A Novel Approach Inducing Transplant Tolerance By Activated Invariant Natural Killer T Cells With Co-Stimulatory Blockade.
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Background: Invariant natural killer T (iNKT) cells are one of the innate lymphocytes that regulate immunity, although it is still elusive how iNKT cells should be manipulated for transplant tolerance. We previously reported that the liposomal formulation of α-galactosylceramide (Lipo-aGC) could enhance an immune-regulative aspect of iNKT cells compared to the conventional aGC. Here we describe a novel approach to induce mixed chimerism (MC) by activating iNKT cells with Lipo-aGC under CD40-CD40L blockade (MR1). Methods and Results: 3Gy irradiated BALB/c mice were transplanted B6 bone marrow cells (BMCs) with/without Lipo-aGC and/or several dosage of MR1. Only combination therapy of Lipo-aGC plus suboptimal-MR1 could establish robust MC (table). Mice established MC completely accepted subsequent cardiac allografts in a donor-specific manner (figure). High amounts of Th2-cytokines were detected right after iNKT-cell activation, while subsequent IFN-γ production by NK cells was effectively inhibited by MR1. Expansion of regulatory T cells (Tregs) was observed in MC mice, and Treg-depletion on 1 day before transplantation resulted in a MC brake. Further, iNKT-cell knockout mice failed both MC establishment and Tregs expansion (table). Conclusion: These results collectively suggest that our new protocol makes it possible to induce donor-specific tolerance by enhancement of the innate regulatory mechanism in place of the conventional immunosuppression.Table: No Caption available.Figure: No Caption available.Keywords:
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Post-transplant immunosuppression almost always includes a combination of drugs and approaches based on a patient's individual situation, organ transplanted, and current developments in the field. Depending on these factors, approaches could include Induction immunosuppression, Maintenance immunosuppression, or Anti-rejection immunosuppression.
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For children with liver transplants (LT), achieving an "ideal outcome" is a balancing act: too little immunosuppression begets graft injury; too much begets systemic complications. We aimed to delineate the parental perspective on this tightrope.Parents of children with LT completed an internet-based survey about their child's immunosuppression.Children of respondents (n = 82) were a median 4 years from primary LT (range 0-22); 73% were on immunosuppression monotherapy. Parents' top concerns were related to immunosuppression complications; 46% were more concerned about immunosuppression complications than rejection; only 17% were more concerned about rejection than immunosuppression complications. Among parents of children on immunosuppression monotherapy, 29% still worried more about immunosuppression complications than rejection, 48% expressed equal concern for both. Time since LT (0-4 vs. >4 years) was not associated with concern level for rejection or immunosuppression complications. Caregivers were significantly more certain that their child's immunosuppression regimen was correct to prevent rejection than to mitigate complications (p < .005).Caregivers of children with LTs reported higher levels of concern and uncertainty about immunosuppression complications than rejection risk. Understanding parent and patient perspectives on IS, and incorporating them into immunosuppression counseling and decision-making, is critical to achieving truly "ideal" long-term outcomes.
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Liver disease
Orthotopic liver transplantation
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Abstract With the continued improvements in outcome following liver transplantation, the drawbacks associated with conventional immunosuppression regimens become increasingly apparent. Although up to 70% of patients develop a histological infiltrate of the graft (acute rejection), many of these will resolve spontaneously, and chronic rejection is rare. If a robust form of allograft acceptance or tolerance can be established, then immunosuppression can be withdrawn along with all the accompanying risks. The liver is already known to be associated with downregulated immune responses; the mechanism for this is unclear, but may be related to a number of mechanisms known to be involved in peripheral tolerance. There are many strategies being studied for achieving allograft tolerance, including the use of modern immunosuppressants, antibodies that target key molecules in the immune response, and recruitment of leukocytes to allografts. In the interim, it is necessary to look for safe protocols that allow trials of tolerance strategies without putting patients at increased risk.
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This chapter explains the evolution of haemodialysis (HD), peritoneal dialysis (PD), and transplantation. HD, as a routine treatment for renal failure, was initiated in the 1960s, followed by continuous ambulatory PD in the late 1970s. The recognition of the need for immunosuppression in transplantation in the 1960s enabled it to become the preferred treatment for many patients. Kidney transplantation as a therapeutic and practical option for renal replacement therapy was first reported in published literature at the turn of the twentieth century. The first known attempts at renal transplantation on humans were made without immunosuppression between 1906 and 1923 using pig, sheep, goat, and subhuman primate donors. These first efforts were conducted in France and Germany but others followed. The recognition of the need for immunosuppression in transplantation in the 1960s enabled it to become the preferred treatment for many patients.
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Purpose of review Conquering allograft rejection remains an elusive goal in spite of recent breakthroughs in the field of immunosuppression. Much of the problem lies in the toxicity and side-effects of long-term use of systemic immunosuppressant drugs, which are sometimes ineffective in controlling rejection, but also hinder establishment of transplant tolerance. In this review, we discuss novel technologies that use grafts engineered with immunomodulatory molecules as a means of inducing tolerance. Recent findings Several recent studies have demonstrated the feasibility of engineering cells, tissues, or solid organ grafts with immunoregulatory biologics to achieve long termgraft survival without the use of chronic immunosuppression. This approach was shown to primarily change the ratio of T effector versus CD4+CD25+FoxP3+ T regulatory cells within the graft microenvironment in favor of attaining localized tolerance induction and maintenance. Summary Localized immunomodulation using biologic-engineered allografts represent a new paradigm for achieving long-term graft survival in the absence of chronic use of immunosuppression. The manipulation of the graft, rather than the recipient, not only ensures short- and long-term safety by minimizing the adverse effects of immunosuppression, but also allows retention of immune competency critical for the ability of the recipient to fight infections and cancer.
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Life-long immunosuppression (IS) has always been considered the traditional approach in the management of transplant recipients to protect the hepatic graft from rejection. The liver is a tolerogenic organ with impressive immune regulatory mechanisms that maintain local and systemic immune tolerance to antigens, as well the capability to trigger effective immune responses against pathogens. The King's College team identified independent factors that were associated with sustained IS withdrawal: non-autoimmune liver disease; fewer donor—recipient human leucocyte antigen mismatches; and no previous acute rejection episode. From the reported data it is clear that it is possible safely to reduce and even discontinue IS therapy in up to 40% of selected liver allograft recipients. The identification of tolerance biomarkers is of central importance, in order to be able to develop a protocol that can be applied to all suitable patients.
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Abstract A prospective identification of the estimated 20–50% of pediatric LTX recipients developing operational tolerance would be of great clinical advantage. So far markers of immune tolerance – T‐cell subpopulations or gene expression profiles – have been investigated only retrospectively in successfully weaned patients. Fifty children aged 8–265 months (median 89) were investigated 1–180 months (median 44) after LTX under ongoing immunosuppression. T‐cell subpopulations were measured during regular post‐transplant visits using FACS (Vδ1‐ vs. Vδ2‐γδ‐T cells and Tregs). A Vδ1/Vδ2‐γδ‐T‐cell ratio ≥1.42 previously reported in operational tolerance was found in 12 of 50 (24%) patients. In analogy, a Treg count ≥44 per μL was found in 35 of 50 (70%) patients and a Treg proportion ≥2.23% of CD 3 + ‐T cells in 39 of 50 (78%) patients. Only 9 of 50 patients (18%) fulfilled both criteria. The parameters Vδ1/Vδ2‐γδ‐T‐cell ratio and Tregs were not significantly correlated to each other or with donor type or immunosuppression. Vδ1/Vδ2‐γδ‐T‐cell ratio was more stable in serial examinations compared with Treg analyses. The observed proportion of 18% pediatric LTX patients with potential operational tolerance is in accordance with previous reports. However, clinical experience shows that rejections may happen even after long‐time weaning of immunosuppression. This suggests that operational tolerance is a dynamic process, with uncertain prediction by Vδ1/Vδ2‐γδ‐T‐cell ratio and/or Tregs under immunosuppression.
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