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Pediatric kidney transplant recipients generally have good outcomes post-transplantation. However, the younger age and longer life span after transplantation in the pediatric population make understanding the multifactorial nature of long-term graft survival critical. This investigation analyzes factors associated with 10-year survival to identify areas for improvement in patient care. Kaplan-Meier with log-rank test and univariable and multivariable logistic regression methods were used to retrospectively analyze 7785 kidney transplant recipients under the age of 18 years from January 1, 1998, until March 9, 2008, using United Network for Organ Sharing (UNOS) data. Our end-point was death-censored 10-year graft survival after excluding recipients whose grafts failed within one year of transplant. Recipients aged 5-18 years had lower 10-year graft survival, which worsened as age increased: 5-9 years (OR: 0.66; CI: 0.52-0.83), 10-14 years (OR: 0.43; CI: 0.33-0.55), and 15-18 years (OR: 0.34; CI: 0.26-0.44). Recipient African American ethnicity (OR: 0.67; CI: 0.58-0.78) and Hispanic donor ethnicity (OR: 0.82; CI: 0.72-0.94) had worse outcomes than other donor and recipient ethnicities, as did patients on dialysis at the time of transplant (OR: 0.82; CI: 0.73-0.91). Recipient private insurance status (OR: 1.35; CI: 1.22-1.50) was protective for 10-year graft survival. By establishing the role of age, race, and insurance status on long-term graft survival, we hope to guide clinicians in identifying patients at high risk for graft failure. This study highlights the need for increased allocation of resources and medical care to reduce the disparity in outcomes for certain patient populations., (© 2021 Wiley Periodicals LLC.)

The Milan criteria (MC) have historically determined eligibility for transplantation for hepatocellular carcinoma (HCC). The United Network for Organ Sharing (UNOS) Region 4 expanded the criteria for transplantation in HCC to include a single tumor ≤6 cm or up to 3 tumors with the largest diameter ≤5 cm and total additive diameter ≤9 cm (R4C). The aim of this study was to report the 10-year outcomes of this expanded criteria compared to MC. Transplants performed for HCC in Region 4 between October 2007 and December 2016 were reviewed using the UNOS database. Recipients were categorized based on imaging findings at initial evaluation. A total of 2068 patients were included in the study. There was no significant difference in 10-year patient survival between the groups (53% MC vs 48% R4C, P = .23). There was also no significant difference in recurrence-free survival (54% MC vs 47% R4C, P = .15) or allograft survival (53% MC vs 48% R4C, P = .16). Finally, there was no significant difference in outcomes between the MC and R4C groups when stratifying patients by locoregional therapy. This study demonstrates promising data that the criteria for liver transplantation in HCC can be safely expanded to the R4C without compromising outcomes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Experience suggests transplanting whole liver allografts (WL) from donors weighing <6 kg portends a worse prognosis. Patient and allograft survivals of infants who underwent transplantation with livers from donors ≥6 kg, <6 kg, or technical variant allografts from deceased donors (TV) and those from living donors (LD) were compared., Methods: The United Network of Organ Sharing database was queried for infant orthotopic liver transplantation (≤2 y). Of 5976 orthotopic liver transplantations, 860 patients received TV from deceased donors, 534 received LD split allografts, 509 patients had WL from donors weighing <6 kg, and 4073 remaining patients had WL from donors weighing ≥6 kg. Kaplan-Meier method and log-rank tests were employed., Results: Patients who received WL from donors weighing <6 kg had survival mean of 13.9 y ± 177 d. Overall patient survivals were 76.7%, 71.4%, 68.4%, and 65.9% at 1, 3, 5, and 10 y. This is significantly worse compared with all other groups, both in patient and allograft survival (P ≤ 0.001). In patients whose donors ≥6 kg, overall patient survivals were 82.1%, 78.7%, 77.3%, and 75.4% at 1, 3, 5, and 10 y. Infants who received TV had patient survival of 87.8%, 84.7%, 82.7%, and 80.6% at 1, 3, 5, and 10 y. Infants who received LD allografts had patient survival of 92.4%, 90.7%, 89.6%, and 88.5% at 1, 3, 5, and 10 y., Conclusions: Smaller weight of the donor influences the infant patient outcome. Patients with allografts from donors weighing <6 kg have a worse prognosis compared with those who received TV and LD allografts and those whose donors weigh ≥6 kg. Patients who receive LD allografts had the best survival., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Two strategies to increase the donor allograft pool for pediatric orthotopic liver transplantation (OLT) are deceased donor segmental liver transplantation (DDSLT) and living donor liver transplantation (LDLT). The purpose of this study is to evaluate outcomes after use of these alternative allograft types. Data on all OLT recipients between February 2002 and December 2004 less than 12 years of age were obtained from the United Network for Organ Sharing database. The impact of allograft type on posttransplant survivals was assessed. The number of recipients was 1260. Of these, 52% underwent whole liver transplantation (WLT), 33% underwent DDSLT, and 15% underwent LDLT. There was no difference in retransplantation rates. Immediate posttransplant survivals differed, with WLT patients having improved 30-day patient survivals compared to DDSLT and LDLT patients (P = 0.004). Although unadjusted 1-year patient survivals were better for WLT versus DDSLT (P = 0.01), after risk adjustment, 1-year patient survivals for WLT (94%), DDSLT (91%), and LDLT (93%) were similar (P values > 0.05). Unadjusted allograft survivals were better for WLT and LDLT in comparison with DDSLT (P = 0.009 and 0.018, respectively); however, after adjustment, these differences became nonsignificant (all P values > 0.05). For patients < or = 2 years of age (n = 833), the adjusted 1-year patient and allograft survivals were also similar (all P values > 0.05). In conclusion, in the current era of pediatric liver transplantation, WLT recipients have better immediate postoperative survivals. By 1 year, adjusted patient and allograft survivals are similar, regardless of the allograft type.

Split liver transplantation (SLT) benefits society by increasing the total number of transplants that can be performed, but it is yet unknown if a decreased post-transplant survival (in comparison to whole liver transplantation) would make participation in SLT less appealing to adult liver transplant candidates. A 20-item questionnaire was administered to 50 adult candidates to assess attitudes toward SLT and organ sharing. The overall attitudes of 60% of participants were classified as utilitarian (maximizing benefit to greatest number of candidates), while 26% were classified as self-preserving (maximizing individual benefit) and 14% were undecided. Ninety percent of participants would be willing to share even if expected survival was less than that of whole liver transplantation, and 69% felt that pediatric candidates should have priority over adult candidates. In conclusion, attitudes toward graft sharing and the possibility of compromised survival benefit are not barriers to SLT for most adult liver transplant candidates.

Recent advances in clinical protocols have improved the outcomes of pancreatic islet transplantation (PIT), yet PIT recipients typically require pancreatic islet grafts derived from multiple donors to achieve insulin independence. This along with experimental models of syngeneic PIT, showing that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation, strongly suggest the involvement of nonalloantigen-specific, inflammatory events in partial destruction of the graft following PIT. Interleukin-1beta appears to be among the most important inflammatory mediators, causing pancreatic islet dysfunction and apoptosis through the up-regulation of inducible nitric oxide (NO) synthase and cyclooxygenase-2. Kupffer cells secrete many molecules, including cytokines, NO, and free radicals, which are known to be directly toxic to the pancreatic islets, and depletion or inhibition of Kupffer cells improves outcomes following experimental PIT. Immediately after transplantation, the pancreatic islets are perfused only by portal vein blood until the process of angiogenesis restores arterial blood flow some 7-10 days later. This delayed vascularization may have implications for the expression of leukocyte adhesion molecules, the effects of free radicals, and the role of ischemia-reperfusion injury. Finally, in the immediate post-transplant period, hepatocytes may contribute to pancreatic islet injury through the production of NO. This paper reviews literature regarding the inflammatory events that follow PIT as well as the pathogenesis of diabetes and the pathophysiology of hepatic ischemia-reperfusion and their relation to the survival and function of intrahepatic pancreatic islet grafts.

Background: Fas ligand (FasL) induces apoptosis of cells bearing its receptor Fas, and has been shown to be important in T-cell development and regulation and in immune privilege. We hypothesized that FasL expression by renal allografts might provide protection from rejection., Methods: The murine FasL cDNA was cloned into a replication-defective adenovirus (AdV-FasL). Protein expression was confirmed by immunostaining of AdV-FasL-transduced HeLa cells. Allogeneic kidney transplants were performed between WF (RT1u) donors and Lewis (RT1) recipients. Donor kidneys were perfused in situ with saline alone (control), or 9 x 10(9) plaque-forming units of AdV-FasL. One native kidney was removed at the time of transplant and the other at 6 or 7 days. Uremic death was the endpoint, and deaths within 7 days of transplant were excluded. Transduced allografts were stained for FasL expression using a monoclonal antibody and tested for FasL mRNA production by reverse transcriptase-polymerase chain reaction and Northern blotting., Results: Immunostaining of AdV-FasL-transduced allografts demonstrated efficient gene transfer lasting approximately 2 weeks, and FasL mRNA production in the AdV-FasL-transduced allografts was confirmed by Northern blotting and reverse transcriptase-polymerase chain reaction. Mean survival of animals with AdV-FasL-transduced renal allografts was 27.8 days vs. 11.6 days in control animals (P < 0.05)., Conclusions: (1) Adenoviral vectors can successfully transduce rat kidneys with the FasL cDNA. (2) FasL gene transfer prolongs rat renal allograft survival.

Background: The shortage of cadaveric donor livers is the rate-limiting step in clinical liver transplantation. Split liver transplantation provides a means to expand the cadaveric donor pool. However, this concept has not reached its full potential because of inferior patient and graft survival and high complication rates when traditional ex vivo split techniques are used. Therefore we sought to evaluate the safety, applicability, and effectiveness of a new technique for split liver transplantation., Methods: This study consists of 15 in situ split liver procurements, which resulted in 28 liver transplants. In situ splitting of selected livers from hemodynamically stable cadaveric donors was performed at the donor hospital without any additional work-up or equipment being needed. In situ liver splitting is accomplished in a manner identical to the living-donor procurement. This technique for liver splitting results in a left lateral segment graft (segments 2 and 3) and a right trisegmental graft (segments 1 and 4-8). This procedure required the use of the donor hospital operating room for an additional 1.5-2.5 hr and did not interfere with the procurement of 30 kidneys, 12 hearts, 7 lungs, and 9 pancreata from these same donors., Results: The 6-month and 1-year actuarial patient survival rates were 92% and 92%, respectively, while the 6-month and 1-year actuarial graft survival rates were 86% and 86%, respectively. The 6-month and 1-year actuarial patient survival rate of patients who received a left lateral segment graft was 100% and 100%, respectively, while those who received a right trisegmental graft had 6-month and 1-year rates of 86% and 86%, respectively. The actuarial death-censored graft survival rates at 6 months and 1 year were 80% and 80%, respectively, for the left lateral segment grafts, and 93% and 93%, respectively, for the right trisegmental grafts. Alograft and patient survival was independent of United Network for Organ Sharing status at the time of liver transplantation. No patient developed a biliary stricture, required re-exploration for intra-abdominal hemorrhage, or suffered from portal vein, hepatic vein, or hepatic artery thrombosis, Conclusions: In situ split liver transplantation can be accomplished without complications and provides results that are superior to those obtained previously with ex vivo methods. It abolishes ex vivo benching and prolonged ischemia times and provides two optimal grafts with hemostasis accomplished. This technique decreases pediatric waiting time and allows adult recipients to receive right-sided grafts safely. In situ splitting is the method of choice for expanding the cadaveric liver donor pool.

Induction of tolerance to concordant rat islet xenografts (150 Wistar-Furth [WF] islets) in streptozocin-induced (STZ) diabetic mice (C57BL/6) was determined at three different sites for islet implantation (thymus, kidney capsule, and liver). Islets transplanted into the thymus or kidney capsule were either fresh or cultured at 24 degrees C for 7 days, and the mice received a single injection of either anti-mouse lymphocyte serum (MALS) alone or anti-rat lymphocyte serum (RALS) and MALS. Islets transplanted into the liver via the portal vein were cultured at 24 degrees C for 7 days, and the mice received a single injection of MALS and RALS. To document the induction of tolerance, recipients with islet xenografts surviving > 100 days were made diabetic again by STZ (thymus and liver) or nephrectomy (kidney capsule) and received a second transplant of 150 fresh WF islets in the kidney capsule. Kidney capsule placement of fresh or cultured islets with MALS alone or MALS and RALS did not induce tolerance in a significant number of recipients. The intrathymic transplantation of fresh or cultured islets with MALS alone resulted in prolonged WF islet xenograft survival (mean survival time of 39.7 +/- 7.9 days) but did not result in tolerance, whereas the administration of MALS and RALS with the intrathymic placement of fresh or cultured islets induced tolerance in approximately 50% of the mice. Intrahepatic transplantation of cultured islets with MALS and RALS resulted in tolerance to donor islets in 90% of the recipients. Donor specificity was evaluated by a third major histocompatibility complex-disparate fresh Lewis islet xenograft.(ABSTRACT TRUNCATED AT 250 WORDS)

Allograft rejection results from the specific recognition by host CD8+ T cells of allogeneic major histocompatibility complex (MHC) molecules on the tissue graft. The specificity of this cellular response is determined by the molecular interaction of the T-cell receptor (TCR) on host T cells with the MHC molecule and its bound ligand on the grafted tissue. To better understand the precise manner by which the TCR interacts with the MHC-peptide complex and how to therapeutically intervene, we have studied the allogeneic response to the mouse class I MHC molecule Ld. In this report, the therapeutic potential of a synthetic peptide derived from the TCR V beta 8 variable region that predominates in responses to Ld was tested. This V beta 8-derived peptide was found to dramatically and specifically block the in vivo and in vitro allogeneic response to Ld. Furthermore, this specific blocking is not dependent upon the presence of V beta 8+ effector cells nor does the V beta 8 peptide bind to the Ld ligand binding cleft. We propose that this peptide functions as an antagonist, competing with the native TCR for recognition of the Ld molecule.

The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring allograft function and survival. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic, intrasplenic, s.c., or i.v. injection of 25 x 10(6) syngeneic Buffalo (RT1b) or MHC fully mismatched Lewis (RT1l), ACI (RT1a), or UV-B irradiated Lewis (RT1l) splenocytes. The Buffalo recipients were given 1 cc of rabbit antirat antilymphocyte serum (ALS) i.p. at the time of the donor antigen injection, and 21 days later received a heterotopic Lewis or ACI heart transplant. Only intrathymic alloantigen injection induced a donor-specific tolerance which allowed the cardiac allograft to survive indefinitely (mean survival time [MST] > 176.8 days) in > 86% of the recipients without the need for further immunosuppression, whereas groups receiving antigen injections at other sites rejected cardiac allografts in control time (MST approximately 7.0 days). Histologic examination of long-term tolerated Lewis cardiac allografts revealed the presence of healthy cardiac myocytes without mononuclear infiltration. Buffalo rats with a long-term surviving Lewis cardiac allograft did not reject a second Lewis cardiac allograft (MST > 100.0 days), but rejected a heterotopic ACI cardiac allograft in normal time (MST approximately 7.0 days). By limiting dilution analysis (LDA), maturation of donor-specific CTLs (pCTL) from long-term recipient splenocytes was markedly diminished, whereas third party pCTL was not altered, and T helper-precursors were moderately decreased without alteration in the peripheral CD4+ and CD8+ phenotype frequencies. MLC responses of recipients with long-term surviving cardiac allografts to donor-specific and third party stimulation were not significantly different from naive controls. Microchimerism is unlikely because Lewis allograft survival was also prolonged (MST > 96.0 days) in rats receiving UV-B irradiated Lewis splenocytes which cannot proliferate. The absence of increased allograft survival after transfer of long-term recipient splenocytes into naive animals suggests that donor-specific suppressor cells are not present. Additionally, in vitro lymphocyte proliferative responses to mitogenic or allogeneic stimulation in MLC was not diminished by the addition of these long-term recipient splenocytes. This model emphasizes the importance of exposure of T cell precursors to foreign donor alloantigen in the thymic environment for the development of unresponsiveness to a donor-specific vascularized allograft.

Objective: This study determined the form of cellular donor MHC alloantigen necessary for the induction of intrathymic tolerance., Background: The authors have achieved indefinite donor-specific tolerance, to a fully MHC-disparate rat heterotopic cardiac allograft, after the pretransplant intrathymic injection of unfractionated donor splenocytes and a single injection of rabbit anti-rat lymphocyte serum (ALS), without subsequent immunosuppression., Methods: Male 4-12-week-old Buffalo (RT1b) rats underwent an intrathymic injection of either fractionated Lewis (RT1(1)) red blood cells (purified by Ficoll gradient) or T lymphocytes (purified by nylon wool column and plastic adherence), both of which express only MHC class I alloantigens, or B lymphocytes, macrophages, and dendritic cells (purified by plastic adherence) which express both MHC class I and class II alloantigens. At the completion of alloantigen injection the Buffalo recipient rats were given 1 ml of ALS intraperitoneally. Twenty-one days later a heterotopic Lewis heart was transplanted., Results: The intrathymic injection of the fractions of Lewis MHC class I and class II expressing B lymphocytes, macrophages, and dendritic cells induced a donor-specific tolerance that resulted in indefinite Lewis cardiac allograft survival (MST > 125 days) in all recipients without further immunosuppression, whereas groups receiving MHC class I expressing red blood cell or T lymphocyte injections plus ALS rejected Lewis cardiac allografts with a MST of 7.3 and 16.5 days, respectively, thus indicating that the MHC class II expressing cell is necessary for the induction of intrathymic tolerance. Buffalo recipients with a long-term surviving Lewis cardiac allograft, after Lewis MHC class II expressing cells were still able to reject a third-party heterotopic ACI (RT1a) cardiac allograft in normal time (MST = 7.0 days), but did not reject a second Lewis cardiac allograft (MST > 100 days). Additionally, the intrathymic injection of MHC class II expressing cells resulted in decreased interleukin-2 (IL-2) production and an 80% decrease in in vitro donor-specific cell mediated cytotoxicity, whereas the cytolytic response to a third party was unaltered., Conclusion: Donor MHC class II, and not class I, expressing cells are the cells in donor splenocytes, injected intrathymically, responsible for the development of donor-specific allograft tolerance.

The increasing success of clinical small bowel transplantation in recent years has been due largely to improved nonspecific immunosuppression of the recipient, which carries significant morbidity. The induction of donor-specific tolerance would eliminate the risk of long-term immunosuppression while ensuring graft function and survival. We have demonstrated that the intrathymic injection of donor splenocytes with the simultaneous intraperitoneal administration of rabbit anti-rat lymphocyte serum results in indefinite donor-specific cardiac allograft survival in > 85% of recipients. In this study, we further examined the effect of this tolerance induction protocol on the more immunogenic small bowel allograft. Male Buffalo (RT1b) rats were exposed to donor alloantigen by an intrathymic injection of 25 x 10(6) MHC mismatched unfractionated Lewis (RT1(1)) splenocytes. The Buffalo recipients were given 1 ml of rabbit anti-rat lymphocyte serum intra-peritoneally at the time of the donor antigen injection and 21 days later underwent a heterotopic 15-cm Lewis small bowel transplant. Pretransplant intrathymic Lewis alloantigen and anti-rat lymphocyte serum treatment prolonged Lewis small bowel survival by approximately 2.5 times (mean survival time = 18.0 vs 7.0 days for controls, P < 0.05). These small bowel allografts demonstrated pericryptic T cell infiltrates, areas of cryptic necrosis, and a dense submucosal lymphocytic infiltrate, all consistent with acute resection. In contrast to our studies achieving donor-specific cardiac allograft survival, this protocol did not result in indefinite intestinal allograft survival. No Buffalo recipients developed evidence of graft-versus-host disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The preferential usage of certain T cell receptor (TCR) V beta genes has been well established in several major histocompatibility complex (MHC)-restricted immune responses. However, V beta usage among allogeneic responses remains unclear. Because recent findings of ours and others indicate that V beta 8 predominates in certain Ld-restricted, peptide-specific responses, we examined the V beta 8 usage in allogeneic responses to Ld. To selectively recognize the Ld molecule, cells from BALB/c-H-2dm2 (dm2), the Ld-loss mutant mouse, were stimulated in vitro or in vivo with wild-type BALB/c cells. We report here that after the intraperitoneal administration of the anti-V beta 8 monoclonal antibody (mAb) F23.1, peripheral V beta 8 T cells were depleted from dm2 mice. This in vivo depletion abrogated the ability of dm2 splenocytes to mount a primary response to Ld molecules. This abrogation was specific, since the response of V beta 8-depleted dm2 cells to Kb/Db antigens was the same as that of control nondepleted dm2 cells. Furthermore, in vivo depletion of V beta 8 cells was found to cause a dramatic prolongation of Ld-disparate skin grafts (mean survival time [MST] 22.1 +/- 2.1 vs. 10.3 +/- 1.1 d for saline-treated controls, or 10.9 +/- 1.7 d for controls treated with mAb KJ23 to V beta 17). By contrast, V beta 8 depletion had no effect on recipients grafted with haplotype-mismatched skin or single Dk-locus-disparate skin. These findings demonstrate that V beta 8+ T cells predominate in allogeneic response to Ld but not other alloantigens. The effect of V beta 8 depletion was found to be even more dramatic on recipients grafted with Ld-disparate vascularized heart transplants (MST > 100 vs. 8.6 +/- 0.5 d for controls). In total, these findings establish the efficacy of using mAb to the V beta gene family to specifically and significantly enhance the survival of allografts. The implications of detecting V beta 8 usage in both alloreactive or MHC-restricted TCR responses to the same class I molecule are discussed.