive T cell clones has been described as the main mechanism responsible for the induction of a stable MC. In this study, we demonstrate that a stable MC and skin allograft tolerance can be established across MHC barriers by a noncytotoxic, irradiation-free approach using costimulation blockade plus rapamycin treatment. By using an adoptive transfer model of skin allograft and using specific Vβ TCR probes, we demonstrated that deletion of donor-reactive cytopathic T cell clones is indeed profound in tolerant hosts. Nonetheless, the challenge of tolerant mixed chimeras with 5 million mononuclear leukocytes (MNL) from naive syngeneic mice was neither able to abolish the stable MC nor to trigger skin allograft rejection, a hallmark of peripheral, not central tolerance. Furthermore, in an adoptive transfer model, MNLs harvested from tolerant hosts significantly inhibited the capacity of naive MNLs to reject same donor, but not third-party, skin allografts. Moreover, when we transplanted skin allografts from stable tolerant chimeras onto syngeneic immune-incompetent mice, graft-infiltrating T cells migrated from the graft site, expanded in the new host, and protected allografts from acute rejection by naive syngeneic MNLs. In this model, both deletional and immunoregulatory mechanisms are active during the induction and/or maintenance of allograft tolerance through creation of MC using a potentially clinically applicable regimen.

Regulation of T cell dependent immune responses by TIM family members.

The T cell immunoglobulin mucin (TIM) proteins are type I membrane glycoproteins expressed on T cells and containing common structural motifs. While our understanding on the distribution and functions of TIM family members is still incomplete, data from several recent reports indicate that these proteins, together with T cell receptor and costimulatory signals, regulate the expansion and effector functions of T helper cells. In the current review, we provide evidences indicating that TIM-3 is capable of modulating the function of CD4+CD25+ regulatory T cells and inhibiting aggressive Th1 mediated auto- and allo-immune responses. Similarly, additional data suggest that TIM-2 molecules function by negatively regulating Th2 immune responses. In contrast, TIM-1 appears to be an activation molecule for all T cells, although the mechanisms through which TIM-1 activates T cells remain to be elicited.

The impact of hepatic portoenterostomy on liver transplantation for the treatment of biliary atresia: Early failure adversely affects outcome

Alexopoulos SP, Merrill M, Kin C, Matsuoka L, Dorey F, Concepcion W, Esquivel C, Bonham A. The impact of hepatic portoenterostomy on liver transplantation for the treatment of biliary atresia: Early failure adversely affects outcome.

Outcomes after liver transplantation in patients achieving a model for end-stage liver disease score of 40 or higher.

Background Patients with Model for End-Stage Liver Disease (MELD) scores of 40 or higher are at high risk for liver transplantation. In some regions, the organ donor shortage has resulted in a substantial increase in the number of patients who underwent transplantation with MELD scores of 40 or higher. The objective of this study was to characterize the outcomes of liver transplantation in these patients. Methods A single-center retrospective study evaluating the outcome of liver transplantation in 38 consecutive patients achieving a MELD score of 40 or higher from January 1, 2006, to November 30, 2010, was conducted. Patient and graft survivals and independent risk factors for postoperative death or graft loss were determined. Results Kaplan-Meier–based 1-, 2-, and 3-year patient survival rates were 89%, 82%, and 77% with 1-, 2-, and 3-year graft survival rates of 84%, 75%, and 70.3%, respectively. One of three recipients was on a vasopressor before transplantation, and 13% were mechanically ventilated. Renal replacement therapy was used before operation in 90% of the recipients. Postoperative length of stay averaged 38 days. There was a 42% incidence of postoperative bacteremia and an 18% incidence of bile duct stricture within 6 months. Univariate analysis identified admission-to-transplantation time and recipient diabetes as risk factors for graft failure and patient death. Multivariate analysis confirmed recipient diabetes as a risk factor for patient survival and admission-to-transplantation time of more than 15 days as a risk factor for graft survival. Conclusions Acceptable outcomes are achievable after liver transplantation in patients with MELD scores of 40 or higher but come at high pretransplantation and posttransplantation resource utilization.

National Outcomes of Liver Transplantation for Model for End-Stage Liver Disease Score ≥40: The Impact of Share 35

In certain regions of the United States in which organ donor shortages are persistent and competition is high, recipients wait longer and are critically ill with Model for End‐Stage Liver Disease (MELD) scores ≥40 when they undergo liver transplantation. Recent implementation of Share 35 has increased the percentage of recipients transplanted at these higher MELD scores. The purpose of our study was to examine national data of liver transplant recipients with MELD scores ≥40 and to identify risk factors that affect graft and recipient survival. During the 12‐year study period, 5002 adult recipients underwent deceased donor whole‐liver transplantation. The 1‐, 3‐, 5‐ and 10‐year graft survival rates were 77%, 69%, 64% and 50%, respectively. The 1‐, 3‐, 5‐ and 10‐year patient survival rates were 80%, 72%, 67% and 53%, respectively. Multivariable analysis identified previous transplant, ventilator dependence, diabetes, hepatitis C virus, age >60 years and prolonged hospitalization prior to transplant as recipient factors increasing the risk of graft failure and death. Donor age >30 years was associated with an incrementally increased risk of graft failure and death. Recipients after implementation of Share 35 had shorter waiting times and higher graft and patient survival compared with pre–Share 35 recipients, demonstrating that some risk factors can be mitigated by policy changes that increase organ accessibility.

Pediatric kidney recipients with small capacity, defunctionalized urinary bladders receiving adult-sized kidney without prior bladder augmentation.

Background. Children with small capacity, defunctionalized urinary bladders present unique operative challenges. Thus, traditional practice has included pretransplant bladder augmentation, but this has several adverse consequences. Methods. A single-institutional, retrospective review from January 1, 2004 to December 31, 2008 was conducted. Twelve pediatric patients, whom had not undergone pretransplant bladder augmentation, did not have neurogenic bladders or require preoperative catheterization, and a small capacity defunctionalized bladders were included. All were managed by the same surgeon with a previously described ureteral implantation, and a 7F ureteral stent attached to a large diameter suprapubic catheter was removed in a joint manner without cystoscopy at 2 weeks. Data were collected on patient and graft survival, rejection episodes, urinary tract infection (UTI) requiring antibiotics, grade of vesicoureteral reflux, and posttransplant bladder capacity. Results. One-year patient and graft survival rates were 100%. One patient experienced a clinical rejection episode, which was successfully treated. Five patients (41.7%) had a UTI requiring abx treatment within the first postoperative year, but at 1 year, all patients had sterile urinary tracts. After removal of suprapubic catheters and ureteral stents, all patients were able to void spontaneously. Seven patients had no posttransplant ureteral reflux, three had grade 1 reflux, and two had grade 3 reflux (both successfully treated). The average age estimated pretransplant bladder and 1 year posttransplant bladder capacity was 14.5% and 84% of expected, respectively. Conclusions. In pediatric end-stage renal disease patients with a small capacity defunctionalized bladder, it is reasonable to proceed with kidney transplantation without pretransplant bladder augmentation, thus avoiding an unnecessary surgery.

Regulation of T-Cell Immunity by T-Cell Immunoglobulin and Mucin Domain Proteins

The ability of T helper (TH) precursor cells to differentiate into T effector populations confers the adaptive immune system with a means to protect the host from microbes and react to “foreign” antigenic tissues. T-cell immunoglobulin and mucin domain (TIM) proteins have recently been shown to be novel and critical regulators of T cell subset-driven dependent immune responsiveness. A dichotomy is emerging as to how Tim-3– and Tim-2– related signals respectively impact TH1 and TH2 responses. By comparison, the influence of the Tim-1 pathway seems to be broader and is probably not restricted to a specific type of T helper response. Beyond the mere control of the TH1/TH2 balance, Tim proteins are likely to target other regulatory components of the T cell response. Likewise, it is tempting to speculate that Tim proteins might also modulate the function of other T helper cell subsets such as TH3, TR1 and TH17 cells, among others.

Effects of recipient size and allograft type on pediatric liver transplantation for biliary atresia

The majority of pediatric patients with end‐stage liver disease receive a transplant with a whole liver (WL) allograft. However, smaller recipients with biliary atresia (BA) may have improved outcomes with deceased donor partial liver (DDPL) or living donor allografts. This study compares the national outcomes for liver transplantation in BA, with attention to the interaction between liver allograft type and recipient size. From January 2, 2002 to December 30, 2014, 2123 pediatric patients underwent a primary liver transplant for BA. The majority of transplants (53%) were performed with a WL allograft. Utilization of a WL allograft increased from 42% of recipients weighing ≤ 7 kg to 74% of recipients weighing > 14 kg. The 1‐, 5‐, and 10‐year graft survival in recipients weighing ≤7 kg was significantly superior for living donor liver transplantation (LDLT) (91%, 88%, 84%) and DDPL allografts (90%, 84%, 77%) compared with WL allografts (79%, 75%, 74%; P = 0.005). The 1‐, 5‐, and 10‐year graft survival in recipients weighing >14 kg trended toward being inferior in recipients of DDPL allografts (85%, 85%, 71%) compared with WL allografts (96%, 91%, 86%; P = 0.06). Furthermore, the incidence of vascular thrombosis was highest in WL (13%) compared with LDLT (6%) and DDPL (5%) recipients ≤ 7 kg (P = 0.002). Liver retransplantation was also highest in WL (16%) compared with LDLT (9%) and DDPL (9%) recipients ≤ 7 kg (P = 0.02). In conclusion, strong consideration should be given to the use of technical variant allografts in small recipients with BA requiring liver transplantation. Liver Transplantation 23 221–233 2017 AASLD

Massive pancreatic pseudocyst with portal vein fistula: case report and proposed treatment algorithm.

Pancreatic pseudocyst is a relatively common occurrence resulting from acute or chronic pancreatitis. However, a rare subset of these patients present with a pseudocyst fistulizing into the portal vein. We present the case of a 58 year-old woman with a rapidly expanding pancreatic pseudocyst with portal venous fistulization causing portal vein thrombosis, in addition to biliary and duodenal obstruction. The patient underwent surgical decompression with a cyst-gastrostomy and was well until one week post-operatively when she experienced massive gastrointestinal hemorrhage leading to her death. A review of the literature is presented and a treatment algorithm to manage patients with pancreatic pseudocyst to portal vein fistula is proposed.